Use of Intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment

Collection summary

Background

Like all dementias, Alzheimer’s Disease is an important global public health problem.

Immunoglobulins, traditionally used to prevent or treat infectious diseases have been recently used for other non-communicable conditions including rare neurological diseases.

We report on reviews of the evidence of use and effect of immunoglobulins for Alzheimer’s Disease and Mild Cognitive Impairment.

The existence and significance of Mild Cognitive Impairment are still debated

Results                                                                             

Health Problem and Current Use of the Technology (CUR)

Alzheimer’s Disease is an important public health problem, like all dementias. The existence and significance of Mild Cognitive Impairment are still debated

Description and technical characteristics of technology (TEC)

Immunoglobulins have been tradionatioally used for passive immunisation against  infectious diseases, although in the last decades their use has expanded to include blood disorders, rare neurological disorders and cancer. Safety of the technology (SAF)

Effectiveness of the technology (EFF)

Despite several placebo controlled trials having been carried out and completed and some being underway so far there is no evidence of either positive or negative impact  of IVIG on Alzheimer’s Disease or Mild Cognitive Impairment.

 Costs and economic evaluation (ECO)

In the absence of any discernible difference against placebo, no estimates of a trade-off between costs and benefits can be made at present.

Ethical aspects of the technology (ETH)

The only foreseeable ethical aspect which could be raised by the granting of a MA are the effects of industrial production on the limited supply of blood products used to treat other conditions such as clotting disorders.

Organisational aspects of the technology (ORG)

In the absence of any discernible difference against placebo, no estimates of organisational impact  can be made at present

Social aspects of the technology (SOC)

In the absence of any discernible difference against placebo the social aspects cannot be defined

Legal aspects of the technology (LEG)

In the absence of any discernible difference against placebo the legal aspects cannot be defined

Discussion

The data gathered and synthetized in this Core HTA show that at present there is little evidence of any effect (positive or negative) of IVIG on Alzheimer’s Disease  and Mild Cognitive Impairment. Although the evidence base is still small and several trials are still to be completed or reported, the persisting speculative nature of the pathogenesis of dementia and consequent mechanism of action of any biological product suggest that investment in research of causation might be a better priority.

This is the second of our three JA2 scheduled pilot projects. We have experienced several hitherto unforeseen difficulties during the development of the project.

The first  problem was related to the aftermath of choice of topic. There is little doubt that dementias are an important topic but we were also aware of the potential demands on plasma derivatives for the manufacture of IVIG. This would have a major influence in a delicately balanced market with many highly motivated patient organisations. Choice of an inert comparator, although dictated by the early phase of experimentation of AD IVIG, was also not a traditional choice in any HTA activity and much discussed. The choice has left unresolved disagreements.

The pre-Market Authorisation Application (MAA) nature of the intervention being assessed also meant that many trials were ongoing or unpublished, even if completed. This carried many implications which added to the difficulties. Data were either not available or were made available indirectly on registers such as clinicaltrials.gov after our manufacturer enquires drew a blank. Register “publication” took place in the autumn of 2014, long after completion of our primary searches in February 2014. Although data were quantitatively plentiful, they lacked detailed description of methods and a full study protocol which made its very inclusion and interpretation contentious. The difficulties came to a head with two distinct points of view regarding the inclusion of data after the main search had taken place. Some investigators were worried about risk of bias being introduced in the assessment, others thought the importance of reporting the largest trial ever conducted (yet inexplicably unpublished two years from completion) to be paramount.

To manage the problems, Coordination asked the Editorial Team for guidance. The Team, made up of all PIs, decided to allow inclusion of the register data. However, to minimize the risk of introducing bias by secondary searching (i.e. post primary search in February 2014) of only two domains, the Team recommended the conduct of an update search for all other domains to coincide with the date of the secondary search of registers. Although the secondary search did not identify any new additional evidence, it generated additional work, further delay and dissatisfaction with the composition of the Team as all members of the domains on which the discussion centered wanted a say.

Several positive points arise from this experience. First, it is clear that the management infrastructure and input were insufficient to deal with the complexity and novelty of the work. Second, few members of the team had experience in dealing with what were essentially unpublished data. Third, the topic proved to be a good testing ground for dealing with unexpected problems. The experience gained should be reflected in future procedures.

Closing Remarks

The Core Model is not intended to provide a cookbook solution to all problems but to suggest a way in which information can be assembled and structured, and to facilitate its local adaptation. The information is assembled around the nine domains, each with several result cards in which questions and possible answers are reported.

The reasons for having a standardised but flexible content and layout are rooted in the way HTA is conducted in the EU and in the philosophy of the first EUnetHTA Joint Actions production experiment.

HTA is a complex multidisciplinary activity addressing a very complex reality – that of healthcare. Uniformly standardised evidence-based methods of conducting assessments for each domain do not exist1[1]. There are sometimes variations across and within Member States in how things are done and which aspects of the evaluation are privileged. This is especially so for the “softer” domains such as the ethical and social domains.

This pilot represents a useful lesson for methodological development in EUnetHTA Joint Action 2.

Collection methodology

Objective

To produce a Core Health Technology Assessment (HTA) assessing the effects of use of intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment based on the EUnetHTA Core Model and working within the a mixed Collaborative Model organisational framework.

Methods

The work was based on the HTA Core Model on pharmaceuticals (HTA Core Model Application for Pharmaceuticals version 2.0), which was developed during the EUnetHTA Joint Actions 1 and 2.

The first phase was the selection of the technology to be assessed using the Core Model; this phase was carried out through a three-step process that is described in our MSP.

Then a check of Partners’ availability to assume responsibility for taking the lead in one of the nine evaluation domains was carried out. At the same time, the nine domain teams were built-up in accordance with partners’ preferences and some general guidelines (see the MSP).

Finally the specific work plan was shared, according with the general WP4 3-year work plan and objectives. This specific work plan included the phases scheduled in the “HTA Core Model Handbook” (Production of Core HTAs and structured HTA information).

An editorial team was set up for discussion and major decisions on basic principles and solutions related to the content of core HTA. The editorial team was chaired by Tom Jefferson (Agenas) and included  all  primary investigators of the domains.

To allow collaboration between partners a draft protocol for Core Model use was agreed by the researchers involved. The research questions for each of the eight domains of the Core Model were formulated and the corresponding relevant assessment elements (AEs) were selected. The legal domain was included in the assessment.

The research strategy was carried out by Agenas with input from the other partners.

Evidence from published and manufacturer sources was identified, retrieved, assessed, and included according to pre-specified criteria, and summarised to answer each AE. Domain assessments were done by a single agency and by different investigators from different agencies, in a mixed organisational model.

The final text has not been proof read or copyedited.

Introduction to collection

This brief document provides background information on the preparation and development of the Core HTA on use of Intravenous immunoglobulins for Alzheimer’s disease including Mild Cognitive Impairment. The core HTA document was produced during the course of the second EUnetHTA Joint Action (JA2) 2012-2015.

The idea behind EUnetHTA’s Core Model is to provide a framework for structuring relevant HTA information while at the same time facilitating local use and adaptation of the information or guiding its production.

The Model is based on nine dimensions or “domains” of evaluation:

1. Health Problem and Current Use of the Technology (CUR)
2. Description and technical characteristics of technology (TEC)
3. Safety (SAF)
4. Effectiveness (EFF)
5. Costs and economic evaluation (ECO)
6. Ethical analysis (ETH)
7. Organisational aspects (ORG)
8. Social aspects (SOC)
9. Legal aspects

The Core Model application on pharmaceuticals was tested by assessing the effects of use of intravenous immunoglobuliuns for Alzheimer’s disease including Mild Cognitive Impairment. We produced a Core HTA structured as the eight documents that follow, one for each domain. The Legal Domain was not included in the used version of the Pharmaceuticals application but we produce it and add as appendix.

This Core HTA was prepared using a mixed Collaborative Model (COLMOD). Two different model of collaboration were tested during the first EUnetHTA Joint Action: in one, groups of researchers from different HTA Institutions produced the domain texts; in the other model, one of the national or sub-national HTA participating agencies took responsibility for the production of each domain. For the Core HTA on use of intravenous immunoglobuliuns for Alzheimer’s disease including Mild Cognitive Impairment, some domains were produced using the first collaborative model, while other domains were produced using the secondcollaborative model, with a lead agency. The experimental organisational model added an element of challenge but probably helped to forge strong links across participants.

In the next few months an intensive validation programme including interviews and consultations will elicit comments and feedback both from those who contributed to the Core HTA and from those who read a Core HTA for the first time. As scheduled in the 3-year work plan, the Core HTA will be sent to the Stakeholder Advisory Group (SAG) for feedback before the final Public Consultation, during which the Core HTA will be made publicly available.

The results from the Validation and SAG consultation should provide useful information to improve the product.

Scope

Technology	Immunoglobulins (IGG) Description Naturally occurring proteins produced by the body’s immune system to combat foreign antigens
Intended use of the technology	Treatment Treatment of Alzheimer’s disease Target condition Alzheimer’s disease Target condition description Alzheimer's disease (AD) or Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. Target population Target population sex: Any. Target population age: elderly. Target population group: Patients who have the target condition. Target population description AD is diagnosed mostly in people over 65 years of age, although there is an early-onset form that can occur much earlier. According to Wikipedia in 2006, there were 26.6 million sufferers worldwide.
Comparison	placebo, not doing anything or Usual supportive care Description There is no MA for IGGs for AD yet and there is no other intervention licensed for use in AD so the comparison would have to be against placebo or best supportive care
Outcomes	Description of aims of technology (TECH) Regulatory status (CUR) Cognitive function (EFF) Harms (SAF) Cost effectiveness compared to alternatives (ECO) Potential impact on plasma derivative market (ORG/Medico-legal) Impact on family and carers (SOC) Appropriateness of use in relation to solidity of evidence(ETH)

Health Problem and Current Use of the Technology

Authors: Antonio Migliore, Tapani Keranen, Sinikka Sihvo

Summary

Target Condition

Dementia is an overall term for a decline in mental ability severe enough to reduce a person's ability to perform everyday activities. Alzheimer's disease is the most common type of dementia, which accounts for 60 to 80 percent of cases. Alzheimer's is a progressive disease, where dementia symptoms gradually worsen over time. According to DSM-IV criteria for Alzheimer’s disease, memory deficit must be objectively demonstrated plus at least one other cognitive deficit: aphasia (abnormal speech), executive function impairment (difficulty with planning, judgment, mental flexibility, abstraction, problem-solving, etc.), agnosia (impaired recognition of people or objects), or apraxia (impaired performance of learned motor skills). These cognitive deficits must result in impairment in performance of daily activities. The diagnosis is confirmed by post mortem evidence of neurofibrillary tangles and neuritic plaques in excess of those found in normal ageing of the brain (ICD-10). Those with Alzheimer's live an average of 3.6 to 6.6 years after the diagnosis, depending on age and other health conditions. In the newest Diagnostic and Statistical Manual of Mental Disorders (DSM-5) “dementia” is replaced by “major neurocognitive disorder”. Mild cognitive impairment (MCI) describes a transitional state between normal aging and pathological decline. Many terms and definitions have been used to describe mild forms of cognitive impairment. According to Petersen et al. mild cognitive impairment is classified as 1) MCI that primarily affects memory is known as “amnestic MCI”, aMCI, and 2) MCI that affects thinking skills other than memory is known as “nonamnestic MCI”. A person with MCI is at an increased risk of developing Alzheimer's disease and other dementias, however, many individuals revert to normal or do not progress. The conversion rate from MCI to Alzheimer's is low, about 7 % in community based samples and 15% in specialized care samples. Therefore, MCI diagnosis alone cannot be equaled with a pre-dementia stage. In order to allow treatments like medication, MCI diagnosis should be supplemented with predictors of a rapid cognitive decline, such as older age, vascular risk factors, neurological symptoms, apoE ɛ4 genotype, etc.). In the DSM-5 a term “mild neurocognitive disorder” is used instead of mild cognitive impairment. Intravenous immunoglobulins (IVIG) are expected to have potentially beneficial effects on the pathogenetic process of Alzheimer’s disease by stabilizing cognitive functioning in patients with mild-to-moderate Alzheimer’s disease. The neuroprotective mechanisms of IVIG are not well known. If MCI would be identified early this would allow earlier treatment to slow progression of AD or even prevent it. Early interventions are likely to be more effective than if the disease is already advantaged. Slowing the progression of AD with IVIG or other therapies could have major impact on the need for care and burden of the disease.

Target Population

Target populations for IVIG therapy are: i) Patients with Mild Cognitive Impairment; ii) Patients with mild-to-moderate Alzheimer’s disease, as defined by validated criteria and with MMSE score between 15 and 26; iii) Patients with moderate-to-severe Alzheimer’s disease, as defined by validated criteria and with MMSE score less than or equal to 14. The worldwide prevalence estimates are given usually for dementia than for Alzheimer’s disease since the possibilities to make correct diagnosis can vary. In addition, estimates vary between studies. The age-standardised prevalence of dementia among populations > 60 years is 5-7%. In 2010 it was estimated that there are over 35 million people worldwide living with dementia. These numbers are expected to double every 20 years to 65.7 million in 2030 and to 115.4 million in 2050. According to worldwide meta-analysis of studies between 1984-2008, the prevalence of Mild Cognitive Impairment was 24.6% but varied between 21.5-71.5%. For people > 65 years the MCI incidence varied between 21.5-71.3/1000 person years.

Current Management of the Condition

There are no established treatments for MCI. In contrast to MCI, there are several pharmacological possibilities for the treatment of AD. Currently available drug treatments for AD are considered symptomatic. It is recommended that patients with AD and mild to moderate dementia are initially treated with one of the cholinesterase inhibitors (ChEIs), i.e. donepezil, galantamine, or rivastigmine. These drugs have been shown as having efficacy on cognitive function, global outcome, and ADL functions. ChEIs can be used also in the severe form of AD either alone or in combination with the glutamate antagonist memantine. Memantine can also be used alone in patients with severe AD and in patients who have contraindications or who are intolerant to ChEIs.

Utilisation

IVIG are not used for Alzheimer’s disease including Mild Cognitive Impairment in any of the EUnetHTA partners answered the survey. However, while some partners explicitly excluded the use of IVIG for the mentioned indications, some others stated that, given the characteristics of the internal monitoring and reimbursement system, it’s impossible exclude the off-label use of IVIG.

Regulatory Status

IVIG are currently used as first line therapy for various condition. However, some new indications are emerging and extensions in the indications could be proposed. At time of writing, no manufacturers have submitted requests to EMA for the market approval of the IVIG for Alzheimer’s disease including Mild Cognitive Impairment.

Introduction

This domain aims to give a broad overview on Alzheimer’s disease (AD) including Mild Cognitive Impairment (MCI) in terms of definition, diagnosis, current management, burden, as well as utilization and regulatory status of the IVIG.

Methodology

Frame

The collection scope is used in this domain.

Technology	Immunoglobulins (IGG) Description Naturally occurring proteins produced by the body’s immune system to combat foreign antigens
Intended use of the technology	Treatment Treatment of Alzheimer’s disease Target condition Alzheimer’s disease Target condition description Alzheimer's disease (AD) or Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. Target population Target population sex: Any. Target population age: elderly. Target population group: Patients who have the target condition. Target population description AD is diagnosed mostly in people over 65 years of age, although there is an early-onset form that can occur much earlier. According to Wikipedia in 2006, there were 26.6 million sufferers worldwide.
Comparison	placebo, not doing anything or Usual supportive care Description There is no MA for IGGs for AD yet and there is no other intervention licensed for use in AD so the comparison would have to be against placebo or best supportive care
Outcomes	Description of aims of technology (TECH) Regulatory status (CUR) Cognitive function (EFF) Harms (SAF) Cost effectiveness compared to alternatives (ECO) Potential impact on plasma derivative market (ORG/Medico-legal) Impact on family and carers (SOC) Appropriateness of use in relation to solidity of evidence(ETH)

Assessment elements

	Topic	Issue	Relevant	Research questions or rationale for irrelevance
A0002	Target Condition	What is the disease or health condition in the scope of this assessment?	yes	What is the disease in the scope of this assessment?
A0003	Target Condition	What are the known risk factors for the disease or health condition?	yes	What are the known risk factors for the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI)?
A0004	Target Condition	What is the natural course of the disease or health condition?	yes	What is the natural course of the Alzheimer’s disease (AD) and the Mild Cognitive Impairment (MCI)?
A0005	Target Condition	What are the symptoms and burden of disease for the patient at different stages of the disease?	yes	What are the symptoms and burden of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) for the patient at different stages of the disease?
A0006	Target Condition	What are the consequences of the disease or the health condition for the society (i.e. the burden of the disease)?	yes	What are the consequences of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) for the society (i.e. the burden of the disease)?
A0009	Target Condition	What aspects of the consequences / burden of disease are targeted by the technology?	yes	What aspects of the consequences / burden of disease are targeted by the intravenous immunoglobulin (IVIG) therapy?
A0007	Target Population	What is the target population in this current assessment of the technology?	yes	What is the target population in this current assessment of intravenous immunoglobulin (IVIG) therapy?
A0023	Target Population	How many people belong to the target population?	yes	How many people belong to the target population?
A0017	Current Management of the Condition	What are the differences in the management for different stages of the disease or health condition?	yes	What are the differences in the management for the different stages of the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI)?
A0018	Current Management of the Condition	What are the other typical or common  alternatives to the current technology?	yes	What are the other typical or common alternatives to intravenous immunoglobulin (IVIG) therapy?
A0024	Current Management of the Condition	How is the disease or health condition currently diagnosed according to published guidelines and in practice?	yes	How are Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) currently diagnosed according to published guidelines and in practice?
A0025	Current Management of the Condition	How is the disease or health condition currently managed according to published guidelines and in practice?	yes	How are the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) currently managed according to published guidelines and in practice?
A0001	Utilisation	For which health conditions and for what purposes is the technology used?	yes	For which health conditions and for what purposes are intravenous immunoglobulins (IVIG) used?
A0011	Utilisation	How much is the technology utilised currently and in the future?	yes	How much are intravenous immunoglobulins (IVIG) utilised currently and in the future?
A0012	Utilisation	What kind of variations in use are there across countries/regions/settings?	yes	What kind of variations in the use of intravenous immunoglobulins (IVIG) are there across countries/regions/settings?
G0009	Utilisation	Who decides which people are eligible for the technology and on what basis?	yes	Who decides which people are eligible for intravenous immunoglobulin (IVIG) therapy and on what basis?
B0003	Utilisation	What is the phase of development and implementation of the technology and the comparator(s)?	yes	What is the phase of development and implementation of intravenous immunoglobulins (IVIG)?
F0001	Utilisation	Is the technology a new, innovative mode of care, an add-on to or modification of a standard mode of care or replacement of a standard mode of care?	yes	Is intravenous immunoglobulin (IVIG) therapy a new, innovative mode of care, an add-on to or modification of a standard mode of care or replacement of a standard mode of care?
A0020	Regulatory Status	What is the marketing authorisation status of the technology?	yes	What is the marketing authorisation status of intravenous immunoglobulins (IVIG)?
A0021	Regulatory Status	What is the reimbursement status of the technology across countries?	yes	What is the reimbursement status of intravenous immunoglobulins (IVIG) across countries?

Methodology description

Domain frame

The project scope is applied in this domain.

Information sources

The result cards CUR1, CUR2, CUR3, CUR4, CUR5, CUR6, CUR8, CUR9, CUR10, CUR11, CUR12, CUR14, and CUR18 have been produced using the results from the basic searches (done for the whole project) and additional, unsystematic literature searches performed by the authors {Appendix CUR-1}. Secondary studies were the main additional information sources considered. The result cards CUR7 and CUR13 have been produced using the findings reported in the document named “Use of Intravenous immunoglobulins for Mild Cognitive Impairment and Alzeheimer’s disease – Protocol” prepared by authors teams from SAF and EFF domains and presented in {Appendix SAF-7}. The result cards CUR15, CUR16, CUR17, CUR19, and CUR 20 have been produced using the results from the surveys carried out among the WP4 stakeholder advisory group (WP4 SAG) and EUnetHTA partners. The surveys are described in details in {Appendix CUR-3}.

Quality assessment tools or criteria

This domain presents descriptive information and rigorous quality assessment was believed not necessary by the domain’s authors. Quality assessment has not been performed for any of the considered citations.

Analysis and synthesis

Descriptive analysis was performed on different information sources. Results have been presented in narrative form. No numerical data analysis has been performed.

Result cards

Target Condition

Target Population

Current Management of the Condition

Utilisation

Regulatory Status

Discussion

According to the information available at the time of writing, IVIG are not used for Alzheimer’s disease including Mild Cognitive Impairment in any of the EUnetHTA partners who answered the survey. However, while some partners explicitly excluded the use of IVIG for the mentioned indications, some others stated that, given the characteristics of the internal monitoring and reimbursement system, it’s impossible to exclude the off-label use of IVIG {Appendix CUR-3}. No manufacturers have submitted requests to EMA for the market approval of the IVIG for Alzheimer’s disease including Mild Cognitive Impairment {Appendix CUR-3}.

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Appendices

Appendix CUR-1 (strategy of the additional, unsystematic literature searches performed by the authors of this domain).

Appendix SAF-7 (document named “Use of Intravenous immunoglobulins for Mild Cognitive Impairment and Alzeheimer’s disease – Protocol” prepared by the authors team from SAF domain).

Appendix CUR-3 (surveys carried out by the WP4 Leader among the stakeholder advisory group, SAG, and EUnetHTA partners).

Description and technical characteristics of technology

Authors: Jesús González-Enríquez, Nadine Berndt, Houria Mouas

Summary

Features of the technology

Intravenous immunoglobulins (IVIG), human normal immunoglobulin for intravascular administration (ATC code J06BA02), is a medicinal product derived from human plasma of at least thousands of healthy voluntary donors, prepared industrially, containing polyclonal antibodies to produce passive immunity and other protective effects. Human normal immunoglobulin is a highly purified protein extracted from human plasma. It contains immunoglobulin G (IgG), which is a type of antibody. IgG works by restoring abnormally low IgG levels to their normal range in the blood.

There are several IVIG producers and many market authorized presentations of the product. The resulting products are generally believed to be equally effective for treatment of the autoimmune and immunodeficiency disorders. Products presentations vary in concentration of human normal immunoglobulins in 1 ml of solution.

There has been a rapid expansion in the use of intravenous immunoglobulin (IVIG) for an ever growing number of conditions and often used more extensively than the authorized indications (“off-label use”). IVIG has had a major impact in neurology, haematology, immunology, rheumatology and dermatology. Intravenous immunoglobulin (IVIG) has been successfully used to treat a number of immune-mediated diseases of the central and peripheral nervous system. Although underlying mechanisms of action of IVIG have not been fully explained, it is known that IVIG can interfere with the immune system at several levels. IVIG is being used as a treatment in many different conditions, including primary and secondary antibody deficiency states, haematological diseases, neurological diseases and other conditions.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19.

There is reassuring clinical experience regarding the lack of hepatitis A or Parvovirus.

B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

It is strongly recommended that every time that IVIG preparation is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Serious reactions are uncommon. Adverse reactions occur more often when a patient is either receiving IVIG for the first time, or switching from one preparation to another or when there has been a long interval since the previous infusion. Certain patient groups are at higher risk for serious complications, such as those receiving high dose IVIG, patients with dehydration, the elderly, and those with preexisting renal or cardiovascular disorders, previous IVIG treatment complications, history of migraine, diabetes, concomitant use of nephrotoxic drugs, sepsis and fluid volume depletion. Many reactions are dose rate-related. Hematologic and thrombotic complications include hemolysis, neutropenia, and thrombotic and thromboembolic events. Some risk factors, such as high doses of IVIG, and certain underlying disorders, have been identified. The most important renal complication is acute renal failure, which is caused by sucrose-containing preparations, but can occur with any IVIG product.

Intravenous immunoglobulin (IVIG) products are being investigated as potential agents for treatment or prevention of AD. Polyclonal naturally occurring autoantibodies against amyloid β are found in serum of healthy persons and are reduced in AD patients.

IVIG has not been approved for prevention or treatment of AD and mild cognitive impairment. IVIG products are thought to contain the full range of antibodies present in the human repertoire. IVIG’s mechanisms of action in different disorders are generally poorly understood. It contains several antibodies that have the potential to reduce AD-type pathology, but whether these antibodies can actually do so is unclear. The IVIG trials reported to date in AD patients have produced conflicting findings. Newer research and developing human trials are becoming established for the use of intravenous immunoglobulins (IVIG) for the treatment and prevention of Alzheimer’s disease. At present there is no cure for AD. Symptomatic treatment of dementia with cholinesterase-inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists is considered as standard of care, particularly in mild to moderate Alzheimer’s disease. In addition to the symptomatic treatments currently marketed, a host of potentially disease-modifying therapies have been studied, and numerous others are in development. At present time there is no effective drug to treat or delay the progression from mild cognitive impairment (MCI) to dementia.

Investments and tools required to use the technology

IVIG is usually administered in an infusion center or health care facility, indicated by specialized medical staff and supervised by health professionals. IVIG can be given in the hospital, doctor’s office, or patients’ home. In any setting, nurses administer most of the transfusions. They should complete an accredited blood transfusion education program and be assessed upon their competency. Accredited nurses are responsible for checking blood and blood products, administering IVIG, monitoring patients during transfusion, and carrying out the appropriate actions should an adverse effect occur, ensuring adequate documentation in the medical notes, and reporting of transfusion reactions or other incidences related to the transfusion.

Detailed documentation of IVIG infusions should include the patient’s current health status and any changes in this status in the period between IVIG infusions; serological testing; record of brand, manufacturer, lot number, expiry date, dose and identification of the patient, any pre-medications which were given; time duration the infusion and specific rate titrations which were made; and any problems or adverse reactions the patient experienced during the infusion and how they were managed. A signed informed and written consent should be obtained from the patient, who should have received full information on the description of IVIG, their nature of blood product, the associated risks and benefits as well as alternatives to this treatment. The administration of IVIG should be carefully monitored and observed for any symptoms or alteration of vital signs throughout the infusion period and after administration. In addition, a monitoring of the renal function and diuresis is required as well as a good hydration of the patient.

Quality controls are required to guarantee the consistency of IVIG batches and to limit the risks of adverse reactions that have shown to be linked to the presence of certain proteins, biological ⁄microbial or chemical impurities. A set of quality control assays are needed to guide manufacturers in the development of IVIG preparations, to control the conditions of production and to guarantee the quality, safety and consistency of the products. Prescribed manufacturing procedures at the plasma collection centers and plasma-testing laboratories need to be designed in that way that they reduce the risk of transmitting viral infection. Risk reducing measures include careful selection of donors for plasma pools, testing for viral markers at multiple stages which allow for the detection of plasma viruses and the application of rigorously validated methods of testing. Quality controls for plasma derivatives include determination of chemical parameters, protein content, content of stabilizers and residues of chemicals used for the production or viral inactivation and various safety parameters. Some IVIGs products require refrigeration whereas others can be stored at room temperature. As such, lyophilized products are generally stored at room temperature before reconstitution. However, all liquid IVIG products optimally require refrigerated transport and storage between 2°C and 8°C. Blood products should be transported in dedicated and validated containers and be stored within glass containers, which are closed with rubber stoppers. It is important to follow the manufacturer’s specifications regarding storage and refrigeration requirements of each product, since the recommendations may vary per IVIG product.

Training and information needed for utilizing the technology

The health professional using IVIG requires specific knowledge and skills in order to be competent to treat patients with IVIGs. A hospital based IVIG program should provide education, training and protocols for staff to ensure the appropriate management and use of IVIGs, including transport, storage, use of equipment and infusion techniques. The training should include education related to documentation, patient consent, difference among IVIG brands, selection of a brand on the basis of patients’ risk factors, contraindications, needs, action plans for adverse events, rapid infusion protocols, and setup of infusion pumps, tubing and filter equipment.

Patients should be eligible for IVIGs only in case they give consent for transfusion of blood and/or blood products. One or several patient and/or family education sessions may be required to inform patients and/or family about what IVIG are and what they are used for, the fact that IVIGs are not licensed for use in the treatment of Alzheimers’ disease and mild-cognitive-impairment (off-label use), what one needs to know before using IVIGs, how and how often it is administered, the approximate duration of each infusion times, potential risks and benefits of its use, the potential of virus transmissions, contra-indications, so that informed consent may be obtained. Information about such things as new modalities of treatment, legislative initiatives and insurance issues may also be valuable. Patients and their families should equally be provided with written information brochures concerning the IVIGs. A risk assessment may be carried out to ensure the patient and family understand the need for treatment and how it is administered. 

Introduction

Intravenous immunoglobulins (IVIG), human normal immunoglobulin for intravascular administration (ATC code J06BA02), is a medicinal product derived from the pool of human plasma of at least thousands of healthy voluntary donors, prepared industrially, containing polyclonal antibodies to induce passive immunity and other protective effects. Human normal immunoglobulin is a highly purified protein extracted from human plasma. It contains immunoglobulin G (IgG), which is a type of antibody. IgG acts by restoring abnormally low IgG levels to their normal range in the blood.

There are several IVIG producers and many market authorized presentations of the product. The resulting products are generally believed to be equally effective for treatment of the autoimmune and immunodeficiency disorders. Products presentations vary in concentrations of human normal immunoglobulins in 1 ml of solution.

There has been a rapid expansion in the use of intravenous immunoglobulin (IVIG) for an ever growing number of conditions. IVIG has had a major impact in neurology, haematology, immunology, rheumatology and dermatology.

Intravenous immunoglobulin (IVIG) has been successfully used to treat a number of immune-mediated diseases of the central and peripheral nervous system. Although underlying mechanisms of action of IVIG have not been fully explained, it is presumed that IVIG can interfere with the immune system at several levels. IVIG has not been approved for prevention or treatment of AD and mild cognitive impairment. IVIG products contain the full range of antibodies present in normal population. IVIG’s mechanisms of action in different disorders are generally poorly understood. It contains several antibodies that have the potential to reduce AD-type pathology, but whether these antibodies can actually do so is unclear. Newer research and human clinical trials are conducted for the use of intravenous immunoglobulins (IVIG) for the treatment and prevention of Alzheimer’s disease.

The aim of this Domain is to describe and review the technical characteristics of IVIG. The aspects considered in this domain are correlated with the selected relevant issues and research questions. We try to describe the technology and its technical characteristics to get an overall understanding on its functioning, indications and use.

Methodology

Frame

The collection scope is used in this domain.

Technology	Immunoglobulins (IGG) Description Naturally occurring proteins produced by the body’s immune system to combat foreign antigens
Intended use of the technology	Treatment Treatment of Alzheimer’s disease Target condition Alzheimer’s disease Target condition description Alzheimer's disease (AD) or Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. Target population Target population sex: Any. Target population age: elderly. Target population group: Patients who have the target condition. Target population description AD is diagnosed mostly in people over 65 years of age, although there is an early-onset form that can occur much earlier. According to Wikipedia in 2006, there were 26.6 million sufferers worldwide.
Comparison	placebo, not doing anything or Usual supportive care Description There is no MA for IGGs for AD yet and there is no other intervention licensed for use in AD so the comparison would have to be against placebo or best supportive care
Outcomes	Description of aims of technology (TECH) Regulatory status (CUR) Cognitive function (EFF) Harms (SAF) Cost effectiveness compared to alternatives (ECO) Potential impact on plasma derivative market (ORG/Medico-legal) Impact on family and carers (SOC) Appropriateness of use in relation to solidity of evidence(ETH)

Assessment elements

	Topic	Issue	Relevant	Research questions or rationale for irrelevance
B0001	Features of the technology	What is this technology and the comparator(s)?	yes	What are Intravenous Inmunoglobulins (IVIG)? What are the potential comparators for IVIG use in Alzheimer’s disease and Mild Cognitive Impairment?
B0002	Features of the technology	What is the approved indication and claimed benefit of the technology and the comparator(s)?	yes	What is the approved indication and claimed benefit of IVIG?
B0003	Features of the technology	What is the phase of development and implementation of the technology and the comparator(s)?	yes	What is the phase of development and implementation of intravenous immunoglobulins (IVIG)?
B0004	Features of the technology	Who performs or administers the technology and the comparator(s)?	yes	Who performs or administers IVIG?
B0005	Features of the technology	In what context and level of care are the technology and the comparator used?	yes	In what context and level of care are IVIG used?
A0022	Other	Who manufactures the technology?	yes	Who manufactures IVIG?
B0007	Investments and tools required to use the technology	What material investments are needed to use the technology?	yes	What material investments are needed to use IVIG?
B0008	Investments and tools required to use the technology	What kind of special premises are needed to use the technology and the comparator(s)?	yes	What kind of special premises are needed to use IVIG?
B0009	Investments and tools required to use the technology	What equipment and supplies are needed to use the technology and the comparator?	yes	What equipment and supplies are needed to use IVIG?
B0010	Investments and tools required to use the technology	What kind of data and records are needed to monitor the use of the technology and the comparator?	yes	What kind of data and records are needed to monitor the use of IVIG ?
B0011	Investments and tools required to use the technology	What kind of registers are needed to monitor the use the technology and comparator?	yes	What kind of registers are needed to monitor the use IVIG?
B0012	Training and information needed to use the technology	What kind of qualification and quality assurance processes are needed for the use or maintenance of the technology?	yes	What kind of qualification and quality assurance processes are needed for the use or maintenance of IVIG?
B0013	Training and information needed to use the technology	What kind of training and information is needed for the personnel/carer using this technology?	yes	What kind of training and information is needed for the personnel/carer using IVIG?
B0014	Training and information needed to use the technology	What kind of training and information should be provided for the patient who uses the technology, or for his family?	yes	What kind of training and information should be provided for the patients who uses IVIG o for their families?
B0015	Training and information needed to use the technology	What information of the technology should be provided for patients outside the target group and the general public?	no	Potential intervention for a specific clinical situation. In the current situation it is not relevant to examine the needs of information provision for the general population or patients outside the target group, because the intervention is highly specific. However, if the intervention will turn out to be effective in the future, there might be an interest to provide information on the IVIGs to the relevant target population and probably also to the general public, thus they are informed about the existence of this treatment.

Methodology description

Domain frame

The project scope is applied in this domain.

Information sources

- Basic systematic search. Common (basic) literature search strategy run for the whole project (Immuno database).

- Additional search for published literature in PubMed and internet search of grey literature using Google, HTA database.  Review of the reference lists and bibliographies of selected studies identified through the basic systematic search.

- Manufacturers and companies web sites, Micromedex Drugdex Database.

- Search for IVIG authorization of immunoglobulins in EU website, EMEA data files, national and European law, other European notified bodies.

Quality assessment tools or criteria

No quality assessment tool was used. We use unsystematic approach and selection of relevant updated general reviews and specific documents.

Analysis and synthesis

The sources were sufficient to answer the questions. We did not perform additional data analysis. No quality assessment of the sources was made.

The results are presented in text format, supplemented by overview tables.

Descriptive analysis on different information sources. The assessment elements questions are answered and reviewed by cooperation of Domain investigators.

Result cards

Features of the technology

Other

Investments and tools required to use the technology

Training and information needed to use the technology

References

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Safety

Authors: Luca Vignatelli, Luciana Ballini, Susanna Maltoni, Jelena Barbaric, Mirjana Huic, Pernilla Östlund

Summary

Aim

To determine safety of treatment with intravenous immunoglobulin (IVIG) in adults with Mild Cognitive Impairment (MCI) or Alzheimer’s disease (AD) (adverse events due to IVIG treatment compared with current practice).

A secondary objective was to map available evidence against the technology’s evidence profile.

Methods

We performed a systematic review according to Cochrane methodology on evidence from biomedical and HTA databases; publicly available clinical trial (CT) registers were also accessed. Qualitative and quantitative syntheses were planned.

To assess risk of bias of included randomized controlled trials (RCTs) the risk of bias system proposed by the Cochrane Handbook for Systematic Reviews of Interventions was used. Overall quality of evidence for each outcome was assessed and synthesised according to the GRADE approach.

Results

Among the published clinical studies four met the inclusion criteria. One small multiple dose, placebo-controlled RCT treated 16 patients with mild-to-moderate AD for 12 weeks; one phase 2, dose-finding, placebo-controlled RCT treated 56 patients with mild-to-moderate AD for 24 weeks – 48 assigned to IVIG and 14 assigned to placebo;  and two prospective interventional non-controlled studies included a total 13 patients with mild-to-moderate AD.

Missing publication was documented for other two completed RCTs in subjects with mild-to-moderate AD. One of the two unpublished studies {NCT00818662}, a phase 3 double-blind, placebo-controlled, two dose arm RCT, aiming at testing the safety and effectiveness of IVIG for patients with mild-to-moderate AD, had its results posted on a clinical trial register in October 23rd 2014, after completion of this report. The authors and the sponsor had been previously contacted (May 2014) but did not provide any data. As this study, according to decision of Editorial Team, met inclusion criteria, release of this report was postponed in order to include it in the analysis despite the fact that available data did not permit a comprehensive evaluation of the methodology and conduction of the study due to the absence of information posted. The Authors and the Sponsor had been previously contacted (May 2014) but did not provide any data. Manufacturer was not contacted again to provide additional information.

In the two published RCTs, the proportion of participants who experienced any AEs was similar in IVIG and placebo group. Most AEs in the IVIG group were mild or moderate. No deaths occurred in these trials. The incidence of AEs leading to study discontinuation was higher for IVIG group than placebo group; three patients on IVIG in one RCT and one patient in another RCT did not complete the study because of AEs. In one RCT, 10 SAEs were observed in eight patients with higher proportion (not statistically significant) in the placebo group (4/42, 10%, vs 4/14, 29%, respectively, p=0.078). In the same RCT, ischaemic stroke was registered in one patient on IVIG and microhaemorrhages at MRI occurred more than expected in the IVIG group (6/42, 14%, vs 0/14), but were asymptomatic. One small RCT used 0.25% human albumin as comparator, therefore bias could have been introduced due to inappropriate choice of placebo.

The unpublished RCT included 383 patients (completing the study: 302) that were randomized to one of two doses of IVIG (Gammagard Liquid 10%, 400 mg/kg bodyweight or 200 mg/kg bodyweight, every two weeks) or one of two doses of placebo (0.25% human albumin solution infused at 4mL/kg or at 2 mL/kg, every two weeks) for 70 weeks. Available data do not permit an evaluation of the methodology and conduction of the study due to the absence of information posted. The confidence in effect estimates at study level is very low, according to GRADE approach. The proportions of participants who experienced Serious AEs (53/262, 20.2% vs 26/121, 21.5%) and non-Serious AEs (230/262, 87.8% vs 103/121, 85.1%) were similar in IVIG and placebo group. Four patients in the IVIG group died and reasons were not reported, whilst no death occurred in placebo group. Most frequent AEs in experimental arm were as follows: headache (24%), rash (15.3%), infusion site extravasation (14.5%), diarrhoea (14.1%), hypertension (12.2%), blood pressure increased (11.8%), fall (11.5%), depression (11.5%), dizziness (11.1%), vomiting (10.7%), nausea (10.3%).

The confidence in effect estimate for overall evidence on all considered outcomes is very low, according to GRADE approach.

Data on 13 patients only were available from two other interventional prospective non-controlled studies.

Two additional ongoing RCTs have been identified: one including subjects with MCI, and one including subjects with mild-to-moderate AD. These trials are reported to and expected to end in November 2014 and December 2016, respectively. Patients with moderate-to-severe AD are not considered by any study.

Conclusion

No conclusion can be drawn on the safety of IVIG for subjects with MCI and AD due to the poor - in term of quantity and quality – evidence presently available. The safety analysis was based on studies with mild-to-moderate AD treated with different doses of IVIG . None of the retrieved studies included patients with MCI and moderate-to-severe AD. Conclusive evidence from unpublished and ongoing studies are necessary before setting up RCTs on long term safety of IVIG in patients with MCI, mild-to-moderate and moderate-to-severe AD.

Introduction

The Safety Domains describes the direct and indirect harms of a technology for patients, staff and environment, and how to reduce the risk of harms {HTA Core Model Handbook Online, Version 1.5}. The safety issues specific to pharmaceutical technologies (drug safety, patient safety, adverse drug reactions, patient susceptibility) were considered while working on the safety domain {“Endpoints used in REA of pharmaceuticals – Safety”, available at http://www.eunethta.eu/outputs/methodological-guideline-rea-pharmaceuticals-safety}.

Adverse reactions were reported in up to 20% of all IVIG infusions and potentially serious systemic reactions occur in 2% to 6% of patients. Serious adverse events reported were: acute renal failure, anaphylaxis; aseptic meningitis; backache; chest discomfort; chest pain; haemolysis; haemolytic anemia; hepatitis; hypokalemic nephropathy; hyponatremia; myocardial infarction; pulmonary embolism; tachycardia; thrombosis; transfusion related acute lung injury {Micromedex Drugdex database, 2014}. Some reactions appeared  during the IVIG infusion (immediate reactions) others after the IVIG infusion (delayed reactions) {Singh-Grewal 2006}. Adverse reactions appearing during the infusion or within the 24 hours after infusion include rate-related reactions (phlogistic and anaphylactoid reactions, 2-20% of patients), headache (around 20% of patients) and true IgE-mediated anaphylaxis (in IgA-deficient patients) (< 1% of patients) {Silvergleid 2013}. Reactions emerging 24 hours after the infusion include headache/aseptic meningitis, acute kidney injury, hemolysis, venous thrombosis, and the possibility of myocardial infarction, transient ischemic attacks, and stroke {Silvergleid 2013}.

Objectives

Primary objective: to assess the safety of IVIG in adults with one the following conditions

• MCI
• Mild-to-moderate AD
• Moderate-to-severe AD

Secondary objectives:

• to map available evidence against the technology’s evidence profile, i.e. the body of evidence needed to demonstrate its safety in the above reported target conditions
• to identify research gaps

Methodology

Frame

The collection scope is used in this domain.

Technology	Immunoglobulins (IGG) Description Naturally occurring proteins produced by the body’s immune system to combat foreign antigens
Intended use of the technology	Treatment Treatment of Alzheimer’s disease Target condition Alzheimer’s disease Target condition description Alzheimer's disease (AD) or Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. Target population Target population sex: Any. Target population age: elderly. Target population group: Patients who have the target condition. Target population description AD is diagnosed mostly in people over 65 years of age, although there is an early-onset form that can occur much earlier. According to Wikipedia in 2006, there were 26.6 million sufferers worldwide.
Comparison	placebo, not doing anything or Usual supportive care Description There is no MA for IGGs for AD yet and there is no other intervention licensed for use in AD so the comparison would have to be against placebo or best supportive care
Outcomes	Description of aims of technology (TECH) Regulatory status (CUR) Cognitive function (EFF) Harms (SAF) Cost effectiveness compared to alternatives (ECO) Potential impact on plasma derivative market (ORG/Medico-legal) Impact on family and carers (SOC) Appropriateness of use in relation to solidity of evidence(ETH)

Assessment elements

	Topic	Issue	Relevant	Research questions or rationale for irrelevance
C0001	Patient safety	What kind of harms can use of the technology cause to the patient; what are the incidence, severity and duration of harms?	yes	What is the frequency of immediate and delayed serious and non-serious adverse events in patients with Mild Cognitive Impairment and in patients with Alzheimer’s disease treated with IVIG?
C0002	Patient safety	Are the harms related to dosage or frequency  of applying the technology?	yes	Do the incidence and severity of adverse events of IVIG change with different dosing and administration schemes when used in patients with Mild Cognitive Impairment or Alzheimer’s disease?
C0008	Patient safety	How safe is the technology in relation to the comparator(s)?	yes	What are the incidence, severity and duration of adverse events when compared with placebo or with drugs approved (acetylcholinesterase inhibitors, memantine) for the treatment of Alzheimer’s disease?
C0007	Patient safety	Are there special issues in the use of the technology that may increase the risk of harmful events?	yes	Do IVIG interfere with or are affected by other treatments used in patients with Mild Cognitive Impairment or in patients with Alzheimer’s disease?
C0004	Patient safety	How does the frequency or severity of harms change over time or in different settings?	no	No special issues, only issues related to IV preparations; an issue could be the amount of IgA contained in IVIG preparation that will be explored in another question (C0060)
C0005	Patient safety	Are there susceptible patient groups that are more likely to be harmed through use of the technology?	no	Patients eligible for treatment with IVIG are old patients usually with co-morbidities thus we may considered all the treated patients as very susceptible to adverse events.
C0060	Safety risk management	How does the safety profile of the technology vary between different generations, approved versions  or products?	yes	Does the safety profile of IVIG vary according to mode of production or between different IVIG approved versions or products when used in patients with Mild Cognitive Impairment and Alzheimer’s disease?
C0061	Safety risk management	Can different organizational settings increase or decrease harms?	no	IVIG are supposed to be administered in an hospital setting (IV administration). Not sure if consider irrelevant this question: to be discussed, perhaps it could be important to state that the administration should be carried out in an hospital setting (not an ambulatory setting) where a resuscitating service is available
C0062	Safety risk management	How can one reduce safety risks for patients (including technology-, user-, and patient-dependent aspects)?	no	Better in TECH domain
C0063	Safety risk management	How can one reduce safety risks for professionals (including technology-, user-, and patient-dependent aspects)?	no	We consider that risks for professionals are quite low, comparable to those of every product to be administered through a parenteral route
C0064	Safety risk management	How can one reduce safety risks for environment (including technology-, user-, and patient-dependent aspects)	no	Same risks as every other biological waste
C0020	Occupational safety	What kind of occupational harms can occur when using the technology?	no	Occupational harms are supposed to be those related to IV drugs, not specific for IVIG
C0040	Environmental safety	What kind of risks for public and environment may occur when using the technology?	no	Same risks as every other biological waste.

Methodology description

Criteria for considering studies

Types of studies

All published and unpublished randomised controlled trials (RCTs), prospective controlled and non-controlled studies (interventional). For unpublished studies we accepted results from publicly available controlled trials’ registers (decision made by Editorial Team). Report on animal models, pre-clinical and biological studies, narrative reviews, editorials, opinions, were excluded.

Types of participants (target population)

Adult (18+ years) patients of any sex who have one of the target conditions:

1. Patients with MCI (ICD-9-CM Diagnosis Code 331.83; ICD-10-CM G31.84) as defined by validated criteria.
2. Patients with AD (ICD-9-CM Diagnosis Code 331.0; ICD-10-CM G30.9), as defined by validated criteria.

Types of interventions

IVIG any dose, any regimen, any product, alone or in combination with non-pharmacological interventions, and/or with approved drugs (acetyl cholinesterase inhibitors, memantine).

Types of control treatments

• Placebo or drugs approved for symptomatic treatment of AD: acetylcholinesterase inhibitors, approved to be used in patients with mild-to-moderate AD, and memantine, approved to be used in patients with moderate-to-severe AD.

Types of outcomes and outcome measures

We looked for

1. immediate (emerging during the infusion of IVIG) and delayed (emerging after infusion) serious and non-serious adverse events [Issue domain Patient Safety C0001]
2. incidence and severity of adverse events with different dosing and administration schemes of IVIG [Issue domain Patient Safety C0002]
3. incidence, severity and duration of adverse events when compared with placebo or with drugs approved (acetylcholinesterase inhibitors, memantine) for the treatment of AD [Issue domain Patient Safety C0008]
4. incidence of interactions between IVIG and other treatments used in patients with MCI  or AD [Issue domain Patient Safety C0007]

Search methods for identification of studies

Electronic searches

The following databases were searched:

Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, TOXLINE, EMBASE, LILACS, ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group) and national and international trials registers (Australian New Zealand Clinical Trials Register (ANZCTR), http://www.anzctr.org.au/; metaRegister of Controlled Trials (mRCT), http://www.controlled-trials.com/mrct/; ClinicalTrials.gov. www.clinicaltrials.gov/; NIH Clinical Research Studies, http://clinicalstudies.info.nih.gov/; EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/; International Clinical Trials Register Platform (ICTRP), http://www.who.int/ictrp/en/). We searched also the websites of the regulatory agencies (US Food and Drug Administration-MedWatch (http://www.fda.gov/Safety/MedWatch/default.htm), European Medicines Evaluation Agency (http://www.ema.europa.eu), Australian Adverse Drug Reactions Bulletin (http://www.tga.gov.au/safety/ews-monitoring.htm), and UK Medicines and Healthcare products Regulatory Agency (MHRA) pharmacovigilance and drug safety updates (http://www.mhra.gov.uk/Safetyinformation/index.htm).

Initial search was carried out on February 24^th 2014 and an update was carried out close to the release of the report on December 16^th 2014.

See Appendix 6 for detailed search strategies. The strategy for MEDLINE was translated for other databases. No language or date of publication restrictions were applied.

Searching other resources

In addition we checked conference proceedings for relevant abstracts, and contact individual researchers working in this field, organizations and pharmaceutical companies to identify additional RCTs, especially those unpublished. We also checked the reference lists of all studies identified by the above methods.

Data collection and analysis

Selection of studies

The titles and abstracts of all studies identified by the search were screened independently by two investigators (ASSR). Full text was retrieved for all studies considered potentially relevant. Two investigators then identified studies for inclusion or exclusion (ASSR). Different selection results were discussed in order to achieve consensus. A third person was involved to resolve discrepancies (AAZ and SBU).

Data extraction and management

A data extraction form was developed and piloted specifically for this review. For each study, data were extracted on: participants (including inclusion and exclusion criteria, baseline investigations, co-treatments); interventions; outcomes; study design; results. For eligible studies, when data on outcomes of interest were missing or incompletely reported investigators contacted the Authors for additional information. Data extracted were the number of participants with the outcome of interest in each group at each time point.

Assessment of risk of bias of included studies and of overall quality of evidence

To assess risk of bias of included RCTs the risk of bias system proposed by the Cochrane Handbook for Systematic Reviews of Interventions {Higgins et al. 2011} was used. Overall quality of evidence for each outcome was assessed and synthesised according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach {Guyatt 2011a; Balshem 2011; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2013}, and presented in table. This approach specifies four levels of quality:

• High: further research is very unlikely to change our confidence in the estimate of effect;
• Moderate: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimates;
• Low: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate;
• Very low: we are very uncertain about the estimate.

Data synthesis

Studies were grouped by target conditions included in this protocol. A descriptive summary of the included studies with details about study design, numbers and characteristics of enrolled patients, intervention/s and comparator/s, outcomes, and results is provided in tables and plain text format. We adopted definitions and terminology of safety according to the Medical Dictionary for Regulatory Activities (MedDRA) Terminology (http://www.meddra.org/).

Quantitative results are expressed as point estimates together with associated 95% confidence intervals (95% CI) and  p-values. We had planned, if possible, to carry out a meta-analysis with graphical display of results and assessment of heterogeneity, according to the Cochrane Handbook for Systematic Reviews of Interventions {Higgins et al. 2011}.

To map available evidence against the technology’s evidence profile, for each research question the results from available evidence and upcoming evidence were charted in order to describe stage of development and to highlight research gaps. Available evidence refer to published or unpublished studies with available data and upcoming evidence refer to unpublished without available data and ongoing studies.

Description of studies

Results of the search

The first electronic searches strategy (February 24^th 2014) yielded 515 citations, after removal of duplicates. Of these, 388 were directly excluded, because judged not relevant.

Of the remaining 127 citations, 116 did not meet our inclusion criteria and were excluded from safety assessment (primary objectives). Three published studies (corresponding to 11 records) were included {Dodel 2004, Dodel 2013, Relkin 2009}. Periodic checks of registers of ongoing trials revealed that  the results of one of the RCT {NCT00818662} tracked on clinical trial registries had been posted on ClinicalTrials.gov by the study sponsor in October 23rd 2014. Thus this study was included (decision made by Editorial Team) and the remaining 115 citations excluded. The second electronic search strategy (December 16^th 2014) yielded 71 citations, after removal of duplicates. One published study {Arai 2014} was included. From the final periodic check of registers of ongoing trials (December 16^th 2014) there was no further status change for included ongoing trials.

See PRISMA study flow diagram in Appendix 1{Figure A1}.

Excluded studies

The reasons for exclusion of the 115 records were as follows: in vitro/animal studies (n=13); other treatments (n=22); review papers (n=31); comments/editorials/news (n=14); other topics (n=4); studies on the current use of IVIG (n=2); case control studies (n=2); study without data on outcomes (n=1). The remaining 26 citations corresponding to 12 interventional studies did not fulfil our inclusion criteria. Of these 12 studies, 6 resulted as completed and published only as abstracts {Hara 2011, Kondo 2011, Kountouris 2000, Papatriantafyllou 2006, Rovira 2011, Relkin 2012}; 1 were completed but unpublished {NCT00299988 }; 2 studies are ongoing {NCT01300728, NCT01561053}, 2 studies had been planned but they were terminated prematurely {NCT01524887, NCT01736579}; and one published study was excluded because retrospective {Devi 2008}. The above 12 interventional studies were found eligible only for the evidence mapping against the technology’s evidence profile.

Included studies with published results

The four included studies - summarised in Appendix 2, - were were two RCTs, one small multiple-dose and one dose-finding  {Dodel 2013, Arai 2014}, and two prospective interventional non-controlled studies {Dodel 2004, Relkin 2009}.

The first RCT {Dodel 2013} was an exploratory phase 2 dose finding double-blind, block-randomised, placebo-controlled study aiming at testing the safety, effective dose, and infusion interval of treatment with intravenous immunoglobulin for patients with mild-to-moderate AD. Participants were 58 subjects (modified intention-to-treat population: 57; per protocol population: 45) with probable AD (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria), with a mini-mental state examination score 16–26 and age 50–85 years at baseline. Patients had to have been taking a stable dose of an approved AD drug for at least 3 months before screening; 36 out of 41 patients in IVIG (88%) used acetylcholinesterase inhibitor or memantine as well as 11 out of 14 (79%) patients in Placebo group.

Participants were randomized to one of six doses of IVIG (0.2 g/kg, 0.5 g/kg or 0.8 g/kg every 4 weeks; 0.1 g/kg, 0.25 g/kg, or 0.4 g/kg every 2 weeks) or to placebo (0.9% isotonic sodium chloride every 4 weeks or every 2 weeks). Treatment duration was 24 weeks. Primary outcome was the difference of the median area under the curve (AUC) of plasma concentration of Aβ1–40 between placebo groups and the six intervention groups, measured from last infusion to final visit. Other surrogate outcomes were the difference of AUC for plasma concentration of Aβ1–42 and of anti-Aβ autoantibodies; the difference of plasma concentration of Aβ1–40, Aβ1–42 and anti-Aβ autoantibodies at week 24 compared with baseline; the change in CSF concentration of Aβ1–40, Aβ1–42, anti -Aβ autoantibodies and p-tau181, 24 h after last infusion compared with baseline; the difference between baseline and week 24 of change in whole brain volume, hippocampus volume; glucose metabolism. Moreover some patient important outcomes were considered: difference in scores at baseline and at week 24 on the AD assessment scale-cognitive part (ADAS-cog), the clinical dementia rating scale-sum of boxes, the Alzheimer’s Disease Cooperative Study-activities of daily living scale, the mini-mental state examination; adverse events. The study - funded by Octapharma AG – was conducted in hospitals, research centres and private clinics of Germany and USA.

The second RCT {Arai 2014} was an exploratory multiple dose, double-blind, randomised, placebo-controlled study aiming at testing the safety and tolerability of treatment with IVIG for patients with mild-to-moderate AD. Participants were 16 subjects (intention-to-treat and per protocol population: 16) with probable AD (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria), with a mini-mental state examination score 16–26 and age 50–89 years at baseline. Patients could have been taking a stable dose of an approved AD drug (cholinesterase inhibitors, memantine) for at least 120 days prior baseline. However no data were reported about the use of these drugs.

Participants were randomized to one of two doses of IVIG (0.2 g/kg, 0.4 g/kg every 2 weeks) or to placebo (50 mL 0.25% human albumin solution every 2 weeks). Treatment duration was 12 weeks and follow up lasted up to 26 weeks. The outcome measures were safety and tolerability including adverse events (AE), assessed also by vital signs, physical and neurological examinations, 12-lead electrocardiogram, clinical laboratory evaluations, and brain MRI scans. AE were coded according to system organ classes using the Medical Dictionary for Regulatory Activities (version 14.1). Moreover MMSE score change 14 weeks after the end of treatment (week 26 of follow up) was considered. The study was conducted in 5 centres of Japan. No information was provided about funding. The study does not report a Study Registration number.

The other two studies {Dodel 2004, Relkin 2009} (interventional prospective non-controlled studies) had small populations (n = 13) of subjects with AD (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria) and tested the safety and the clinical effect of various schemes of IVIG administration (0.4 g/kg every 2 weeks; 0.4 g/kg on three consecutive days every 4 weeks; 0.4 g/kg every week; 1 g/kg every 2 weeks; 2 g/kg every 4 weeks) for 3-6 months of duration. The outcomes considered were difference between baseline and end of treatment of cognitive functions according to various scales/tools (Wechsler Adult Intelligence Scale; Wechsler Memory Scale; Boston Naming Test; ADAS-cog; MMSE; Visual construction abilities), immunologic surrogate outcomes (changes before and after infusion of serum or CSF anti-Abeta antibody, changes of CSF Abeta 40 and Abeta42), adverse events. Two studies {Dodel 2004, Relkin 2009} received both public and manufacturer’s funding; in the third study {Devi 2008} the source of funding was not reported.

Included unpublished studies with results posted in clinical trials registers (Editorial Team decision)

The included unpublished study - summarised in Appendix 2, - were one RCT {NCT00818662}.

The following information refers to data posted by the study sponsor on one trial register (ClinicalTrials.gov) in October 23rd 2014. The Authors and the sponsor were previously contacted (May 2014). They responded but did not provide results. The Authors and the sponsor were not contacted again.

The included RCT {NCT00818662} was a phase 3 double-blind, placebo-controlled, two dose arm study aiming at testing the safety and effectiveness of IVIG for patients with mild-to-moderate AD. Participants were 383 patients (patients completing the study: 302; intention-to-treat population not declared) with probable AD (criteria not reported), with a mini-mental state examination score of 16–26 and age 50–89 years at baseline. Included patients had been taking a stable dose of an approved Alzheimer’s disease drug for at least 3 months before screening (not reported number of patients on treatment). Participants were randomized to one of two doses of IVIG (Gammagard Liquid 10%, 400 mg/kg bodyweight every two weeks, or 200 mg/kg bodyweight every two weeks) or one of two doses of placebo (0.25% human albumin solution infused at 4 mL/kg every two weeks or at 2 mL/kg every two weeks), for 70 weeks. The randomization ratio was 2:2:1:1.

Co-primary outcomes were change from baseline at 18 months in the Alzheimer´s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) and change from baseline at 18 months in the Alzheimer´s Disease Cooperative Study Activities of Daily Living (ADCS-ADL). Other patients important outcomes considered in the study were: change at 9 months in ADAS-Cog, change at 9 months in ADCS-ADL, change at 9 and 18 months in Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCSC-GIC), change at 18 months in the Neuropsychiatric Inventory (NPI), change at 18 months in the Logsdon Quality of Life in Alzheimer's Disease (QOLAD) of patients and caregivers. Other outcomes assessed in the study but not considered in this review were: Modified MiniMental State Examination (3MS), Wechsler Adult Intelligence Scale Revised Digit Span, FAS Verbal Fluency, Animals Category Fluency, Trail Making Test Part A and Part B, Clock Drawing Test. The study - funded by Baxter Healthcare Corporation and conducted in USA and Canada – started in December 2008 and ended in December 2012.

Included unpublished studies without results posted in clinical trials registers

Seven more studies - summarised in Appendix 3 - were carried out but not published as full papers, resulting as protocols in ClinicalTrial.gov {NCT00299988 } or abstracts at congress {Hara 2011, Kondo 2011, Kountouris 2000, Papatriantafyllou 2006, Relkin 2012, Rovira 2011}.

The NCT00299988 study {NCT00299988} was a phase 2 randomized, placebo-controlled trial, conducted in USA. Participants were 24 subjects with mild-to-moderate AD. Four schemes of intravenous immunoglobulin (ranging from 0.2 g/kg every 2 weeks to 0.8 g/kg every months) were compared to placebo. Treatment duration was 6 months. Primary outcome were ADAS-Cog and ADCS-CGIC. Other outcomes were cognitive functions measured by other scales/tools (MMSE; ADCS-ADL; NPI; GDS), quality of life (scales not reported), immunologic surrogate outcomes (plasma and CSF anti-amyloid antibody titers and beta amyloid levels), imaging surrogate outcomes (Positron Emission Tomography: FDG Cerebral Glucose Utilization, PIB Cerebral Amyloid Distribution, PK11195 Microglial Activation), adverse events. The study - funded by Weill Medical College of Cornell University Collaborators and by Baxter BioScience – was completed in April 2010 but results are still unpublished. For this study an open label extension of three years was carried out in 16 subjects in order to assess the long-term safety the IVIg infusion, but results are similarly unpublished as full paper (available only an abstract, Relkin 2012). Authors of the study were contacted in May 2014, and although they responded, they did not provide results.

Other four studies {Hara 2011, Kondo 2011, Papatriantafyllou 2006, Rovira 2011} applied a before-and-after design to small samples (n = 4 to 10) of subjects with AD testing the safety and effectiveness of various schemes of IVIg administration for 3-62 months of duration. The outcomes considered were difference between baseline and end of treatment of cognitive functions according to various scales/tools, surrogate outcomes, adverse events. These studies are still unpublished as full paper (available only as abstracts). The Authors of these studies were contacted. Two of them responded without providing results, stating that the studies will be probably published.

Finally, one study {Kountouris 2000} applied a non-randomized controlled design to 16 subjects with AD comparing the effectiveness of IVIg infusion together with piracetam versus the administration of piracetam only, for 12 months of duration. The outcome considered was the cognitive function assessed by the MMSE. This study is unpublished as full paper (available only as abstract). The Author of this study was contacted, without response.

Terminated studies

Two other studies - summarised in Appendix, Table 3: Characteristics of terminated studies – are terminated {NCT01736579, NCT01524887}, that is stopped prematurely.

An open label extension of three years of one of the above reported RCTs NCT00818662 was planned {NCT01736579} in order to assess the long-term safety of the IVIg infusion. The study was terminated in 2013 after enrollment of 6 patients because the preceding phase 3 study did not demonstrate efficacy on the co-primary endpoints.

The NCT01524887 study {NCT01524887} was a phase 3 randomized, placebo-controlled trial planned to include subjects with mild-to-moderate AD in order to test two unspecified schemes of intravenous immunoglobulin versus placebo for a treatment duration of 18 months. Primary outcome considered were ADAS-Cog and ADCS-ADL. The study - devised by Baxter Healthcare Corporation – was terminated in 2013 without enrollment of any patients because the first phase 3 study {NCT00818662} did not demonstrate efficacy on the co-primary endpoints.

Ongoing studies

Two more studies - summarised in Appendix 3– are still ongoing {NCT01300728, NCT01561053}.

The NCT01300728 study {NCT01300728}, is a phase 2 randomized, placebo-controlled trial, that is ongoing in USA. Participants are 50 subjects with MCI, amnestic type (single or multi domain) according to Petersen criteria (Petersen 1999) and supported by a CDR score of 0.5. IVIg infusion (0.4 g/kg every 14 days for a total of five infusions in two months) will be compared to placebo. Primary outcome is change in ventricular volumetric as measured by MRI (time frame: baseline and 24 month). Other outcomes are conversion from amnestic MCI to AD, cognitive functions measured by other scales/tools (ADAS-cog; MMSE; Clinical Dementia Rating and Sum of Boxes), other imaging surrogate outcomes, adverse events. The study - funded by Sutter Health – will be completed in November 2014.

The NCT01561053 study {NCT01561053}, is a phase 2/3 randomized, placebo-controlled trial, that is ongoing in USA and Spain. Participants are 350 subjects with mild-to-moderate Alzheimer Disease (National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association criteria). IVIg (Flebogamma DIF) infusion (at unspecified high and low dose) together with plasmapheresis or plasmapheresis alone will be compared to a sham procedure. Primary outcome is increase in cognitive scores as measured by A<DAS-Cog (time frame 14 months). Other outcomes are change in: cognitive, functional and neuropsychiatric scores (measured by MMSE, NPS battery, ADCS-ADL, NPICDR-Sb, ADCS-CGIC, CSDD, C-SSRS), surrogate immunological outcomes (levels of AB1-40 and AB1-42, T-tau and P-tau in CSF; levels of AB1-40 and AB1-42 in plasma), surrogate imaging outcomes (structural changes in volume of the hippocampus, posterior cingulate area, and other associated areas at MRI; brain functional changes through FDG-PET), adverse events. The study - funded by Grifols Biologicals Inc. – will be completed in December 2016.

Risk of bias in included studies

The RCT NCT00818662 was a phase 3 double-blind, placebo-controlled, two dose arm study. Available data (posted on ClinicalTrials.gov, last access December 5 2014) do not permit an evaluation of the methodology and conduction of the study due to the absence of information posted. Authors and Manufacturer were not contacted again and risk of bias was assessed by Principal Investigator. A risk of attrition bias was present (81 out of 383 randomized patients did not complete the study). The study was industry sponsored. The overall risk of bias of this study was judged to be “high”. For details on study’s risk of bias please see Table 1.

Table 1. Risk of bias table for NCT00818662.

Bias	Judgement	Support for judgement Cochrane Risk of Bias; Criteria from EUnetHTA guideline, Internal validity of randomized controlled trials
Random sequence generation adequate (selection bias)	Unclear	No details on random generation.
Allocation concealment adequate (selection bias)	Unclear	No details on allocation concealment.
Blinding of patients (performance bias)	Unclear	No details on blinding.
Blinding of treating personnel (performance bias)	Unclear	No details on blinding.
Blinding of outcome assessment (detection bias)	Unclear	No details on blinding.
Incomplete outcome assessment unlikely (attrition bias)	High risk	383 patients were randomized: 127 IVIG 400mg/kg; 135 IVIG 200mg/kg; 58 Placebo 4mL/kg; 63 Placebo 2mL/kg. 82 (21.4%) patients did not complet the trial: 23 (18.1%) IVIG 400mg/kg; 33 (24.4%) IVIG 200mg/kg; 9 (15.5%) Placebo 4mL/kg; 16 (25.4%) Placebo 2mL/kg
ITT principle appropriately implemented (attrition bias)	Unclear risk	No details on ITT analysis.
Selective outcome reporting unlikely (reporting bias)	Low risk	No main discrepancies between the protocol and the reported results are present.
Other bias	High risk	Sponsored study Two Study  Directors are reported Study Director: Norman Relkin, MD, PhD Alzheimer's Disease Cooperative Study (ADCS) Study Director: David Gelmont, MD Baxter Healthcare Corporation Role of the funding source “Restriction Description: Agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication (by USCD) or 12 months after study completion. Baxter requires a review of results communications (e.g., for confidential information) ≥45 days prior to submission or communication. Baxter may request an additional delay of ≤45 days(e.g., for intellectual property protection)”

The second included RCT {Dodel 2013} was an exploratory dose-finding, phase 2 study with a small sample size, unbalanced baseline characteristics among the treatment groups (use of acetylcholinesterase inhibitors or memantine: 88% in IVIG group vs 79% in placebo group), risk of attrition bias (IVIG group: 6 withdrawals out of 42 subjects, 14.3%; placebo group: 5 withdrawals out of 14 subjects, 36%), industry sponsored. For details on study’s risk of bias please see Table 2.

Table 2. Risk of bias table for Dodel 2013.

Bias	Judgement	Support for judgement Cochrane Risk of Bias; Criteria from EUnetHTA guideline, Internal validity of randomized controlled trials
Random sequence generation adequate (selection bias)	Low risk	“Patients were randomly allocated to receive one of three doses of intravenous immunoglobulin (0・2 g/kg, 0・5 g/kg, or 0・8 g/kg) or placebo (0・9% isotonic sodium chloride) every 4 weeks, or half of that dose (0・1 g/kg, 0・25 g/kg, or 0・4 g/kg) every 2 weeks. The randomisation was done with a computer-generated randomisation list created by the contract research organisation with SAS (version 9.1.3). Patients were allocated through an interactive web response service in block sizes of eight.”
Allocation concealment adequate (selection bias)	Low risk	See above.
Blinding of patients (performance bias)	Low risk	“The study drug was contained in ethylene vinyl acetate bags masked by opaque pouches. It was prepared at local pharmacies and dispensed by pharmacists who were not masked to the allocation. Infusion was done by a physician who was masked to the patient’s allocation and not involved in any assessments. Patients, caregivers, investigators assessing outcomes, staff of imaging facilities and of the clinical research organisation were masked to treatment allocation, but the statistician and the person responsible for the final PET analyses were not.”
Blinding of treating personnel (performance bias)	Low risk	See above.
Blinding of outcome assessment (detection bias)	Low risk	See above.
Incomplete outcome assessment unlikely (attrition bias)	High risk	Flow chart, page 234. The drop-out rate in the trial was considerable; 89 patients were screened and 58 were randomly assigned; 2 patients were not treated; 42 assigned to intravenous immunoglobulin and 14 assigned to placebo; 6 withdraw in IVIgG group and 5 in Placebo group. 45 (77.6%) patients (out of 58) completed 24 weeks of treatment, with different rates of discontinuation between groups /6 out of 42 assigned IVIgG (14.28%): 5 out of 14 assigned to Placebo (35.7%)/. The characteristics of the dropped-out participants compared with the completed participants have not been reported.
ITT principle appropriately implemented (attrition bias)	Unclear risk	“For safety data, continuous variables were analysed with standard summary statistics and frequency tables. The safety analysis was based on 56 patients, of whom 42 patients were in the intravenous immunoglobulin group and 14 were in the placebo group.” Flow chart, page 234. Authors mentioned Intention-to-treat analysis (ITT) and Per-protocol analysis (PPT) but from flow char is visible that the modified intent-to-treat (mITT) was used, which (marginally) differ from ITT, as patients randomised but not initiated on the study medication are excluded (2 patients). Proportion and p value are written, without CI.
Selective outcome reporting unlikely (reporting bias)	Unclear risk	3/42 patients on IVIG did not complete the study because of AEs:  one 68-year-old women in the high-dose treatment group due to ischemic stroke (middle cerebral artery infarction), one patient due to 14 new asymptomatic microbleeds at week 12 on MRI scan and one due to reasons neither written in the article nor visible in trial registers. CI not shown for proportion of patient with documented AEs and SAEs. AEs were not prespecified primary or secondary endpoints.
Other bias	High risk	Some demographic and baseline characteristic were not similar between groups (for example sex, bodyweight, duration of symptoms, use of acetylcholinesterase inhibitor or memantine, total tau concentration, microbleeds, normalized whole brain volume). The patient characteristics (e.g. comorbidities) or medications at baseline or at end of study (e.g. doses used) in different study groups are not reported in sufficient detail. The trial is sponsored by pharmaceutical industry. The sample size was determined empirically, on the basis of a previous study. Small sample size of each treatment group and within IVIgG group, very small control (placebo) group. “Role of the funding source The study sponsor was partly responsible for the study design. The clinical research organisation (ClinResearch, now Aptiv Solutions, Cologne, Germany) had responsibility for data monitoring and analysis according to the statistical analysis plan developed by the sponsor as well as for writing trial reports for regulatory authorities. The sponsor had a role in data interpretation, but no role in data collection. After the database lock and study unmasking, all of the investigators had full access to the study data and had final responsibility for data analysis. The report was written and reviewed by the authors and the sponsor. The decision to submit the report for publication was made jointly by RD, FJ, MF, and the sponsor.” COI: 2 authors are employees of Octapharma; some authors received consultancy fee or funding for research or travel support to meetings or speaker fee, some are board member.

 

The third RCT {Arai 2014} was a multiple dose study with a small sample size, unclear selection bias, unclear performance and detection bias, and other bias. The study does not report a Study Registration number. For details on study’s risk of bias please see Table 3.

Table 3. Risk of bias table for Arai 2014.

Bias	Judgement	Support for judgement Cochrane Risk of Bias; Criteria from EUnetHTA guideline, Internal validity of randomized controlled trials
Random sequence generation adequate (selection bias)	Unclear risk	Not reported details about random sequence generation
Allocation concealment adequate (selection bias)	Unclear risk	Not reported details about allocation concealment
Blinding of patients (performance bias)	Unclear risk	Double blind but not reported details about appearance of IVIG treatment and placebo
Blinding of treating personnel (performance bias)	Unclear risk	Double blind but not reported details about appearance of IVIG treatment and placebo
Blinding of outcome assessment (detection bias)	Unclear risk	Double blind but not reported details about appearance of IVIG treatment and placebo
Incomplete outcome assessment unlikely (attrition bias)	Low risk	All included patients completed the study
ITT principle appropriately implemented (attrition bias)	Unclear risk	There is no Flow chart. “The population for safety analyses was defined as all randomly assigned subjects from whom post-treatment safety data has been collected at least once.” All included patients completed the study.
Selective outcome reporting unlikely (reporting bias)	Unclear risk	The study does not report a Study Registration number.
Other bias	High risk	All authors declare that they have no conflicts of interest associated with this manuscript, however five of them have affiliation with Baxter Limited, Tokyo, Japan. Small sample size. Very small control group which received as placebo 0.25% human albumin, that could induce AEs and SAE. Medications at baseline or at end of study (e.g. doses used) are not reported in sufficient detail for the different study groups. Short duration of study.

The two non-controlled interventional studies {Dodel 2004, Relkin 2009} had a very small sample size and absence of blinding of assessment of clinical outcomes; Dodel 2004 had an inadequate follow up duration (6 months); the other {Relkin 2009} was industry sponsored.

Result cards

Patient safety

Safety risk management

Discussion

No conclusion can be drawn on the safety of IVIG for subjects with MCI and AD due to the poor - in term of quantity and quality – evidence presently available. The safety analysis was based on patients with mild-to-moderate AD {Arai 2014, Dodel 2004, Relkin 2009, Dodel 2013, NCT00818662} treated with different doses of IVIG. Any evidence is lacking for MCI and moderate-to-severe AD.

The few available data – three RCTs {Arai 2014, Dodel 2013, NCT00818662} and two prospective interventional uncontrolled studies {Dodel 2004, Relkin 2009} - confirm the short-term safety profile of IVIG known from other populations of patients {Silvergleid 2013, Singh 2006}. One of the trials (NCT00818662), previously tracked completed but not published, had final results posted by the study sponsor in October 23rd 2014. Inclusion of this study in the assessment was decided by Editorial Team. Authors and sponsor were previously contacted (May 2014) but they did not provide any data. No further contacts were sought.

IVIG was generally well tolerated and in three RCTs {Arai 2014, Dodel 2013, NCT00818662} overall rates of IVIG AEs were similar to those in the placebo group. The majority of AEs that occurs during IVIG treatment was not serious and seemed to be manageable. Higher SAEs rates were observed in placebo group, without statistically significant difference. However the confidence in safety estimates for overall evidence on all considered outcomes is very low, according to GRADE method, due to high risk of bias.

In Arai 2014, one patient on IVIG did not complete the study because of rash on the extremity and the trunk with mild elevations in aspartate amino transferase, alanine amino transferase, and lactose dehydrogenase. This small sample size study, with high risk of bias and short duration of treatment, included only 16 patients with control group who received 0.25% human albumin as placebo. Human albumin could induce AEs and SAE.

In Dodel 2013, three patients on IVIG did not complete the study because of AEs: ischaemic stroke (1 patient), microhaemorrhages on MRI scan without symptoms (1 patient), not reported (1 patient). No deaths occurred during the treatment. A SAE which was observed in one patient on IVIG, ischaemic stroke, is a known serious adverse event for IVIG treatment. Increased risk for thrombotic events is known in patients with history of venous or arterial thrombosis, advanced age, prolonged immobilization, multiple cardiovascular risk factors, coagulation disorders, estrogen use, indwelling central vascular catheters, and possible or confirmed hyperviscosity {Micromedex Drugdex database, 2014}. Moreover cerebral microhaemorrhages at MRI (without clinical symptoms) were observed in six patients in IVIG arms versus none in placebo arms; one patient did not complete the study for this reason. The clinical significance of these findings is not clear, and the link to IVIG administration cannot be excluded.

In NCT00818662, four patients in the IVIG group died and reasons were not reported whilst no deaths occurred in placebo group.

In another prospective non-controlled study, one patient was admitted to the hospital two weeks following IVIG due to confusion, that resolved within few days {Dodel 2004}.

Due to the small samples, the possibility of other unexpected and SAEs, specific for the target population of interest, cannot be excluded.

We have documented the missing publication of another RCT {NCT00299988}, and of other six interventional non-controlled studies. All these studies included subjects with mild-to-moderate AD.

Other two ongoing RCTs have been recorded: one phase 2, dose-finding, including 50 subjects with MCI {NCT01300728}, and one phase 2/3, including 350 subjects with mild-to-moderate AD {NCT01561053}. Trials are reported to or expected to end in November 2014 and December 2016, respectively.

Included studies were conducted in hospitals, research centres and private clinics of Japan, Germany and USA. The tested therapeutic schemes and the duration of treatment are very different. The IVIGs used in included studies were Gammagard by Baxter Healthcare Corporation {NCT00818662} and Octagam by Octapharma AG {Dodel 2013}. The study by Arai et al. {Arai 2014} does not specify the label of the IVIG treatment. The ongoing RCTs are testing Flebogamma by Grifols S.A. and NewGam by Sutter Health. The latter study tests IVIG (high dose or low dose) together with plasmapheresis against plasmapheresis alone or against infusion of 20% albumin.

Implications for practice

At present there is limited evidence on safety of IVIG in adults with mild-to-moderate AD, and no evidence for adults with MCI and moderate-to-severe AD.

Implications for research

Publication bias was identified in the evidence base of subjects with mild-to-moderate AD. Two RCTs have been recently completed but not published {NCT00299988, NCT00818662}. One of them had its results recently posted on a clinical trial register {NCT00818662}; these data were included the present review. Another RCT including 350 patients will be ended within the next two years {NCT01561053}. Future access to these data might provide valuable evidence to assess safety of IVIG for these patients. No further trials would be advised before publication of these studies.

One small study on subjects with MCI {NCT01300728} is awaiting completion. It would produce only preliminary short term data. Other studies – if suitable – will have to be devised to assess safety in the long term.

The category of moderate-to-severe AD is not considered for future study, probably because the rationale of IVIG for advanced AD is weak or absent.

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Appendices

Appendix 1

Figure A1. Flow charts of study selection for the “safety domain”.

Appendix 2

Included studies

Table A2.1: Characteristics of included studies (see Appendix 5 for more details)

Reference	Study design	Participants	Intervention (duration)	Control	SAF issues	SAF outcome measure	Funding
Arai 2014	multiple dose, placebo controlled, RCT	16 patients (12 experimental group; 4 control group) with mild-to-moderate Alzheimer Disease	one of two doses of intravenous immunoglobulin (0·2 g/kg, 0·4 g/kg) every 2 weeks (12 weeks)	placebo (50-mL 0.25% human albumin solution) every 2 weeks	Patient safety C0001	Frequency of immediate and delayed serious and non-serious adverse events	Not reported
					Patient safety C0002	Frequency of immediate and delayed adverse events for different dosing and administration schemes
					Patient safety C0008	Frequency, severity and duration of immediate and delayed adverse events of IVIG and comparators
Dodel 2004	Interventional prospective non-controlled study	5 patients with Alzheimer Disease (4 mild-to-moderate; 1 moderate-to-severe)	IVIG (OctagamH) 0.4 g/kg on three consecutive days every 4 weeks (6 months)	None	Patient safety C0001	Frequency of immediate and delayed serious and non-serious adverse events	Public Octapharma (Lagenfeld, Germany) provided IVIG
Dodel 2013	phase 2, dose-finding; placebo controlled, RCT	58 patients (42 experimental group; 14 control group) with mild-to-moderate Alzheimer Disease	one of three doses of intravenous immunoglobulin (0·2 g/kg, 0·5 g/kg, or 0·8 g/kg) every 4 weeks, or half of that dose (0·1 g/kg, 0·25 g/kg, or 0·4 g/kg) every 2 weeks (24 weeks)	placebo (0·9% isotonic sodium chloride) every 4 weeks or every 2 weeks	Patient safety C0001	Frequency of immediate and delayed serious and non-serious adverse events	Octapharma AG
					Patient safety C0002	Frequency of immediate and delayed adverse events for different dosing and administration schemes
					Patient safety C0008	Frequency, severity and duration of immediate and delayed adverse events of IVIG and comparators
NCT00818662 (update on clinicaltrial.gov:  October 23th 2014)	phase 3 RCT	383 patients with mild-to-moderate AD (262 experimental group; 121 control group)	IVIG (Gammagard Liquid) 200 mg or 400 mg/kg every 2 weeks (70 weeks)	Placebo: Human Albumin 0.25% 4 mL/kg or 2 mL/kg; every 2weeks (70 weeks)	Patient safety C0001	Frequency of immediate and delayed serious and non-serious adverse events	Baxter Healthcare Corporation
					Patient safety C0002	Frequency of immediate and delayed adverse events for different dosing and administration schemes
					Patient safety C0008	Frequency, severity and duration of immediate and delayed adverse events of IVIG and comparators
Relkin 2009	Prospective  interventional dose finding study	8 patients with mild-to-moderate Alzheimer Disease	one of four IVIg (Gammagard S/D) doses (0.4 g/kg/2 weeks, 0.4 g/kg/week, 1 g/kg/2 weeks and 2 g/kg/4 weeks) (6 months + 9 months)	None	Patient safety C0001	Frequency of immediate and delayed serious and non-serious adverse events	Public and Baxter Bioscience Corporation
					Patient safety C0002	Frequency of immediate and delayed adverse events for different dosing and administration schemes

 

Appendix 3

Excluded studies

Table A3.1: Characteristics of unpublished studies, randomized controlled studies (see Appendix 5 for more details).

Reference	Last update	Study design	Participants	Intervention (duration)	Control	SAF issues	SAF outcome measure	Funding
NCT00299988	2010	phase 2 RCT	24 patients with mild-to-moderate Alzheimer Disease	one of four doses of IVIg (from 0·2 g/kg every 2 weeks to 0·8 g/kg  every month) (6 months)	Placebo	Patient safety C0001	Frequency of immediate and delayed serious and non-serious adverse events	Public, Baxter BioScience
						Patient safety C0002	Frequency of immediate and delayed adverse events for different dosing and administration schemes
						Patient safety C0008	Frequency, severity and duration of immediate and delayed adverse events of IVIG and comparators

 

Table A3.2: Characteristics of unpublished studies, other designs (see Appendix 5 for more details).

Reference	Last update	Study design	Participants	Intervention (duration)	Control	SAF issues	SAF outcome measure	Funding
Kountouris 2000	2000	Open label, non-randomized controlled tria	16 patients with Alzheimer Disease	IVIg (Octagam) 0,2 g/Kg + piracetam (12 months)	Piracetam	None	None	Not reported
Papatriantafyllou 2006	2006	Uncontrolled longitudinal study	6 patients with mild-to-moderate Alzheimer Disease	total dose of 0.4g/Kg IVIG in three consecutive days every 4 weeks (6 months)	None	None	None	Not reported
Hara 2011	2011	Uncontrolled longitudinal study	10 patients with Alzheimer Disease	IVIG (5.5-62.3 months)	None	None	None	Not reported
Kondo 2011	2011	Uncontrolled longitudinal study	4 patients with Alzheimer Disease	0.4 g/kg of IVIg for 3 consecutive days every month for 3 months	None	Patient safety C0001	Frequency of immediate and delayed serious and non-serious adverse events	Not reported
Rovira 2011	2011	Open label pilot uncontrolled longitudinal study	4 patients with mild-to-moderate Alzheimer Disease	0.5 g/kg of IVIG (Flebogamma DIF, Grifols) every 2 weeks (6 months)	None	Patient safety C0001	Frequency of immediate and delayed serious and non-serious adverse events	Not reported
Relkin 2012 (open extension of NCT00299988)	2012	12 month open label extension of a Phase II, double blind placebo controlled study	16 patients with mild-to-moderate Alzheimer Disease	IVIg (Gammagard, Baxter) 0.4g/ kg/2 weeks (36 months)	None	None	None	Not reported

 

Table A3.3: Characteristics of terminated studies (see Appendix 5 for more details).

Reference	Last update	Study design	Participants	Intervention (duration)	Control	Funding
NCT01524887	2013 The study was terminated without enrol any patient because the first Phase 3 did not demonstrate efficacy on the co-primary endpoints	phase 3 RCT	patients with mild-to-moderate AD	Experimental: IVIG, 10% at Dose A (high dose) or Dose B (low dose) (18 months)	Placebo	Baxter Healthcare Corporation
NCT01736579	2013 The study was terminated after enrolment of 8 patients  because the first Phase 3 did not demonstrate efficacy on the co-primary endpoints	open label extension previous study (NCT00818662)	patients with mild-to-moderate AD	IVIG (Gammagard Liquid) 200 mg or 400 mg/kg every 2 weeks (3 years)	None	Baxter Healthcare Corporation

 

Table A3.4: Characteristics of ongoing studies.

Reference	Study design	Participants	Intervention (duration)	Control	SAF issues	SAF outcome measure	Funding
NCT01300728 (estimated completion November 2014)	phase 2 RCT	50 patients with MCI	IVIG (NewGam) at 0.4 g/kg every 14 days for a total of five infusions (two months)	Placebo	Patient safety C0001	Frequency of immediate and delayed serious and non-serious adverse events	Sutter Health
					Patient safety C0008	Frequency, severity and duration of immediate and delayed adverse events of IVIG and comparators
NCT01561053 (estimated completion December 2016)	phase 2/3 RCT	350 patients with mild-to-moderate Alzheimer Disease	Plasmapheresis alone or with infusion of 20% albumin and IVIG high dose or low dose (14 months)	Sham procedure	Patient safety C0001	Frequency of immediate and delayed serious and non-serious adverse events	Instituto Grifols, S.A.
					Patient safety C0002	Frequency of immediate and delayed adverse events for different dosing and administration schemes
					Patient safety C0008	Frequency, severity and duration of immediate and delayed adverse events of IVIG and comparators

 

Appendix 4

State of development of research on safety of IVIG

To describe the stage of development of current and future research on safety on IVIG for MCI and AD we tabled the studies against the evidence profile.

Available evidence

Comparative data about immediate and delayed adverse events of IVIG are available on patients with mild-to-moderate AD from one phase 1 RCT (16 patients), one phase 2 RCT (58 patients) and one phase 3 RCT (383 patients). The remaining two prospective interventional non-controlled studies on a total of 13 patients add very little information.

Upcoming evidence

Three RCTs will be able to add comparative data about immediate and delayed adverse events of IVIg – according to different dosing and administration schemes – for few hundreds of patients. The remaining prospective interventional non-controlled studies will add very little information.

Table A4.1: Stage of development of research on safety on IVIG for MCI and AD.

IVIg for MCI and AD
Issue	Outcome measure			Available evidence	Upcoming evidence
Patient safety [C0001]	Frequency of immediate and delayed serious and non-serious adverse events at any time			3 interventional prospective non-controlled studies: Dodel 2004, Relkin 2009 (13 pts) 3 RCTs: Arai 2014 (16 pts), Dodel 2013 (58 pts) , NCT00818662 (383 pts)	3 interventional prospective non-controlled studies: Kondo 2011, Rovira 2011, Relkin 2012 (24 pts) 3 RCTs: NCT00299988 (24 pts), , NCT01300728 (50 pts), NCT01561053 (350 pts)
Patient safety [C0002]	Frequency of immediate and delayed adverse events for different dosing and administration schemes at any time			1 before-and-after study: Relkin 2009 (8 pts) 3 RCTs: Arai 2014 (16 pts), Dodel 2013 (58 pts); NCT00818662 (383 pts)	2 RCTs: NCT00299988 (24 pts), NCT01561053 (350 pts)
Patient safety [C008]	Frequency, severity and duration of immediate and delayed adverse events of IVIg and comparators at any time			3 RCTs: Arai 2014 (16 pts), Dodel 2013 (58 pts); NCT00818662 (383 pts)	3 RCTs: NCT00299988 (24 pts), NCT01300728 (50 pts), NCT01561053 (350 pts)
Patient safety [C0007]	Presence/absence of interference between drugs at any time			None	-

 

Appendix 5

Characteristics of included studies

Randomized controlled trials

Study title: NCT00818662

Study characteristics

Study design: 'A Randomized, Double-Blind, Placebo-Controlled, Two Dose Arm, Parallel Study of the Safety and Effectiveness of Immune Globulin Intravenous (Human), 10% (IGIV, 10%) for the Treatment of Mild-to-Moderate Alzheimer´s Disease'

Study Registration number: NCT00818662 (Last access December 5, 2014), study ID 160701

Country: USA & Canada

Centre: Multicentre, 44 locations

Ethics Committee Approval: health authorities in the above countries

Sponsor: Baxter Healthcare Corporation

Study period (study start, study end): December 2008 to December 2012

Patient characteristics

Patients with mild-to-moderate Alzheimer's disease Age of patients 50 to 89 Sex: Both sexes (M/F unclear) Disease severity:  mild-to-moderate (as stated in the title, see above), and 'as determined by a Mini Mental State Examination (MMSE) score of 16 - 26 inclusive' (inclusion criterion) AD therapy (cholinesterase inhibitor; memantine): ' On stable doses of FDA approved AD medication(s) for at least 3 months prior to screening. These medications must be continued throughout this study.' (inclusion criterion)

Intervention

IVIG (Gammagard Liquid) 200 mg or 400 mg/kg every 2 weeks (70 weeks)

Control

Placebo: Human Albumin 0.25% 4 mL/kg; solution infused at 4 mL/kg/2weeks or 2 mL/kg solution infused at 2 mL/kg/2weeks (70 weeks)

Outcomes

Cognitive functions measured by ADAS-Cog Activities of daily living measured by ADCS-ADL

Flow of patients

No of patients enrolled: 702 participants enrolled; 308 were screen failures; 4 were discontinued before randomization; and 7 were withdrawn after randomization, but prior to receiving investigational product. Therefore 383 participants were randomized, 262 assigned to intervention group (127 to 400 mg/kg regimen; 135 to 200 mg/kg regimen), 121 to placebo (58 to 4 mL/kg  regimen; 63 to 2 mL/kg  regimen); 302 completed the study: 206 assigned to intervention group (104 to 400 mg/kg regimen; 102 to 200 mg/kg regimen), 96 to placebo (49 to 4 mL/kg  regimen; 47 to 2 mL/kg  regimen).

Number of analysed patients: 302 available for effectiveness data, 383 for safety data;. Results unpuplished and posted in clinicaltrial.gov record.

Author Disclosure (Conflict of interest): Not applicable 

 

Study title: Arai 2014

Study characteristics

Study design: multiple dose, randomised, placebo-controlled trial

Study Registration number: not reported

Country: Japan

Centre: 5 research centres in Japan

Ethics Committee Approval: Not reported (Quote „This study was conducted in accordance with the applicable laws and regulations, including but not limited to the International Conference on Harmonization Guidelines for Good Clinical Practice, the ethical principles that have their origins in the Declaration of Helsinki, and Japan Good Clinical Practice. The institutional review board of each organization reviewed and approved the protocol and the informed consent form before any of the patients were enrolled.“

Sponsor: Not reported.

Study period (study start, study end): Not reported

Patient characteristics

Patients with mild-to-moderate Alzheimer’s disease Age of patients: Intervention groups 72.9 (9.2) years, placebo group 71.5 (11.3) years Sex: Intervention groups 9F/3M, Placebo group 4F/0M Disease severity:  MMS score of 16-26, modified Hachinski-Rosen score of less than 5 (as stated in inclusion criteria) AD therapy (cholinesterase inhibitor; memantine): Quote „Any therapy appropriate to the subject’s condition was permitted during the study. Concomitant medications with the potential to affect cognition, other than cholinesterase inhibitors and/or memantine, were to be maintained on a stable dose regimen for 30 days prior to the baseline evaluations. This included injectable medications such as anxiolytics, sedatives, hypnotics, antipsychotics, antidepressants, over-thecounter sleeping aids, anti-allergy medications, thyroid supplements, and vitamin B12 supplements. The use of cholinesterase inhibitors for the symptomatic treatment of AD was allowed when the following conditions were met: (i) the subject’s dose regimen had been stable for 120 days prior to baseline; (ii) the subject was free of significant side effects attributable to such drugs; and (iii) the subject and caregiver agreed that, barring unforeseen circumstances, they would continue the advised regimen for the duration of the trial. In contrast, subjects who discontinued the use of cholinesterase inhibitors and/or memantine within 60 days of baseline were excluded from the trial“. The use of these drugs was not specified.

Intervention

One of two doses of intravenous immunoglobulin (0·2 g/kg, 0·4 g/kg) every 2 weeks (12 weeks)

Control

placebo (50-mL 0.25% human albumin solution (25% human albumin in a sterile nonpyrogenic formation for intravenous injection, mixed with sterile physiological saline (1:99)) every 2 weeks

Outcomes

safety and tolerability including adverse events (AE), vital signs, physical and neurological examinations, 12-lead electrocardiogram, clinical laboratory evaluations, and brain MRI scans Other: MMSE

Flow of patients

No of patients enrolled: assessed for eligibility not reported, 16 randomised, all treated, 12 assigned to intervention groups, 4 to placebo

Number of analysed patients 12 per protocol/12 ITT analysis in the intervention group, 4 per protocol/4 ITT analysis in the placebo group.

Author Disclosure (Conflict of interest) Yes, p. 165 (Quote “All authors declare that they have no conflicts of interest associated with this manuscript).

 

Study title: Dodel 2013

Study characteristics

Study design: Phase 2, dose finding, block randomised, placebo-controlled trial

Study Registration number: ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759)

Country: USA & Germany

Centre: Hospitals, research centres and private clinics, 5 in Germany, seven in the USA

Ethics Committee Approval: Yes, by each site's ethics comitteee and the regulatory authorities (FDA and Paul-Ehrlich Institute)

Sponsor: Octapharma AG.

Study period (study start, study end): February 2009 to March, 2010

Patient characteristics

Patients with mild-to-moderate Alzheimer’s disease Age of patients: Intervention group 69.4(7.3) years, placebo group 72.0(10.2) years Sex: Intervention group 15F/26M, Placebo group 9F/5M Disease severity:  MMS score of 16-26, modified Hachinski-Rosen score of less than 5 (as stated in inclusion criteria) AD therapy (cholinesterase inhibitor; memantine): 'Patients had to have been taking a stable dose of an approved Alzheimer’s disease drug for at least 3 monthsbefore screening; use reported in Table 1: intervention group 36(88%), Placebo group 11(79%)

Intervention

One of three doses of intravenous immunoglobulin (0·2 g/kg, 0·5 g/kg, or 0·8 g/kg) every 4 weeks, or half of that dose (0·1 g/kg, 0·25 g/kg, or 0·4 g/kg) every 2 weeks (24 weeks)

Control

placebo (0·9% isotonic sodium chloride) every 4 weeks or every 2 weeks

Outcomes

Cognitive functions measured by ADAS-Cog, CDR-GS Other: MMSE Activities of daily living measured by ADCS-ADL Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42) Variation of imaging signs (change in ventricular volumetric as measured by MRI)

Flow of patients

No of patients enrolled: 89 assessed for eligibility, 58 randomised, 2 not treated, 42 assigned to intervention group, 14 to placebo

Number of analysed patients 36 per protocol/41 ITT analysis in the intervention group, 9 per protocol/14 ITT analysis in the placebo group.

Author Disclosure (Conflict of interest) Yes, p. 242-243

 

Other designs (interventional prospective non-controlled studies study)

Study title: Dodel 2004

Study characteristics

Study design Pilot interventional prospective non-controlled study

Study Registration number: Not reported in the paper

Country: Germany

Centre: Unclear; ' Six individuals were recruited from specialised outpatient clinics for cognitive disorders'

Ethics Committee Approval: Yes, ' by the local ethical committee of the Philipps-University, Marburg'

Sponsor: 'supported  in part by the Alzheimer Forschungsinitiative (grant: 00806), Germany'; ' Octapharma (Lagenfeld, Germany) provided the intravenous immunoglobulins and Eli Lilly and Company (Indianapolis, USA) provided the Ab antibodies for this study.'

Study period (study start, study end): Not reported in the paper

Patient characteristics

Patient's with Alzheimer's disease (4 mild-to-moderate; 1 moderate-to-severe) Age of patients: 55-64 years Sex: 3M/2F Disease severity: Unclear AD therapy (cholinesterase inhibitor; memantine): 4 participants on Donepezil 10mg, 1 on Rivastigmine 12mg

Intervention

IVIG (OctagamH) 0.4 g/kg on three consecutive days every 4 weeks (6 months)

Control

none

Outcomes

Cognitive functions measured by ADAS-Cog Other: MMSE, CERAD neuropsychological test battery Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)

Flow of patients

No of patients enrolled: 6

Number of analysed patients:5, 1 refused to get a lumbar puncture at the end of study

Author Disclosure (Conflict of interest): Not clearly stated

 

Study title Relkin 2009

Study characteristics

Study design: Prospective interventional non-controlled 6 months IVIg dose ranging study, followed by a 3 months washout period, and then extension of 9 months of IVIg

Study Registration number: Not reported in the paper

Country: USA

Centre: Unclear (see below)

Ethics Committee Approval: Yes, ' by the Weill Cornell Institutional Review Board (IRB) and the Scientific Advisory Committee of the Weill Cornell General Clinical Research Center (GCRC)'

Sponsor: ‘in part, by the General Clinical Research Center at the Weill Medical College of Cornell University, NIH/NCRR Grant M01 RR00047. Additional financial supportwas provided by Baxter Bioscience Corporation, by NIH grant AG-021033, and the Stern Family Fund (MW) as well as the gifts from the Hoyt, Chen, and Koplow families (NR). IVIg for the study was also supplied by Baxter Bioscience Corporation.'

Study period (study start, study end): Not reported in paper

Patient characteristics

Patients with mild-to-moderate Alzheimer's disease Age of patients: 67 to 86 years (mean 74.3) Sex: 1M/7F Disease severity: mild, 'MMSE scores ranged from 20 to 29 (mean 23.5)? AD therapy (cholinesterase inhibitor; memantine): ' All subjects were receiving stable doses of a cholinesterase inhibitor and in some cases memantine for at least 3 months prior to enrolling in the study.'

Intervention

one of four IVIG (Gammagard S/D) doses (0.4 g/kg/2 weeks, 0.4 g/kg/week, 1 g/kg/2 weeks and 2 g/kg/4 weeks) (6 months + 9 months)

Control

none

Outcomes

Cognitive functions measured by MMSE Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)

Flow of patients

No of patients enrolled: 8, 2 in each dose group

Number of analysed patients: 8, 2 in each dose group

Author Disclosure (Conflict of interest): Marc E.Weksler, Paul Szabo, and Norman R. Relkin have received grants for research from Baxter Bioscience Corporation.

 

 

Characteristics of excluded studies

Published studies

Study title: Devi 2008

Study characteristics

Study design Observational retrospective study

Study Registration number Not applicable

Country: USA

Centre: Not clearly reported, probably  Lenox Hill Hospital, New York (see below)

Ethics Committee Approval: Yes, ' institutional review board of Lenox Hill Hospital in New York, New York'

Sponsor: 'This study did not have a sponsor.'

Study period (study start, study end): Not reported

 

Patient characteristics

Patients with Alzheimer's disease Age of patients 74 ±7.5 Sex 5M/5F Disease severity: Unclear  AD therapy (cholinesterase inhibitor; memantine): Not reported

Intervention

IVIG 0.4 g/kg every 2 weeks (3-6 months)

Control

none

Outcomes

Cognitive functions measured by WAIS, WMS, Boston

Flow of patients

No of patients enrolled.  Not applicable

Number of analysed patients 18 recieved IVIgs, 10 analysed

Author Disclosure (Conflict of interest): ‘The editor in chief has reviewed the conflict of interest checklist provided by the author and has determined that none of the authors have any financial or any other kind of personal conflicts with this letter.’

 

Unpublished studies.

Randomized controlled trials

Study title: NCT00299988 2010

Study characteristics

Study design: 'A Placebo-controlled, Randomized, Double-Blind Phase II Clinical Study of Gammagard Intravenous Immunoglobulin (IVIg) for Treatment of Mild to Moderate Alzheimer's Disease'

Study Registration number: NCT00299988 (Last access September 18, 2014), study ID 0512008265

Country: USA

Centre: Unclear

Ethics Committee Approval: United States Institutional Review Board

Sponsor: Weill Medical College of Cornell University, Baxter BioScience, National Institutes of Health (NIH)

Study period (study start, study end): February 2006 to April 2010

Patient characteristics

Patients wth mild-to-moderate Alzheimer's disease Age of patients. 50 and older Sex: Both Disease severity: mild to moderate (as stated in the title, see above), and 'as determined by a Mini Mental State Examination (MMSE) score of 14 - 26 inclusive' (inclusion criterion) AD therapy (cholinesterase inhibitor; memantine): 'On stable doses of approved AD medications for at least 3 months.' (inclusion criterion ,details not provided)

Intervention

one of four doses of IVIG Gammagard (from 0•2 g/kg every 2 weeks to 0•8 g/kg  every month) (6 months)

Control

placebo

Outcomes

Cognitive functions measured by ADAS-Cog Other: ADCS-CGIC Activities of daily living measured by ADCS-ADL Behavioural changes measured by Neuropsychiatric Inventory (NPI) Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42) Variation of imaging signs (change in SUVR at PIB-PET) Generic health related quality of life Disease specific health related quality of life Activities of daily living measured by ADCS-ADL Behavioural changes measured by Neuropsychiatric Inventory (NPI) Generic health related quality of life Disease specific health related quality of life

Flow of patients

No of patients enrolled: Estimated enrollment 24

Number of analysed patients. Not applicable, press release and publication documented, but no results posted in clinical.gov record.

Author Disclosure (Conflict of interest): Not applicable

 

Other designs

Study title: Kountouris 2000

Study characteristics

Study design: Open label, non-randomized controlled  trial

Study Registration number: Not reported

Country: Greece

Centre: Unclear, Diagnostic Neurological Center, Michalakopoulou 45, 11528 Athens Greece?

Ethics Committee Approval: Not reported

Sponsor: Not reported

Study period (study start, study end): Not reported

Patient characteristics

Patients with Alzheimer's disease Age of patients. Not reported Sex: Not reported Disease severity:  'at the initial faze of the disease' AD therapy (cholinesterase inhibitor; memantine): Not reported. ' Both groups received 140 g of peracetam for the 1 year,

Intervention

IVIgG (Octagam) 0,2 g/Kg + piracetam (12 months)

Control

Piracetam

Outcomes

Cognitive functions measured by MMSE

Flow of patients

No of patients enrolled: 16, 8 in each group

Number of analysed patients. Not spceifically reported

Author Disclosure (Conflict of interest): Unclear.  Octagam von OCTA farma A.G. provided the treatment?

 

Study title: Papatriantafyllou 2006

Study characteristics

Study design: A pilot, uncontrolled longitudinal study

Study Registration number: Not reported

Country: Greece

Centre: Unclear, Memory Clinic, Neurology Department, General Hospital of Athens?

Ethics Committee Approval: Unclear

Sponsor: Unclear

Study period (study start, study end): Unclear

Patient characteristics

Patients with mild-to-moderate Alzheimer's disease Age of patients: 55–78 Sex: 3M/3F Disease severity:   Mini Mental State Examination scores 14—24 AD therapy (cholinesterase inhibitor; memantine): ' The patients were allowed to keep their previous medication which was steady for the last six months.'

Intervention

total dose of 0.4g/Kg IVIG in three consecutive days every 4 weeks (6 months)

Control

none

Outcomes

Cognitive functions measured by MMSE

Flow of patients

No of patients enrolled: 6

Number of analysed patients: 5, reasons for withdrawal/drop-out not reported.

Author Disclosure (Conflict of interest): None, disclosed by all authors

 

Study title: Hara 2011

Study characteristics

Study design: Uncontrolled longitudinal study

Study Registration number: Not reported

Country: USA

Centre: Shankle Clinic, Newport Beach, California?

Ethics Committee Approval: Not reported

Sponsor: Not reported

Study period (study start, study end): Not reported

Patient characteristics

Patients with Alzheimer's disease Age of patients: Not reported Sex: Not reported Disease severity: Not reported AD therapy (cholinesterase inhibitor; memantine): ' All patients also received Exelon and Namenda at all times.'

Intervention

IVIG (5.5-62.3 months)

Control

none

Outcomes

Cognitive functions measured by Memory Performance Index, and the Functional Assessment Staging test

Flow of patients

No of patients enrolled: 17 Patients (10 Alzheimer’s disease, 4 Lewy body disease and 3 mixed Alzheimer’s disease)

Number of analysed patients.8/17 for cognitive, 16/17 for functional tests, 8/17 for FAST staging

Author Disclosure (Conflict of interest): Not reported

 

Study title: Kondo 2011

Study characteristics

Study design: Uncontrolled longitudinal study

Study Registration number: Not reported

Country: Japan

Centre: Unclear

Ethics Committee Approval: Not reported

Sponsor: Not reported

Study period (study start, study end): Not reported

Patient characteristics

Patient's with Alzheimer's disease Age of patients: Not reported Sex: Not reported Disease severity:  Not reported AD therapy (cholinesterase inhibitor; memantine): Not reported

Intervention

0.4 g/kg of IVIg for 3 consecutive days every month for 3 months

Control

none

Outcomes

Cognitive functions measured by MMSE

Flow of patients

No of patients enrolled: 4

Number of analysed patients. 4, full data for 3, one withrew because of generalized seizure after the first session

Author Disclosure (Conflict of interest): Unclear

 

Study title: Rovira 2011

Study characteristics

Study design: Single centre, open label pilot uncontrolled longitudinal study

Study Registration number: Not reported

Country: Spain

Centre: Single, unclear

Ethics Committee Approval: Not reported

Sponsor: Not reported

Study period (study start, study end): Not reported

Patient characteristics

Patients with mild-to-moderate Alzheimer's disease Age of patients: Not reported Sex: Not reported Disease severity:  Mild to moderate AD therapy (cholinesterase inhibitor; memantine): ' receiving stable donepezil treatment who previously had participated in a proof-of-concept study on plasmapheresis with 5% Human Albumin Grifols'

Intervention

0.5 g/kg of IVIg (Flebogamma DIF, Grifols) every 2 weeks (6 months)

Control

none

Outcomes

Cognitive functions measured by ADAS-Cog, CDR-GS, MMSE

Flow of patients

No of patients enrolled: 4

Number of analysed patients.4

Author Disclosure (Conflict of interest): Unclear

 

Study title: Relkin 2012 (open extension of NCT00299988)

Study characteristics

Study design: 12 month open label extension of a Phase II, double blind placebo controlled study

Study Registration number: original study NCT00299988

Country: USA

Centre: Unclear

Ethics Committee Approval: Institution Review Bord;  'an IRB-approved extension protocol'

Sponsor: Unclear

Study period (study start, study end): Beginning at post-enrollment month 18

Patient characteristics

Patients with mild-to-moderate Alzheimer's disease Age of patients: supposedly as in  NCT00299988; 50 and older Sex: supposedly as in  NCT00299988; Both Disease severity: supposedly as in  NCT00299988; mild to moderate (as stated in the title, see above), and 'as determined by a Mini Mental State Examination (MMSE) score of 14 - 26 inclusive' (inclusion criterion) AD therapy (cholinesterase inhibitor; memantine): supposedly as in  NCT00299988; 'On stable doses of approved AD medications for at least 3 months.' (inclusion criterion, details not provided)

Intervention

IVIG (Gammagard, Baxter) 0.4g/ kg/2 weeks (36 months)

Control

none

Outcomes

Cognitive functions measured by ADAS-Cog, ADCS-CGIC Activities of daily living measured by ADCS-ADL Behavioural changes measured by Neuropsychiatric Inventory (NPI) Generic health related quality of life Disease specific health related quality of life

Flow of patients

No of patients enrolled: 16, 5 in placebo group; 11 in intervention group

Number of analysed patients: 16? Unclear

Author Disclosure (Conflict of interest): Unclear

 

Terminated studies

Randomized controlled trials

Study title: NCT01524887 2013

Study characteristics

Study design: ' A Phase 3 Randomized, Double-blind, Placebo-Controlled Study of the Safety and Effectiveness of Immune Globulin Intravenous (Human), 10% Solution (IGIV, 10%) for the Treatment of Mild to Moderate Alzheimer's Disease'

Study Registration number: NCT01524887 (Last access September 18, 2014)

Country: USA, Australia, Belgium, Canada, Japan, Poland, Spain, United Kingdom

Centre: Multiple (70 in total)

Ethics Committee Approval: Yes, by health authorities in respective countries

Sponsor: Baxter Healthcare Corporation

Study period (study start, study end): January 2012- March 2015

Patient characteristics

Age of patients: 50 to 89 years Sex: Both, M/F not reported Disease severity:  Mild to moderate, as stated in the title (see above), and inclusion criterion 'Dementia of mild to moderate severity defined as Mini-Mental State Examination (MMSE) 16-26 inclusive at screening' AD therapy (cholinesterase inhibitor; memantine): As stated in inclusion criterion: ' On stable doses of AD medication(s) for at least 12 weeks prior to screening. These medications must be continued throughout this study.'

Intervention

IVIG (unspecified High and Low doses) (18 months)

Control

Placebo

Flow of patients

No of patients enrolled: Estimated enrollment 530

Number of analysed patients: 'The study was terminated because the first Phase 3 did not demonstrate efficacy on the co-primary endpoints. The known safety profile remained unchanged.'

Author Disclosure (Conflict of interest): N/A

 

Other designs

Study title: NCT01736579 2013

Study characteristics

Study design: Interventional, parallel groups, non randomized, open label study (' A Study of the Long-Term Safety and Efficacy of Immune Globulin Intravenous (Human), 10% Solution (IGIV, 10%) in Mild to Moderate Alzheimer´s Disease')

Study Registration number: NCT01736579 (Last access September 18, 2014)

Country: USA & Canada

Centre: Unclear

Ethics Committee Approval: Yes, by health authorities in respective countries

Sponsor: Baxter Healthcare Corporation

Study period (study start, study end): November 2012 to April 2016 (final data collection date)

Patient characteristics

Age of patients: 51 and older Sex: Both Disease severity: mild to moderate (as stated in the title, see above) AD therapy (cholinesterase inhibitor; memantine): Unclear

Intervention

IVIg IVIG (Gammagard Liquid) 200 mg or 400 mg/kg every 2 weeks (3 years)

Control

None

Flow of patients

No of patients enrolled: 6

Number of analysed patients. N/A ' The study was terminated because the first Phase 3 did not demonstrate efficacy on the co-primary endpoints. The known safety profile remained unchanged.'

Author Disclosure (Conflict of interest). N/A

 

Appendix 6

Search strategy 

Database: Pubmed

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014*
1	"Immunoglobulins, Intravenous"[Mesh]	9526
2	venimmun OR "modified immune globulin" OR "ivig" OR "endobulin" OR "alpha globin" OR venoglobulin OR sandoglobulin OR "intraglobin" OR "globulin n" OR "privigen" OR "gamunex" OR "gammagard" OR "gamimmune" OR "gamimune" OR "flebogamma dif" OR "intravenous ig" OR "iveegam" OR "immunoglobulins iv" OR "immunoglobulins ivig" OR "immunoglobulins ivigs" OR "iv immunoglobulin" OR "iv immunoglobulins"[All Fields]	15230
3	1 OR 2	15230
4	"Mild Cognitive Impairment"[Mesh]	1647
5	"Alzheimer Disease"[Mesh]	64256
6	“Mild Cognitive Impairment"[title/abstract] OR dementia*[Title/Abstract] OR Alzheimer*[Title/Abstract] OR MCI[Abstract/Title]	137580
7	4 OR 5 OR 6	144293
8	3 AND 7	82	24

*search re-run with the same date limit in February 18 2015, in order to capture references previously not indexed  with Mesh terms.

 

Database: EMBASE

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	‘immunoglobulin'/exp/dd_iv	22907
2	'endobulin':ab,ti OR 'ivig':ab,ti OR 'alpha globin':ab,ti OR venoglobulin:ab,ti OR sandoglobulin:ab,ti OR 'intraglobin':ab,ti OR 'globulin n':ab,ti OR 'privigen':ab,ti OR 'gamunex':ab,ti OR 'gammagard':ab,ti OR 'gamimmune':ab,ti OR 'gamimune':ab,ti OR 'flebogamma dif':ab,ti OR 'intravenous ig':ab,ti OR 'iveegam':ab,ti OR 'immunoglobulins iv':ab,ti OR 'immunoglobulins ivig':ab,ti OR 'immunoglobulins ivigs':ab,ti OR 'iv immunoglobulin':ab,ti OR 'iv immunoglobulins':ab,ti OR 'intravenous antibodies':ab,ti OR 'intravenous antibody':ab,ti OR 'intravenous immunoglobulin':ab,ti OR 'intravenous immunoglobulins':ab,ti AND [embase]/lim	14395
3	1 OR 2	31178
4	'dementia'/de OR 'alzheimer disease'/exp OR 'mild cognitive impairment'/exp	173965
5	3 OR 4	359	42

 

Database: Cochrane Central Register of Controlled Trials

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	MeSH descriptor: [Immunoglobulins, Intravenous] explode all trees	616
2	('endobulin':ab,ti or 'ivig':ab,ti or 'alpha globin':ab,ti or venoglobulin:ab,ti or sandoglobulin:ab,ti or 'intraglobin':ab,ti or 'globulin n':ab,ti or 'privigen':ab,ti or 'gamunex':ab,ti or 'gammagard':ab,ti or 'gamimmune':ab,ti or 'gamimune':ab,ti or 'flebogamma dif':ab,ti or 'intravenous ig':ab,ti or 'iveegam':ab,ti or 'immunoglobulins iv':ab,ti or 'immunoglobulins ivig':ab,ti or 'immunoglobulins ivigs':ab,ti or 'iv immunoglobulin':ab,ti or 'iv immunoglobulins':ab,ti or 'intravenous antibodies':ab,ti or 'intravenous antibody':ab,ti or 'intravenous immunoglobulin':ab,ti or 'intravenous immunoglobulins':ab,ti)	2379
3	1 OR 2	2467
4	MeSH descriptor: [Alzheimer Disease] explode all trees	2065
5	MeSH descriptor: [Mild Cognitive Impairment] explode all trees	65
6	Alzheimer or "mild cognitive impairment" or "mild cognitive impairments"	5163
7	4 OR 5 OR 6	5198
8	3 AND 7	10	5

 

Database: Lilacs, Ibec, Medcarib

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	tw: immunoglobulin* AND (alzheimer* OR dementia OR ”mild cognitive impairment”)	11	0

 

Database: Isi web of Knowledge

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	Topic=(Venimmun OR "modified immune globulin" OR "ivig" OR "endobulin" OR "alpha globin" OR venoglobulin OR sandoglobulin  OR "intraglobin" OR "globulin n" OR "privigen" OR "gamunex" OR "gammagard" OR "gamimmune") OR "gamimune" OR "flebogamma dif" OR "intravenous ig" OR "iveegam" OR "immunoglobulins iv" OR "immunoglobulins ivig" OR "immunoglobulins ivigs" OR "iv immunoglobulin" OR "iv immunoglobulins" OR "intravenous antibodies" OR "intravenous antibody" OR "intravenous immunoglobulin" OR "intravenous immunoglobulin" OR "intravenous immunoglobulins")
2	Topic=(mci[title/abstract] OR "Mild Cognitive Impairments"[title/abstract] OR "Mild Cognitive Impairment"[title/abstract] OR dementia*[Title/Abstract] OR alzheimer*[Title/Abstract])
3	1 AND 2	138	30

 

Clinical Registers

ALOIS: a comprehensive register of dementia studies

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunlobulin*	7	0

metaRegister of Controlled Trials (mRCT), including ISRCTN (International Standard Randomised Controlled Trial Number Register)

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	(immunoglobulin*) and (Alzheimer or dementia or “mild cognitive impairment”)	2	0

ClinicalTrials.gov

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	(alzheimer* OR dementia* OR "mild cognitive impairment") AND ( immunoglobulin*)	51	21

NIH Clinical research studies

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunoglobulin* and Alzheimer	0	0

EU Clinical Trials Register website

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunoglobulin* and Alzheimer	4	0

International Clinical Trials Register Platform (ICTRP)

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunoglobulin* and Alzheimer	4	0

Websites of the regulatory agencies

US Food and Drug Administration-MedWatch

http://www.fda.gov/Safety/MedWatch/default.htm:

Search terms: (Immunoglobulin OR Immunoglobulins OR Immune globulin OR Gammagard OR Octagam OR Newgam, OR Flebogamma) AND (dementia OR Alzheimer OR mild)

Search Date 25/02/2014: 0 documents.

Search Date 15/12/2014: 0 documents.

 

European Medicines Agency

http://www.adrreports.eu/IT/index.html

Search by topic: Immunoglobulin, Gammagard, Octagam, Newgam, Flebogamma

Search Date: 25/02/2014: 0 document

Search Date 15/12/2014: 0 document

 

Australian Adverse Drug Reactions Bulletin

http://www.tga.gov.au/safety/ews-monitoring.htm

Search by topic: Immunoglobulin, Gammagard, Octagam, Newgam, Flebogamma

Search Date: 25/02/2014: 2 documents, 0 relevant

Search Date 15/12/2014: 2 documents (same as above), 0 relevant

 

UK Medicines and Healthcare products Regulatory Agency (MHRA) pharmacovigilance and drug safety updates

http://www.mhra.gov.uk/Safetyinformation/index.htm)

Search terms: Immunoglobulin AND Alzheimer OR dementia OR mild cognitive.

Search Date: 25/02/2014: 7 documents retrieved; 0 relevant

Search Date: 15/12/2014: 4 documents retrieved; 0 relevant

Appendix 7

Use of Intravenous immunoglobulins for Mild Cognitive Impairment and Alzeheimer’s disease - PROTOCOL

Clinical Effectiveness

Authors: Luca Vignatelli, Luciana Ballini, Susanna Maltoni, Jelena Barbaric, Mirjana Huic, Pernilla Östlund.

Summary

Aim

To determine whether treatment with intravenous immunoglobulins (IVIG) in adults with Mild Cognitive Impairment (MCI) or Alzheimer’s disease (AD) improves clinical outcomes and quality of life, has impact on patients’ satisfaction, hospitalization rate and institutionalization delay compared with current practice.

Secondary objective was to map available evidence against the technology’s evidence profile.

Methods

We performed a systematic review according to Cochrane methodology on evidence from biomedical databases; publicly available clinical trials registers were also searched. Qualitative and quantitative syntheses were done. To assess risk of bias of included RCTs the risk of bias method proposed by the Cochrane Handbook for Systematic Reviews of Interventions was used. Overall quality of evidence for each outcome was assessed and synthesised according to the GRADE approach.

Results

Among the four published clinical studies none met the inclusion criteria. Missing publication was documented for two completed RCTs in subjects with mild-to-moderate AD. One of the two studies {NCT00818662}, a phase 3 double-blind, placebo-controlled, two dose arm RCT, aiming at testing the safety and effectiveness of IVIG for patients with mild-to-moderate AD, had its results posted on a clinical trial register in October 23rd 2014, after completion of this report. The authors and the sponsor had been previously contacted (May 2014) but did not provide any data. As this study, according to decision of Editorial Team, met inclusion criteria, release of this report was postponed in order to include it in the analysis. Available data do not permit an evaluation of the methodology and conduction of the study due to the absence of information posted. Manufacturer was not contacted again to provide more data. The confidence in effect estimate for overall evidence on all considered outcomes is very low, according to GRADE approach. Participants were 383 patients (completing the study: 302) that were randomized to one of two doses of IVIG (Gammagard Liquid 10%, 400 mg/kg bodyweight or 200 mg/kg bodyweight, every two weeks) or one of two doses of placebo (0.25% human albumin solution infused at 4mL/kg or at 2 mL/kg, every two weeks) for 70 weeks. Any important clinical outcomes such as cognitive functions (ADAS-Cog, ADCSC-GIC), activity of daily living (ADCS-ADL) and quality of life (both in patients and caregivers according to QOLAD) did not differ between IVIG and placebo groups.

Two additonal ongoing RCTs have been identified: one including subjects with MCI, and one including subjects with mild-to-moderate AD. These trials are reported to and expected to end in November 2014 and December 2016, respectively. Patients with moderate-to-severe AD are not considered by any study.

Conclusion

We found limited evidence of very low quality suggesting lack of effectiveness of IVIG in adults with mild-to-moderate AD and no evidence for adults with MCI or moderate-to-severe AD. Conclusive evidence from unpublished and ongoing studies are necessary before setting up RCTs on long term effectiveness of IVIG in patients with MCI, mild-to-moderate and moderate-to-severe AD.

Introduction

Background

The Clinical Effectiveness Domains describes the range and size of beneficial health effects expected through the use of the technology {HTA Core Model Handbook Online, Version 1.5}. The two key elements are that effective interventions should be directly compared and studied in patients who are typical of day-to-day health care settings {HTA Core Model Application for Pharmaceuticals, 2.0}.

AD is a chronic neurodegenerative disorder strongly associated with the formation and accumulation of extracellular plaques of amyloid-beta (Aβ) protein in the brain that is followed by synaptic dysfunction, inflammation and eventually neuronal death (Ballard 2011; Silvergleid 2013). It is suggested that IVIG might have beneficial effects on the pathogenic processes of AD (Dodel 2013) and even at the stage of MCI, by interfering positively with metabolism of amyloid β that seems to be reduced in subjects at risk for AD.

The causal chain suggesting a clinical benefit from the use of IVIG for MCI and AD appears as follows:

- amyloid β (Aβ) is the metabolic product of the amyloid precursor protein, an element placed in the normal cell membrane (Ballard 2011; National Institute on Aging 2011);

- abnormal increase of amyloid β in the brain - as beta-amyloid plaques - is probably the first expression of the pathological process that damages neurons in AD (Ballard 2011; National Institute on Aging 2011);

- biomarkers of the metabolism of Amyloid Precursor Protein are amyloid β40, amyloid β42, Anti-Aβ autoantibodies (Ballard 2011; Du 2002); all these products can be measured in cerebrospinal fluid and serum (Buchhave 2012; Dodel 2013; Du 2002; Jack 2013);

- amyloid β metabolism seems to be reduced in patients with AD; in particular it is reported that cerebrospinal fluid and serum amyloid β40 and amyloid β42 could be lower than normal in patients with MCI and AD, and that cerebrospinal fluid and plasma titers of anti–Aβ antibodies are lower in AD patients compared with controls (Jack 2013; Relkin 2009);

- natural polyclonal anti-Aβ autoantibodies are present in normal human blood (Dodel 2002; Weksler 2002);

- it is hypothesised that an immune-mediated amyloid-β degrading pathway may be physiologically present and its actions clinically significant in humans;

- early observations report that after IVIG treatment a significant increase in total anti-Aβ autoantibodies concentration can be produced in the plasma of patients with AD (Dodel 2002; Relkin 2009); peripherally administered antibodies against Aβ can induce a shift of Aβ from the CSF to the blood, thereby reducing the cerebral Aβ burden (the “peripheral sink hypothesis”) and with increased plasma concentration and decreased CSF concentration of Aβ;

- it is hypothesised that IVIG use for passive immunotherapy in AD could slow the disease progression (Dodel 2002; Dodel 2013; Loeffler 2013; Relkin 2009) and use in patients with MCI could avoid or delay the onset of AD.

Objectives

Primary objectives:

1. To assess the effectiveness of IVIG in adults with MCI.
2. To assess the effectiveness of IVIG (alone or in combination with other treatments) in adults with mild-to-moderate AD.
3. To assess the effectiveness of IVIG (alone or in combination with other treatments) in adults with moderate-to-severe AD.

Secondary objectives:

• to map available evidence against the technology’s evidence profile, i.e. the body of evidence needed to demonstrate its effectiveness in the above reported target conditions
• to identify research gaps.

Methodology

Frame

The collection scope is used in this domain.

Technology	Immunoglobulins (IGG) Description Naturally occurring proteins produced by the body’s immune system to combat foreign antigens
Intended use of the technology	Treatment Treatment of Alzheimer’s disease Target condition Alzheimer’s disease Target condition description Alzheimer's disease (AD) or Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. Target population Target population sex: Any. Target population age: elderly. Target population group: Patients who have the target condition. Target population description AD is diagnosed mostly in people over 65 years of age, although there is an early-onset form that can occur much earlier. According to Wikipedia in 2006, there were 26.6 million sufferers worldwide.
Comparison	placebo, not doing anything or Usual supportive care Description There is no MA for IGGs for AD yet and there is no other intervention licensed for use in AD so the comparison would have to be against placebo or best supportive care
Outcomes	Description of aims of technology (TECH) Regulatory status (CUR) Cognitive function (EFF) Harms (SAF) Cost effectiveness compared to alternatives (ECO) Potential impact on plasma derivative market (ORG/Medico-legal) Impact on family and carers (SOC) Appropriateness of use in relation to solidity of evidence(ETH)

Assessment elements

	Topic	Issue	Relevant	Research questions or rationale for irrelevance
D0006	Morbidity	How does the technology affect the progression (or recurrence) of the target condition?	yes	Are IVIG effective in slowing or avoiding progression from Mild Cognitive Impairment to Alzheimer’s disease when compared to placebo? Are IVIG effective in improving biomarkers of progression from Mild Cognitive Impairment to Alzheimer’s disease when compared to placebo? Are IVIG effective in improving imaging markers of progression from Mild Cognitive Impairment to Alzheimer’s disease when compared to placebo? Are IVIG effective in slowing disease progression from mild-to-moderate to moderate-to-severe Alzheimer’s disease (measured with MMSE) when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving biomarkers of progression in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving imaging markers of progression in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving biomarkers of progression in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine? Are IVIG effective in improving imaging markers of progression in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0005	Morbidity	How does the technology affect symptoms and findings (severity, frequency) of the target condition?	yes	Are IVIG effective in improving neuropsychiatric symptoms in patients Mild Cognitive Impairment when compared to placebo? Are IVIG effective in improving behavioural symptoms in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving behavioural symptoms in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0001	Mortality	What is the expected beneficial effect of the intervention on overall mortality?	yes	Are IVIG effective in reducing overall mortality in patients with Mild Cognitive Impairment when compared to placebo? Are IVIG effective in reducing overall mortality in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in reducing overall mortality in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0002	Mortality	What is the expected beneficial effect on the disease-specific mortality?	no	Disease-specific mortality is not a plausible outcome for Alzheimer Disease as death in these patients is expected due to complications and not to Alzheimer's disease itself.
D0003	Mortality	What is the effect of the technology on the mortality due to causes other than the target disease?	no	More relevant for the SAF domain
D0011	Function	What is the effect of the technology on patients’ body functions	yes	Are IVIG effective in improving cognitive functions of patients with Mild Cognitive Impairment when compared to placebo? Are IVIG effective in improving cognitive functions of patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving cognitive functions of patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0016	Function	How does use of the technology affect activities of daily living?	yes	Are IVIG effective in improving activities of daily living of patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving activities of daily living of patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0014	Function	What is the effect of the technology on work ability?	no	Already covered by the assessment of daily activities.
D0015	Function	What is the effect of the technology on return to previous living conditions?	no	This issue is important for diseases with acute or relapsing course. Alzheimer disease has a progressive course.
D0012	Health-related Quality of life	What is the effect of the technology on generic health-related quality of life?	yes	Are IVIG effective in improving generic health-related quality of life of patients with Mild Cognitive Impairment when compared to placebo? Are IVIG effective in improving generic health-related quality of life of patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving generic health-related quality of life of caregivers of patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving generic health-related quality of life of caregivers of patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0013	Health-related Quality of life	What is the effect of the technology on disease specific quality of life?	yes	Are IVIG effective in improving disease specific health-related quality of life of patients with mild-to- moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving disease specific health-related quality of life of caregivers of patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving disease specific health-related quality of life of caregivers of patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0010	Change-in management	How does the technology modify the need for hospitalization?	yes	Does IVIG impact on the need for hospitalization in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Does IVIG impact on the need for institutionalization in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Does IVIG impact on the need for hospitalization in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine? Does IVIG impact on the need for institutionalization in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0023	Change-in management	How does the technology modify the need for other technologies and use of resources?	no	More relevant for the ORG domain
D0029	Benefit-harm balance	What are the overall benefits and harms of the technology in health outcomes?	yes	What are the overall benefits and harms of IVIG in health outcomes of patients with Mild Cognitive Impairment? What are the overall benefits and harms of IVIG in health outcomes of patients with mild-to-moderate Alzheimer’s disease? What are the overall benefits and harms of IVIG in health outcomes of patients with moderate-to-severe Alzheimer’s disease?
D0017	Patient satisfaction	Was the use of the technology worthwhile?	no	Not important

Methodology description

Criteria for considering studies

Types of studies

All published or unpublished full report of randomised controlled trials (RCTs) were considered for inclusion. For unpublished studies we accepted results from publicly available controlled trials’ registers (decision made by Editorial Team). Report on animal models, pre-clinical and biological studies, narrative reviews, editorials, opinions, were excluded.

To establish stage of development of research of the technology, RCTs as well as interventional prospective controlled and uncontrolled studies were searched for.

Types of participants (target population)

Adult (18+ years) patients of any sex who have one of the target conditions:

1. MCI (ICD-9-CM Diagnosis Code 331.83; ICD-10-CM G31.84) as defined by validated criteria.
2. Mild-to-moderate AD (ICD-9-CM Diagnosis Code 331.0; ICD-10-CM G30.9), as defined by validated criteria and with MMSE score between 15 and 26.
3. Moderate-to-severe AD (ICD-9-CM Diagnosis Code 331.0; ICD-10-CM G30.9), as defined by validated criteria and with MMSE score less than or equal to 14.

Types of interventions

IVIG any dose, any regimen, any product, alone or in combination with non-pharmacological interventions, and/or with approved drugs (acetyl cholinesterase inhibitors, memantine).

Types of control treatments

• MCI: placebo, non-pharmacological treatments or no treatment
• Treatment naïve patients with mild-to-moderate AD: placebo, acetyl cholinesterase inhibitors, non-pharmacological treatments or no treatment
• Patients with mild-to-moderate AD treated with acetyl cholinesterase inhibitors: placebo plus acetyl cholinesterase inhibitors or acetyl cholinesterase inhibitors
• Patients with mild-to-moderate AD intolerant to acetyl cholinesterase: placebo and/or non-pharmacological treatment or no treatment.
• Patients with moderate-to-severe AD treated with memantine: placebo plus memantine, non-pharmacological treatments plus memantine, or memantine
• Patients with moderate-to-severe AD intolerant to memantine: placebo and/or non-pharmacological treatment or no treatment.

Types of outcomes and outcome measures

MCI

Primary outcomes (timeframe: 3 years)

• Progression to AD (timeframe: within 3 years) according to available AD validated criteria (NINCDS-ADRDA, ICD, DSM) [Issue domain Morbidity D0006]

Secondary outcomes

• Overall mortality [Issue domain Mortality D0001];
• Cognition improvement (Cognitive functions measured by ADAS-Cog, MMSE, Clinical Dementia Rating, and Global Change scales measured by Clinical Global Impression of Change (CGI-C), Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), Global Deterioration Scale (GDS)) [Issue domain Function D0011];
• Neuropsychiatric symptoms measured by scales (Neuropsychiatric Inventory – NPI - or other validated scales in the target population) [Issue domain Morbidity D0005];
• Generic health related quality of life measured by common scales (SF-36; EQ-5D) [Issue domain Health-related Quality of life D0012].

Other outcomes

• Variation of biomarkers (change of cerebrospinal fluid Aβ1-42; change of serum anti-Aβ autoantibodies) [Issue domain Morbidity D0006];
• Variation of imaging signs (change in standardized uptake value (SUVR) at PIB-PET; change in ventricular volumetric as measured by MRI) [Issue domain Morbidity D0006].

Mild-to-moderate AD

Primary outcomes (timeframe: at least 1 year)

• Progression to moderate-to-severe AD according to MMSE [Issue domain Morbidity D0006];
• Cognitive outcomes changes (Cognitive functions measured by ADAS-Cog or CDR-GS [Issue domain Function D0011];
• Functional ability changes (Activities of daily living measured by DAD, ADCS-ADL or other validated scales in the target population [Issue domain Function D0016];
• Behavioural changes (Neuropsychiatric Inventory - NPI, the Behavioural Pathology in AD Rating Scale  - BEHAVE-AD, and the Behavioural Rating Scale for Dementia -BRSD) (GPC 2013) [Issue domain Morbidity D0005].

Secondary outcomes (timeframe: at least 1 year)

• Overall mortality [Issue domain Mortality D0001];
• Generic health related quality of life measured by common scales (SF-36; EQ-5D) both in patients and caregivers [Issue domain Health-related Quality of life D0012];
• Disease specific health related quality of life scales both in patients (ADRQL, CBS, DCM, DQoL PWB-CIP, QUALID Scale, QOL-AD, QOLAS, DEMQOL) and caregivers (DEMQOL-Proxy-U; Zarit Burden Interview) [Issue domain Health-related Quality of life D0013];
• Hospitalization [Issue domain Change in management D0010];
• Delay on institutionalization [Issue domain Change in management D0010].

Other outcomes

• Variation of biomarkers (change of cerebrospinal fluid Aβ1-42; change of serum anti-Aβ autoantibodies) [Issue domain Morbidity D0006];
• Variation of imaging signs (change in standard uptake value ratio - SUVR) at PIB-PET; change in ventricular volumetric as measured by MRI) [Issue domain Morbidity D0006].

Moderate-to-severe AD

Primary outcomes (timeframe: at least 1 year)

• Cognitive outcomes changes (Cognitive functions measured by SIB, ADAS-Cog, MMSE[Issue domain Function D0011];
• Functional ability changes (Activities of daily living measured by DAD, ADCS-ADL or other validated scales in the target population [Issue domain Function D0016].
• Behavioural changes (Neuropsychiatric Inventory - NPI, the Behavioural Pathology in AD Rating Scale  - BEHAVE-AD, and the Behavioural Rating Scale for Dementia -BRSD) (GPC 2013) [Issue domain Morbidity D0005].

Secondary outcomes (timeframe: at least 1 year)

• Overall mortality [Issue domain Mortality D0001];
• Generic health related quality of life measured by common scales (SF-36; EQ-5D) in caregivers [Issue domain Health-related Quality of life D0012];
• Disease specific health related quality of life scales both in caregivers (DEMQOL-Proxy-U; Zarit Burden Interview) [Issue domain Health-related Quality of life D0013];
• Hospitalization [Issue domain Change in management D0010];
• Delay of institutionalization [Issue domain Change in management D0010].

Other outcomes

• Variation of biomarkers (change of cerebrospinal fluid Aβ1-42; change of serum anti-Aβ autoantibodies) [Issue domain Morbidity D0006];
• Variation of imaging signs (change in SUVR at PIB-PET; change in ventricular volumetric as measured by MRI) [Issue domain Morbidity D0006].

 

Search methods for identification of studies

Electronic searches

The following databases and clinical trials registers were searched:

Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, LILACS, ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group) and national and international trials registers (Australian New Zealand Clinical Trials Register (ANZCTR), http://www.anzctr.org.au/; metaRegister of Controlled Trials (mRCT), http://www.controlled-trials.com/mrct/; ClinicalTrials.gov. www.clinicaltrials.gov/; NIH Clinical Research Studies, http://clinicalstudies.info.nih.gov/; EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/; International Clinical Trials Register Platform (ICTRP), http://www.who.int/ictrp/en/).

Initial search was carried out on February 24^th 2014 and an update was carried out close to the release of the report on December 16^th 2014.

See Appendix 6 for detailed search strategies. The strategy for MEDLINE was adapted to other databases. No language or date of publication restrictions were applied.

Searching other resources. In addition we checked conference proceedings for relevant abstracts, and contact individual researchers working in this field, organizations and pharmaceutical companies to identify additional RCTs, especially those unpublished. We also checked the reference lists of all studies identified by the above methods.

 

Data collection and analysis

Selection of studies

The titles and abstracts of all studies identified by the search were screened independently by two investigators (ASSR). Full text was retrieved of all studies which any investigator considered potentially relevant. Two investigators then identified studies for inclusion or exclusion independently (ASSR). Different selection results were discussed in order to achieve consensus. A third person was involved to resolve discrepancies (AAZ and SBU).

Data extraction and management

A data extraction form was developed and piloted specifically for this review. For each study, data were extracted on: participants (including inclusion and exclusion criteria, baseline investigations, co-treatments); interventions; outcomes; study design; results. For eligible studies, when data on outcomes of interest were missing or incompletely reported investigators contacted the Authors for additional information. For dichotomous outcomes, data extracted were the number of participants with the outcome of interest in each group at each time point. For continuous outcomes, data extracted were the mean and standard deviation (SD) in each group at each time point. If only change-from-baseline data were available, those were extracted.

Assessment of risk of bias of included studies and of overall quality of evidence

To assess risk of bias of included RCTs the risk of bias system proposed by the Cochrane Handbook for Systematic Reviews of Interventions {Higgins et al. 2011} was used. Overall quality of evidence for each outcome was assessed and synthesised according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach {Guyatt 2011a; Balshem 2011; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2013}, and presented in table. This approach specifies four levels of quality:

• High: further research is very unlikely to change our confidence in the estimate of effect;
• Moderate: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimates;
• Low: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate;
• Very low: we are very uncertain about the estimate.

Data synthesis

Quantitative results were expressed as point estimates together with associated 95% confidence intervals (95% CI) and p-values. We had planned, if possible, to carry out a meta-analysis with graphical display of results and assessment of heterogeneity, according to the Cochrane Handbook for Systematic Reviews of Interventions {Higgins et al. 2011}.

Studies used to map available evidence against the technology’s evidence profile, i.e. the body of evidence needed to demonstrate its effectiveness in the above reported target conditions were grouped by target conditions included in this protocol. A descriptive summary of these studies with details about study design, numbers and characteristics of enrolled patients, intervention/s and comparator/s, outcomes, outcomes’ measures and results is provided in tables and plain text format. In order to map available evidence against the technology’s evidence profile, for each research question the results from available evidence and upcoming evidence were charted in order to describe stage of development and to highlight research gaps. Available evidence refer to published or unpublished studies with available data and upcoming evidence refer to unpublished without available data and ongoing studies..

 

Description of studies

Results of the search

The first electronic searches strategy (February 24^th 2014), yielded 515 citations, after removal of duplicates. Of these, 388 were directly excluded, because judged not relevant. Of the remaining 127 citations, none meet our inclusion criteria and were excluded from relative effectiveness assessment (primary objectives). Checking periodically the registers of ongoing trials, the results of one of the RCT {NCT00818662}, tracked on clinical trial registries, were posted on ClinicalTrials.gov by the study sponsor in October 23rd 2014. Thus this study was included (decision by Editorial Team) and remaining the 126 citations excluded. The second electronic search strategy (December 16^th 2014) yielded 71 citations, after removal of duplicates; 70 were excluded, because judged not relevant, and 1 excluded after evaluation of the full text. From the final periodic check of registers of ongoing trials (December 16^th 2014) there was no further status change for included ongoing trials.

See PRISMA study flow diagram in Appendix 1 {Figure A1}.

Excluded studies

The reasons for exclusion of the 128 records were as follows: in vitro /animal studies (n=13); other treatments (n=22); review papers (n=31); comments/editorials/news (n=14); other topics (n=4); studies on the current use of IVIG (n=2); case control studies (n=2); study without data on outcomes (n=1); interventional studies not fulfilling design inclusion criteria (38 citations corresponding to 16 studies). The latter group of 16 studies were found eligible for the evidence mapping against the technology’s evidence profile: 7 studies resulted as completed and unpublished {Hara 2011, Kondo 2011, Kountouris 2000, Papatriantafyllou 2006, Rovira 2011, NCT00299988, Relkin 2012 }, 2 studies are ongoing {NCT01300728, NCT01561053}, 2 studies had been planned but they were terminated prematurely {NCT01524887, NCT01736579}, and 5 studies were published {Arai 2014, Devi 2008, Dodel 2004, Dodel 2013, Relkin 2009}.

Included studies

No studies fitting our inclusion criteria were found.

Included unpublished studies with results posted in clinical trials registers (Editorial Team decision)

The following information refers to data posted by the study sponsor on one trial register (ClinicalTrials.gov) in October 23rd 2014. The Authors and the sponsor were previously contacted (May 2014). They responded but did not provide results. The Authors and the Sponsor were not contacted again. The included RCT {NCT00818662} was a phase 3 double-blind, placebo-controlled, two dose arm study aiming at testing the safety and effectiveness of IVIG for patients with mild-to-moderate AD. Participants were 383 patients (patients completing the study: 302; intention-to-treat population not declared) with probable AD (criteria not reported), with a mini-mental state examination score of 16–26 and age 50–89 years at baseline. Included patients had been taking a stable dose of an approved Alzheimers disease drug for at least 3 months before screening (not reported number of patients on treatment). Participants were randomized to one of two doses of IVIG (Gammagard Liquid 10%, 400 mg/kg bodyweight every two weeks, or 200 mg/kg bodyweight every two weeks) or one of two doses of placebo (0.25% human albumin solution infused at 4 mL/kg every two weeks or at 2 mL/kg every two weeks), for 70 weeks. The randomization ratio was 2:2:1:1. Co-primary outcomes were change from baseline at 18 months in the Alzheimer´s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) and change from baseline at 18 months in the Alzheimer´s Disease Cooperative Study Activities of Daily Living (ADCS-ADL). Other patients important outcomes considered in the study were: change at 9 months in ADAS-Cog, change at 9 months in ADCS-ADL, change at 9 and 18 months in Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCSC-GIC), change at 18 months in the Neuropsychiatric Inventory (NPI), change at 18 months in the Logsdon Quality of Life in Alzheimer's Disease (QOLAD) of patients and caregivers. Other outcomes assessed in the study but not considered in this review were: Modified MiniMental State Examination (3MS), Wechsler Adult Intelligence Scale Revised Digit Span, FAS Verbal Fluency, Animals Category Fluency, Trail Making Test Part A and Part B, Clock Drawing Test. The study - funded by Baxter Healthcare Corporation and conducted in USA and Canada – started in December 2008 and ended in December 2012.

Characteristics of published, unpublished and ongoing studies used for mapping available evidence against the technology’s evidence profile

Published studies

Five studies (interventional n=4; observational, n=1) were found and summarised in Appendices 3 and 4.

The second RCT by Arai et al. {Arai 2014} was an exploratory multiple dose double-blind, randomised, placebo-controlled study aiming at testing the safety and tolerability of treatment with IVIG for patients with mild-to-moderate AD. Participants were 16 subjects (intention-to-treat and per protocol population: 16) with probable AD (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria), with a mini-mental state examination score 16–26 and age 50–89 years at baseline. Patients could have been taking a stable dose of an approved AD drug (cholinesterase inhibitors, memantine) for at least 120 days prior baseline. However no data were reported about the use of these drugs. Participants were randomized to one of two doses of IVIG (0.2 g/kg, 0.4 g/kg every 2 weeks) or to placebo (50 mL 0.25% human albumin solution every 2 weeks). Treatment duration was 12 weeks and follow up lasted up to 26 weeks. The outcome measures were safety and tolerability. Moreover MMSE score change 14 weeks after the end of treatment (week 26 of follow up) was considered. The study was conducted in 5 centres of Japan. No information was provided about funding. The study does not report a Study Registration number.

The RCT by Dodel et al. {Dodel 2013} was an exploratory phase 2 dose finding double-blind, block-randomised, placebo-controlled study aiming at testing the safety, effective dose, and infusion interval of treatment with IVIG for patients with mild-to-moderate AD. Participants were 58 subjects (modified intention-to-treat population: 57; per protocol population: 45) with probable AD (National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association criteria), with a mini-mental state examination score 16–26 and age 50–85 years at baseline. Patients had to have been taking a stable dose of an approved Alzheimers disease drug for at least 3 months before screening; 36 out of 41 patients in IVIG (88%) used acetylcholinesterase inhibitor or memantine as well as 11 out of 14 (79%) patients in Placebo group. Participants were randomized to one of six doses of IVIG (0.2 g/kg, 0.5 g/kg or 0.8 g/kg every 4 weeks; 0.1 g/kg, 0.25 g/kg, or 0.4 g/kg every 2 weeks) or to placebo (0.9% isotonic sodium chloride every 4 weeks or every 2 weeks). Treatment duration was 24 weeks. Primary outcome was the difference of the median area under the curve (AUC) of plasma concentration of Aβ1–40 between placebo groups and the six intervention groups, measured from last infusion to final visit. Other surrogate outcomes were the difference of AUC for plasma concentration of Aβ1–42 and of anti-Aβ autoantibodies; the difference of plasma concentration of Aβ1–40, Aβ1–42 and anti-Aβ autoantibodies at week 24 compared with baseline; the change in CSF concentration of Aβ1–40, Aβ1–42, anti -Aβ autoantibodies and p-tau181, 24 h after last infusion compared with baseline; the difference between baseline and week 24 of change in whole brain volume, hippocampus volume; glucose metabolism. Moreover some patient important outcomes were considered: difference in scores at baseline and at week 24 on the AD assessment scale-cognitive part (ADAS-cog), the clinical dementia rating scale-sum of boxes, the AD Cooperative Study-activities of daily living scale, the mini-mental state examination; adverse events. The study - funded by Octapharma AG – was conducted in hospitals, research centres and private clinics of Germany and USA.

The other three studies {Devi 2008, retrospective observational study; Dodel 2004 and Relkin 2009, interventional prospective non-controlled studies} applied to small samples (n = 5 to 10) of subjects with AD (National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association criteria) and tested the safety and the clinical effect of various schemes of IVIg administration (0.4 g/kg every 2 weeks; 0.4 g/kg on three consecutive days every 4 weeks; 0.4 g/kg every week; 1 g/kg every 2 weeks; 2 g/kg every 4 weeks) for 3-6 months of duration. The outcomes considered were difference between baseline and end of treatment of cognitive functions according to various scales/tools (Wechsler Adult Intelligence Scale; Wechsler Memory Scale; Boston Naming Test; ADAS-cog; CDR-GS; MMSE; Visual construction abilities), immunologic surrogate outcomes (changes before and after infusion of serum or CSF anti-Abeta antibody, changes of CSF Abeta 40 and Abeta42), adverse events. Two studies {Dodel 2004, Relkin 2009} received both public and manufacturer’s funding; in the third study {Devi 2008} the source of funding was not reported.

Unpublished studies

Seven more studies - summarised in Appendix 3 - were carried out but not published as full papers, resulting as protocols in ClinicalTrial.gov {NCT00299988 } or abstracts at congress {Hara 2011, Kondo 2011, Kountouris 2000, Papatriantafyllou 2006, Relkin 2012, Rovira 2011}. None of them had results posted in clinical trials registers.

The NCT00299988 study {NCT00299988} was a phase 2 randomized, placebo-controlled trial, conducted in USA. Participants were 24 subjects with mild-to-moderate AD. Four schemes of intravenous immunoglobulin (ranging from 0.2 g/kg every 2 weeks to 0.8 g/kg every months) were compared to placebo. Treatment duration was 6 months. Primary outcome were ADAS-Cog and ADCS-CGIC. Other outcomes were cognitive functions measured by other scales/tools (MMSE; ADCS-ADL; NPI; GDS), quality of life (scales not reported), immunologic surrogate outcomes (plasma and CSF anti-amyloid antibody titers and beta amyloid levels), imaging surrogate outcomes (Positron Emission Tomography: FDG Cerebral Glucose Utilization, PIB Cerebral Amyloid Distribution, PK11195 Microglial Activation), adverse events. The study - funded by Weill Medical College of Cornell University Collaborators and by Baxter BioScience – was completed in April 2010 but results are still unpublished. For this study an open label extension of three years was carried out in 16 subjects in order to assess the long-term safety the IVIg infusion, but results are similarly unpublished as full paper (available only an abstract, Relkin 2012). Authors of the study were contacted in May 2014, and although they responded, they did not provide results.

Other four studies {Hara 2011, Kondo 2011, Papatriantafyllou 2006, Rovira 2011} applied a before-and-after design to small samples (n = 4 to 10) of subjects with AD testing the safety and effectiveness of various schemes of IVIg administration for 3-62 months of duration. The outcomes considered were difference between baseline and end of treatment of cognitive functions according to various scales/tools, surrogate outcomes, adverse events. These studies are still unpublished as full paper (available only as abstracts). The Authors of the these studies were contacted. Two of them responded without providing results, stating that the studies will be probably published.

Finally, one study {Kountouris 2000} applied a non-randomized controlled design to 16 subjects with AD comparing the effectiveness of IVIg infusion together with piracetam versus the administration of piracetam only, for 12 months of duration. The outcome considered was the cognitive function assessed by the MMSE. This study is unpublished as full paper (available only as abstract). The Author of the this study was contacted, without response.

Terminated studies

Two other studies - summarised in Appendix 3– are terminated {NCT01736579, NCT01524887}, that is stopped prematurely.

An open label extension of three years of one of the above reported RCTs {NCT00818662} was planned {NCT01736579} in order to assess the long-term safety of the IVIg infusion. The study was terminated in 2013 after enrollment of 6 patients because the preceding phase 3 study did not demonstrate efficacy on the co-primary endpoints.

The NCT01524887 study {NCT01524887} was a phase 3 randomized, placebo-controlled trial planned to include subjects with mild-to-moderate AD in order to test two unspecified schemes of intravenous immunoglobulin versus placebo for a treatment duration of 18 months. Primary outcome considered were ADAS-Cog and ADCS-ADL. The study - devised by Baxter Healthcare Corporation – was terminated in 2013 without enrollment of any patients because the first phase 3 study {NCT00818662} did not demonstrate efficacy on the co-primary endpoints.

Ongoing studies

Two more studies - summarised in Appendix 3 – are still ongoing {NCT01300728, NCT01561053}.

The NCT01300728 study {NCT01300728} is a phase 2 randomized, placebo-controlled trial, that is ongoing in USA. Participants are 50 subjects with MCI, amnestic type (single or multi domain) according to Petersen criteria (Petersen 1999) and supported by a CDR score of 0.5. IVIg infusion (0.4 g/kg every 14 days for a total of five infusions in two months) will be compared to placebo. Primary outcome is change in ventricular volumetric as measured by MRI (time frame: baseline and 24 month). Other outcomes are conversion from amnestic MCI to AD, cognitive functions measured by other scales/tools (ADAS-cog; MMSE; Clinical Dementia Rating and Sum of Boxes), other imaging surrogate outcomes, adverse events. The study - funded by Sutter Health – will be completed in October 2014.

The NCT01561053 study {NCT01561053} is a phase 2/3 randomized, placebo-controlled trial, that is ongoing in USA and Spain. Participants are 350 subjects with mild-to-moderate Alzheimer Disease (National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association criteria). IVIg (Flebogamma DIF) infusion (at unspecified high and low dose) together with plasmapheresis or plasmapheresis alone will be compared to a sham procedure. Primary outcome is increase in cognitive scores as measured by ADAS-Cog (time frame 14 months). Other outcomes are change in: cognitive, functional and neuropsychiatric scores (measured by MMSE, NPS battery, ADCS-ADL, NPICDR-Sb, ADCS-CGIC, CSDD, C-SSRS), surrogate immunological outcomes (levels of AB1-40 and AB1-42, T-tau and P-tau in CSF; levels of AB1-40 and AB1-42 in plasma), surrogate imaging outcomes (structural changes in volume of the hippocampus, posterior cingulate area, and other associated areas at MRI; brain functional changes through FDG-PET), adverse events. The study - funded by Grifols Biologicals Inc. – will be completed in December 2016.

 

Risk of bias in included studies

The included RCT {NCT00818662} was a phase 3 double-blind, placebo-controlled, two dose arm study. Available data (posted on ClinicalTrials.gov, last access December 5 2014) do not permit an evaluation of the methodology and conduction of the study due to the absence of information posted. Authors and Manufacturer were not contacted again and risk of bias was assessed by Principal Investigators. A risk of attrition bias was present (81 out of 383 randomized patients did not complete the study). The study was industry sponsored. The overall risk of bias of this study was judged to be “high”. For details on study’s risk of bias please see Table 1.

Table 1. Risk of bias table for NCT00818662 trial

Bias	Judgement	Support for judgement Cochrane Risk of Bias; Criteria from EUnetHTA guideline, Internal validity of randomized controlled trials
Random sequence generation adequate (selection bias)	Unclear	No details on random generation.
Allocation concealment adequate (selection bias)	Unclear	No details on allocation concealment.
Blinding of patients (performance bias)	Unclear	No details on blinding.
Blinding of treating personnel (performance bias)	Unclear	No details on blinding.
Blinding of outcome assessment (detection bias)	Unclear	No details on blinding.
Incomplete outcome assessment unlikely (attrition bias)	High risk	383 patients were randomized: 127 IVIG 400mg/kg; 135 IVIG 200mg/kg; 58 Placebo 4mL/kg; 63 Placebo 2mL/kg. 82 (21.4%) patients did not complet the trial: 23 (18.1%) IVIG 400mg/kg; 33 (24.4%) IVIG 200mg/kg; 9 (15.5%) Placebo 4mL/kg; 16 (25.4%) Placebo 2mL/kg
ITT principle appropriately implemented (attrition bias)	Unclear risk	No details on ITT analysis.
Selective outcome reporting unlikely (reporting bias)	Low risk	No main discrepancies between the protocol and the reported results are present.
Other bias	High risk	Sponsored study Two Study  Directors are reported Study Director: Norman Relkin, MD, PhD Alzheimer's Disease Cooperative Study (ADCS) Study Director: David Gelmont, MD Baxter Healthcare Corporation Role of the funding source “Restriction Description: Agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication (by USCD) or 12 months after study completion. Baxter requires a review of results communications (e.g., for confidential information) ≥45 days prior to submission or communication. Baxter may request an additional delay of ≤45 days(e.g., for intellectual property protection)”

 

Result cards

Morbidity

Mortality

Function

Health-related Quality of life

Change-in management

Benefit-harm balance

Discussion

There is limited evidence on IVIG in adults with mild-to-moderate AD and no evidence for adults with MCI or moderate-to-severe AD.

The systematic search of electronic databases retrieved 5 published studies: 2 RCTs {Arai 2014, Dodel 2013}, 2 prospective interventional non-controlled studies {Dodel 2004, Relkin 2009}, and 1 observational study {Devi 2008} – including patients with mild-to-moderate AD. They were not eligible for inclusion and were used to illustrate the state of development of research. No studies were found for MCI and moderate-to-severe AD.

During the periodical check of registers of ongoing trials, a previously tracked completed but not published RCT {NCT00818662} had final results posted by the study sponsor in October 23rd 2014. Inclusion of this study in the assessment was decided by Editorial Team. Authors and sponsor were previously contacted (May 2014) but they did not provide any data. No further contacts were sought. The included RCT is a phase 3 double-blind, placebo-controlled study, including 383 patients with mild-to-moderate AD. Data show that any important clinical outcomes such as cognitive functions (according to ADAS-Cog and ADCSC-GIC), activity of daily living (ADCS-ADL) and quality of life (both in patients and caregivers according to QOLAD) did not differ between IVIG groups (400 mg/kg or 200 mg/kg) versus placebo groups after 70 weeks of treatment. The confidence in effect estimate for overall evidence on all considered outcomes is very low, according to GRADE method, due to high risk of bias.

We have documented the missing publication of another RCT {NCT00299988} and of other six interventional non-controlled studies. All these studies included subjects with mild-to-moderate AD.

Other two ongoing RCTs have been recorded: one phase 2, dose-finding, including 50 subjects with MCI {NCT01300728}, and one phase 2/3, including 350 subjects with mild-to-moderate AD {NCT01561053}. Trials are reported to or expected to end in November 2014 and December 2016, respectively.

The published studies were conducted in hospitals, research centres and private clinics in Germany and USA. The tested therapeutic schemes and the duration of treatment varied substantially. The IVIGs used in published studies were Gammagard by Baxter Healthcare Corporation and Octagam by Octapharma AG. The unpublished study {NCT00818662} – by Baxter Healthcare Corporation - used Gammagard Liquid (200 mg or 400 mg/kg every 2 weeks). The ongoing RCTs are testing Flebogamma by Grifols S.A. and NewGam by Sutter Health. The latter study tests IVIG (high dose or low dose – no other details provided) together with plasmapheresis against plasmapheresis alone or against infusion of 20% albumin.

Implications for practice

At present there is limited evidence on lack of effectiveness of IVIG in adults with mild-to-moderate AD, and no evidence for adults with MCI and moderate-to-severe AD.

Implications for research

Publication bias was identified in the evidence base of subjects with mild-to-moderate AD. Two RCTs have been recently completed but not published {NCT00299988, NCT00818662}. One of them had its results recently posted on a clinical trial register. Another RCT including 350 patients will be ended within the next two years {NCT01561053}. Future complete access to all these data might provide valuable evidence to assess effectiveness of IVIG for these patients. No further trials would be advised before full publication of these studies. One small study on subjects with MCI {NCT01300728} is awaiting completion. It would produce only preliminary short term data on surrogate outcomes. Other studies – if suitable – will have to be devised to assess patient important outcomes in the long term. The category of moderate-to-severe AD is not considered for future study, probably because the rationale of IVIG’s use for advanced AD is weak or absent.

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NCT00818662. Available at http://prsinfo.clinicaltrial.gov/ct2/show/record/NCT00818662?term=NCT00818662&rank=1; last access 16^th December 2014.

NCT01300728. Available http://prsinfo.clinicaltrial.gov/ct2/show/NCT01300728?term=NCT01300728&rank=1, last access 16^th December 2014.

NCT01524887. Available at http://prsinfo.clinicaltrial.gov/ct2/results?term=NCT01524887&Search=Search, last access 16^th December 2014.

NCT01561053. Available at http://prsinfo.clinicaltrial.gov/ct2/show/NCT01561053?term=NCT01561053&rank=1, last access 16^th December 2014.

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Appendices

Appendix 1

Figure A1.1. Flow chart of study selection for the effectiveness domain.

From: {Moher 2009}.

Appendix 2

Included Studies

Table A2.1. Characteristics of included studies (see Appendix 5 for more details).

Reference	Last update	Study design	Participants	Intervention (duration)	Control	EFF issues	EFF outcome measure	Funding
NCT00818662	October 23th 2014 (Clinicaltrials.gov)	phase 3 RCT	383 patients () with mild-to-moderate AD	IVIG (Gammagard Liquid) 200 mg or 400 mg/kg every 2 weeks (70 weeks)	Placebo: Human Albumin 0.25% 4 mL/kg or 2 mL/kg; every 2weeks (70 weeks)	Function D0011	Cognitive functions changes measured by ADAS-Cog at 9 and 18 months	Baxter Healthcare Corporation
						Function D0016	Activities of daily living changes measured by ADCS-ADL at 9 and 18 months
						Function D0011	Cognitive functions changes measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCSC-GIC) at 9 and 18 months
						Morbidity D0005	Behavioural changes measured by Neuropsychiatric Inventory (NPI) at 18 months
						Health-related Quality of life D0013	Disease specific health related quality of life changes in patients measured by Logsdon Quality of Life in Alzheimer's Disease (QOLAD) at 18 months
						Health-related Quality of life D0013	Disease specific health related quality of life changes in caregivers measured by Logsdon Quality of Life in Alzheimer's Disease (QOLAD) at 18 months

Table A2.2. GRADE Evidence profile on effectiveness of IVIG in mild-to-moderate AD, at overall and study level.

Cognitive functions: ADAS-Cog mean score change (± SD) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

7.4 ± 7.95 (105)

8.9 ± 8.20 (100)

8.4 ± 9.37 (95)

-0.8 (-3.1 to 1.5); P = 0.476^

0.7 (-1.6 to 3.0); P = 0.530^

No difference between groups

Very low

Cognitive functions: ADAS-Cog mean score change (± SD) from baseline to 9 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

2.7 ± 5.20 (114)

4.5 ± 6.16 (114)

3.5 ± 6.44 (106)

-0.7 (-2.3 to 0.8); P = 0.368^

0.8 (-0.8 to 2.4); P = 0.319^

No difference between groups

Very low

Cognitive functions: ADCSC-GIC change (units: patients) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

Very much better: 0 Much better: 1 A little better: 6 Same: 15 A little worse: 44 Much worse: 32 Very much worse: 7 (105)

Very much better: 0 Much better: 2 A little better: 1 Same: 15 A little worse: 43 Much worse: 33 Very much worse: 7 (101)

Very much better: 0 Much better: 1 A little better: 3 Same: 16 A little worse: 36 Much worse 32 Very much worse: 4 (92)

-0.1 (-0.3 to 0.2); P = 0.660#

0.0 (-0.2 to 0.3); P = 0.766#

No difference between groups

Very low

Cognitive functions: ADCSC-GIC change (units: patients) from baseline to 9 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

Very much better: 0 Much better: 2 A little better: 7 Same: 33 A little worse: 52 Much worse: 19 Very much worse: 1 (114)

Very much better: 0 Much better: 1 A little better: 3 Same: 33 A little worse: 56 Much worse: 18 Very much worse: 3 (114)

Very much better: 0 Much better: 1 A little better: 7 Same: 36 A little worse: 48 Much worse 12 Very much worse: 0 (104)

0.1 (-0.1 to 0.3); P = 0.306#

0.3 (0.0 to 0.5 ); P = 0.028#

No difference between IVIG 400mg/kg group and Placebo group Difference between 200mg/kg group and Placebo group, in favour of Placebo group

Very low

Activities of daily living: ADCS-ADL mean score change (± SD) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

-11.4 ± 10.49 (104)

-12.4 ± 11.41 (102)

-11.4 ± 12.19 (95)

0.4 (-2.9 to 3.7); P = 0.812^

-0.9 (-4.3 to 2.5); P = 0.602^

No difference between groups

Very low

Activities of daily living: ADCS-ADL mean score change (± SD) from baseline to 9 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

-5.4 ± 7.03 (111)

-6.1 ± 8.13 (116)

-5.8 ± 8.32 (107)

0.3 (-1.8 to 2.4); P = 0.778^

-0.2 (-2.3 to 1.9); P = 0.851^

No difference between groups

Very low

Behaviour: NPI mean score change (± SD) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

3.7 ± 12.93 (104)

4.9 ± 13.30 (102)

2.4 ± 10.77 (94)

0.7 (-2.1 to 3.4); P = 0.640^

2.5 (-0.3 to 5.3); P = 0.075^

No difference between groups

Very low

Disease specific health related quality of life in patients: QOLAD mean score change (± SD) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

-0.5 ± 5.34 (99)

-0.7 ± 4.40 (99)

-1.5 ± 5.20 (86)

1.1 (-0.2 to 2.3); P = 0.094^

1.1 (-0.2 to 2.3); P = 0.094^

No difference between groups

Very low

Disease specific health related quality of life in caregivers: QOLAD mean score change (± SD) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

-3.0 ± 4.97 (99)

-2.5 ± 5.17 (99)

-1.6 ± 5.12 (92)

-1.1 (-2.3 to 0.2); P = 0.096^

-1.0 (-2.2 to 0.3); P = 0.123^

No difference between groups

Very low

§ Not available details for assessing the major sources of bias; presence of risk of attrition bias * Industry funded; detection of publication bias ^Method of analysis: ANCOVA (as reported in clinicaltrial.gov: results combined from 100 imputations from estimates & standard errors from 100 ANCOVA results for fixed effect of treatment, E4 allele of apolipoprotein E carrier status, & continuous covariates age at baseline, baseline ADASCog & education level) # Method of analysis: Mixed Models Analysis.

 

Appendix 3

Excluded studies

Table A3.1: Characteristics of published studies (see Appendix 5 for more details).

Reference	Study design	Participants	Intervention (duration)	Control	EFF issues	EFF outcome measure	Funding
Arai 2014	multiple dose, placebo controlled, RCT	16 patients (12 experimental group; 4 control group) with mild-to-moderate Alzheimer Disease	one of two doses of intravenous immunoglobulin (0·2 g/kg, 0·4 g/kg) every 2 weeks (12 weeks)	placebo (50-mL 0.25% human albumin solution) every 2 weeks	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured MMSE	Not reported
Devi 2008	Observational-retrospective study	10 patients with AD	IVIG 0.4 g/kg every 2 weeks (3-6 months)	None	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by WAIS, WMS, Boston	Not reported
Dodel 2004	Interventional prospective non-controlled study	5 patients with AD (4 mild-to-moderate; 1 moderate-to-severe)	IVIG (OctagamH) 0.4 g/kg on three consecutive days every 4 weeks (6 months)	None	Function D0011	Cognitive functions measured by ADAS-Cog Other: MMSE, CERAD neuropsychological test battery	Public Octapharma (Lagenfeld, Germany) provided IVIG
					Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)
Dodel 2013	phase 2, dose-finding; placebo controlled, RCT	58 patients (42 experimental group; 14 control group) with mild-to-moderate AD	one of three doses of intravenous immunoglobulin (0·2 g/kg, 0·5 g/kg, or 0·8 g/kg) every 4 weeks, or half of that dose (0·1 g/kg, 0·25 g/kg, or 0·4 g/kg) every 2 weeks (24 weeks)	placebo (0·9% isotonic sodium chloride) every 4 weeks or every 2 weeks	Function D0011	Cognitive functions measured by ADAS-Cog, CDR-GS Other: MMSE	Octapharma AG
					Function D0016	Activities of daily living measured by ADCS-ADL
					Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)
					Morbidity D0006	Variation of imaging signs (change in ventricular volumetric as measured by MRI)
Relkin 2009	Interventional prospective  dose finding study	8 patients with mild-to-moderate AD	one of four IVIG (Gammagard S/D) doses (0.4 g/kg/2 weeks, 0.4 g/kg/week, 1 g/kg/2 weeks and 2 g/kg/4 weeks) (6 months + 9 months)	None	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by MMSE	Public and Baxter Bioscience Corporation
					Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)

 

 

Table A3.2: Characteristics of unpublished studies, randomized controlled studies (see Appendix 5 for more details).

Reference	Last update	Study design	Participants	Intervention (duration)	Control	EFF issues	EFF outcome measure	Funding
NCT00299988	2010	phase 2 RCT	24 patients with mild-to-moderate AD	one of four doses of IVIG (from 0·2 g/kg every 2 weeks to 0·8 g/kg every month) (6 months)	Placebo	Function D0011	Cognitive functions measured by ADAS-Cog Other: ADCS-CGIC	Public, Baxter BioScience
						Function D0016	Activities of daily living measured by ADCS-ADL
						Morbidity D0005	Behavioural changes measured by Neuropsychiatric Inventory (NPI)
						Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)
						Morbidity D0006	Variation of imaging signs (change in SUVR at PIB-PET)
						Health-related Quality of life D0012	Generic health related quality of life
						Health-related Quality of life D0013	Disease specific health related quality of life
						Function D0016	Activities of daily living measured by ADCS-ADL
						Morbidity D0005	Behavioural changes measured by Neuropsychiatric Inventory (NPI)
						Health-related Quality of life D0012	Generic health related quality of life
						Health-related Quality of life D0013	Disease specific health related quality of life

 

Table A3.3: Characteristics of unpublished studies, other designs (see Appendix 5 for more details).

Reference	Last update	Study design	Participants	Intervention (duration)	Control	EFF issues	EFF outcome measure	Funding
Kountouris 2000	2000	Open label, non-randomized controlled trial	16 patients with AD	IVIG (Octagam) 0,2 g/Kg + piracetam (12 months)	Piracetam	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by MMSE	Not reported
Papatriantafyllou 2006	2006	uncontrolled longitudinal study	6 patients with mild-to-moderate AD	total dose of 0.4g/Kg IVIG in three consecutive days every 4 weeks (6 months)	None	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by MMSE	Not reported
						Function D0016	Activities of daily living measured by ADCS-ADL
						Morbidity D0005	Behavioural changes measured by Neuropsychiatric Inventory (NPI)
Hara 2011	2011	Uncontrolled longitudinal study	10 patients with AD	IVIG (5.5-62.3 months)	None	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by Memory Performance Index, and the Functional Assessment Staging test	Not reported
Kondo 2011	2011	Uncontrolled longitudinal study	4 patients with AD	0.4 g/kg of IVIGfor 3 consecutive days every month for 3 months	None	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by MMSE	Not reported
						Morbidity D0006	Variation of imaging signs (change in SUVR at PIB-PET)
Rovira 2011	2011	open label pilot uncontrolled longitudinal study	4 patients with mild-to-moderate AD	0.5 g/kg of IVIG (Flebogamma DIF, Grifols) every 2 weeks (6 months)	None	Function D0011	Cognitive functions measured by ADAS-Cog, CDR-GS Other: MMSE	Not reported
						Morbidity D0006	Variation of imaging signs (change in ventricular volumetric as measured by MRI)
Relkin 2012 (open extension of NCT00299988)	2012	12 month open label extension of a Phase II, double blind placebo controlled study	16 patients with mild-to-moderate AD	IVIG (Gammagard, Baxter) 0.4g/ kg/2 weeks (36 months)	None	Function D0011	Cognitive functions measured by ADAS-Cog Other: ADCS-CGIC	Not reported
						Function D0016	Activities of daily living measured by ADCS-ADL
						Morbidity D0005	Behavioural changes measured by Neuropsychiatric Inventory (NPI)
						Health-related Quality of life D0012	Generic health related quality of life
						Health-related Quality of life D0013	Disease specific health related quality of life

Table A3.4: Characteristics of terminated studies (see Appendix 5 for more details)

Reference	Last update	Study design	Participants	Intervention (duration)	Control	Funding
NCT01524887	2013 The study was terminated without enrol any patient because the first Phase 3 did not demonstrate efficacy on the co-primary endpoints	phase 3 RCT	patients with mild-to-moderate AD	Experimental: IVIG, 10% at Dose A (high dose) or Dose B (low dose) (18 months)	Placebo	Baxter Healthcare Corporation
NCT01736579	2013 The study was terminated after enrolment of 8 patients  because the first Phase 3 did not demonstrate efficacy on the co-primary endpoints	open label extension previous study (NCT00818662)	patients with mild-to-moderate AD	IVIG (Gammagard Liquid) 200 mg or 400 mg/kg every 2 weeks (3 years)	None	Baxter Healthcare Corporation

Table A3.5: Characteristics of ongoing studies

Reference	Study design	Participants	Intervention (duration)	Control	EFF issues	EFF outcome measure	Funding
NCT01300728 (estimated completion November 2014)	phase 2 RCT	50 patients with MCI	IVIG (NewGam) at 0.4 g/kg every 14 days for a total of five infusions (two months)	Placebo	Morbidity D0006	Rate of progression or frequency of patients progressed to AD according to according to available AD validated criteria (NINCDS-ADRDA, ICD, DSM) at 24 months	Sutter Health
					Function D0011	Cognitive functions measured by ADAS-Cog, CDR-GS at 24 months Other: MMSE
					Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42) at 24 months
					Morbidity D0006	Variation of imaging signs (change in ventricular volumetric as measured by MRI) at 24 months
NCT01561053 (estimated completion December 2016)	phase 2/3 RCT	350 patients with mild-to-moderate AD	Plasmapheresis alone or with infusion of 20% albumin and IVIG high dose or low dose (14 months)	Sham procedure	Function D0011	Cognitive functions measured by ADAS-Cog Other: MMSE	Instituto Grifols, S.A.
					Function D0016	Activities of daily living measured by ADCS-ADL
					Morbidity D0005	Behavioural changes (Neuropsychiatric Inventory – NPI)
					Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)
					Morbidity D0006	Variation of imaging signs (change in ventricular volumetric as measured by MRI)

 

Appendix 4

Stage of development of research

To describe the stage of development of current and future research on effectiveness on IVIG for MCI and AD we tabled the studies against the evidence profile.

MCI

Available evidence

No evidence is available on effectiveness of IVIG for patients with MCI.

Upcoming evidence

One ongoing phase 2 RCT will be able to provide preliminary data on some important clinical outcomes (frequency of patients progressed to AD and cognitive functions, however in a short time frame (24 months of follow up).

 

Table A4.1: Stage of development of research on effectiveness on IVIG for MCI.

IVIG for MCI
Issue	Outcome	MCI
		Available evidence	Upcoming evidence
Morbidity [D0006]	Rate of progression or frequency of patients progressed	None	1 phase 2 RCT (50 pts)
Mortality [D0001]	Overall mortality rate	None	None
Function [D0011]	Cognitive functions	None	1 phase 2 RCT (50 pts)
Morbidity [D0005]	Neuropsychiatric symptoms/Behavioural changes	None	None
Health-related Quality of life [D0012]	Generic health related quality of life	None	None
Morbidity [D0006]	Variation of biomarkers	None	1 phase 2 RCT (50 pts)
Morbidity [D0006]	Variation of imaging signs	None	1 phase 2 RCT (50 pts)

 

Mild-to-moderate AD

Available evidence

Comparative data about cognitive functions and activity of daily living are available from one phase 2 RCT on 58 patients (see Table A4.2) and and one phase 3 RCT (383 patients), the latter included in the present study. These studies were preceded by three small non-controlled studies investigating mainly effect of IVIG on surrogate outcomes.

Table A4.2: Synopsis of results of the phase 2, dose-finding, RCT by Dodel et al. {Dodel 2013}.

Issues and outcome measures at 24 weeks

IVIg Dose/4 weeks (No. of pts) 0.2 g/kg (6) 0.5 g/kg (8) 0.8 g/kg (7)

Placebo 4 weeks (No. pts =7)

Difference (95% CI) Placebo vs IVIg 4 weeks 0.2 g/kg 0.5 g/kg 0.8 g/kg

Interpretation

IVIg Dose/2 weeks (No. pts) 0.1 g/kg (6) 0.25 g/kg (7) 0.4 g/kg (7)

Placebo 2 weeks (No. pts =7)

Difference (95% CI) Placebo vs IVIg 2 weeks 0.1 g/kg 0.25 g/kg 0.4 g/kg

Interpretation

Function D0011 - Cognitive functions ADAS-cog median change from baseline (range) Higher scores worse

5.3 (–4.7 to 8.7) 1.8 (–8.0 to 24.0) –1.5 (–4.3 to 18.3)

0.3 (–3.3 to 5.0)

–3.8 (–9.3 to 4.0) –0.3 (7.0 to 5.7) 0.8 (–13.3 to 7.3)

No statistically significant difference between groups

2.5 (–3.7 to 6.0) –1.3 (–7.3 to 4.0) 4.5 (–4.0 to 8.3)

–0.3 (–5.3 to 5.0)

–3.0 (–7.0 to 1.7) 2.0 (–4.0 to 7.0) –4.3 (–10.7 to 2.3)

No statistically significant difference between groups

Function D0011 - Cognitive functions CDR-sum of boxes median change from baseline (range) Higher scores worse

0.5 (–1.0 to 3.0) 0.0 (–1.0 to 5.0) 0.3 (–1.5 to 3.0)

–0.5 (–6.0 to 0.0)

–1.5 (–6.5 to 0.0) –0.5 (–6.0 to 0.0) –1.3 (–5.5 to 0.5)

No statistically significant difference between groups

0.0 (–1.0 to 5.0) 0.5 (–2.0 to 2.0) 0.8 (–1.5 to 4.0)

0.0 (–2.5 to 1.5)

–1.3 (–3.5 to 0.5) –0.5 (–2.5 to 1.0) –2.5 (–3.5 to 0.0)

No statistically significant difference between groups

Function D0016 - Activities of daily living ADCS-ADL median change from baseline (range) Higher scores better

–3.0 (–31.0 to 11.0) 0.0 (–15.0 to 11.0) –1.5 (–5.0 to 3.0)

–3.0 (–8.0 to 7.0)

–19.0 (–13.0 to –25.0) –4.5 (–14.0 to 7.0) –1.5 (–8.0 to 6.0)

No statistically significant difference between groups

–0.5 (–11.0 to 4.0) –3.0 (–17.0 to 3.0) –4.0 (–25.0 to 2.0)

2.0 (–6.0 to 10.0)

3.0 (–3.0 to 10.0) 5.0 (–1.0 to 13.0) 6.5 (0.0 to 18.0)

No statistically significant difference between groups

Morbidity D0006 – median change in AUC of plasma Aβ1-40 (range)

–18.0 (–1347.0 to 1068.5) –364.3 (–5834.5 to 1953.5) –351.8 (–1084.0 to 936.5)

–116.3 (–1379.0 to 5266.0)

–32.5 (–1358.0 to 4197.5) 195.3 (–1005.5 to 5302.0) 235.5 (–984.5 to 4329.5)

No statistically significant difference between groups

–13.8 (–1729.0 to 307.0) –32.5 (–1102.5 to 451.5) 47.0 (–341.0 to 72.5)

159.5 (51.5 to 303.0)

159.8 (–124.5 to 1838.5) 200.5 (–51.0 to 474.5) 134.5 (4.5 to 500.5)

Statistically significant difference in the group of 0.4 g/kg: the effect was favoring placebo

Morbidity D0006 - median change in AUC of plasma Aβ1-42 (range)

–41.8 (–244.4 to 336.6) –119.3 (–1220.6to 375.0) –107.5 (–173.5 to 231.0)

–20.5 (–183.7 to 489.0)

30.3 (–234.6 to 346.4) 114.8 (–64.5 to 622.0) 87.00 (–95.7 to 275.5)

No statistically significant difference between groups

3.0 (–109.5 to 74.5) –33.5 (–190.6 to –16.5) –9.5 (–57.0 to 5.0)

24.0 (2.0 to 125.5)

26.5 (–45.0 to 133.5) 63.0 (40.0 to 178.0) 39.0 (–11.5 to –135.0)

Statistically significant difference in the groups of 0.25 and 0.4 g/kg: the effect was favoring placebo. C.I for the latter group are probably misprinted in the paper

Morbidity D0006 – mean (SD) change from baseline normalized whole brain volume (cm3) at MRI

–1.4 (1.8) –1.1 (1.0) –1.6 (1.1)

–0.9 (0.8)

0.5 (–1.7 to 2.7) 0.2 (–1.1 to 1.5) 0.7 (–0.7 to 2.2)

No statistically significant difference between groups

–2.0 (0.8) –1.5 (0.7) –1.4 (1.7)

–1.4 (1.0)

0.6 (–0.8 to 2.0) 0.1 (–1.1 to 1.3) 0.0 (–2.3 to 2.2)

No statistically significant difference between groups

Differences between treatment groups were assessed by t test (two-sided, α=0·05) for biomarkers and MRI results and by calculating Hodges-Lehmann estimates and non-parametric 95% CIs, compared with Wilcoxon rank sum test (normal approximation, two-sided, α=0·05) for the cognitive and functional scales. 

Upcoming evidence

One completed unpublished RCT and one ongoing phase 2/3 RCT will be able to add comparative data on some important outcomes (cognitive functions, activity daily living, behavioural changes) of IVIG – according to different dosing and administration schemes – for some hundreds of patients and on long term (14 months). In the last decade four non-controlled studies result to be completed and unpublished. They will be able to add only very few data on efficacy outcomes.

Table A4.3: Stage of development of research on effectiveness on IVIG for mild-to-moderate AD.

IVIG for mild-to-moderate AD
Issue	Outcome	Mild-to-moderate AD
		Available evidence	Upcoming evidence
Morbidity [D0006]	Rate of progression or frequency of patients progressed	None	None
Mortality [D0001]	Overall mortality rate	None	None
Function [D0011]	Cognitive functions	1 interventional prospective non-controlled study study (5 pts), 1 phase 2 RCT (58 pts), 1 phase 3 RCT (383 pts)	2 uncontrolled longitudinal studies (20 pts), 2 RCTs (764 pts)
Function [D0011]	Activities of daily living	1 phase 2 RCT (58 pts), 1 phase 3 RCT (383 pts)	2 uncontrolled longitudinal studies (22 pts), 2 RCTs (374 pts)
Morbidity [D0005]	Neuropsychiatric symptoms/Behavioural changes	1 phase 3 RCT (383 pts)	2 uncontrolled longitudinal studies (22 pts), 2 RCTs (374 pts)
Health-related Quality of life [D0012]	Generic health related quality of life	None	1 uncontrolled longitudinal studies (16 pts), 1 RCT (24 pts)
Health-related Quality of life [D0013]	Disease specific health related quality of life	1 phase 3 RCT (383 pts)	1 uncontrolled longitudinal study (16 pts), 1 RCT (24 pts)
Change in management [D0010]	Hospitalization	None	None
Change in management [D0010]	Institutionalization	None	None
Morbidity [D0006]	Variation of biomarkers	2 interventional prospective non-controlled studies (13 pts), 1 phase 2 RCT (58 pts)	3 RCTs (764 pts)
Morbidity [D0006]	Variation of imaging signs	1 phase 2 RCT (58 pts)	2 uncontrolled longitudinal studies  studies (20 pts), 2 RCTs (374 pts)

 

Moderate-to-severe AD

Available evidence

No evidence is available on effectiveness of IVIG for patients with moderate-to-severe AD.

Upcoming evidence

No evidence is foreseen to be available on effectiveness of IVIG for patients with moderate-to-severe AD.

Table A4.4: Stage of development of research on effectiveness on IVIG for moderate-to-severe AD.

IVIG for moderate-to-severe AD
Issue	Outcome	Moderate-to-severe AD
.		Available evidence	Upcoming evidence
Mortality [D0001]	Overall mortality rate	None	None
Function [D0011]	Cognitive functions	None	None
Function [D0011]	Activities of daily living	None	None
Morbidity [D0005]	Neuropsychiatric symptoms/Behavioural changes	None	None
Health-related Quality of life [D0012]	Generic health related quality of life	None	None
Health-related Quality of life [D0013]	Disease specific health related quality of life	None	None
Change in management [D0010]	Hospitalization	None	None
Change in management [D0010]	Institutionalization	None	None
Morbidity [D0006]	Variation of biomarkers	None	None
Morbidity [D0006]	Variation of imaging signs	None	None

 

Appendix 5

                                                                                                

Appendix 6

Search strategy

Database: Pubmed

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014*
1	"Immunoglobulins, Intravenous"[Mesh]	9526
2	venimmun OR "modified immune globulin" OR "ivig" OR "endobulin" OR "alpha globin" OR venoglobulin OR sandoglobulin OR "intraglobin" OR "globulin n" OR "privigen" OR "gamunex" OR "gammagard" OR "gamimmune" OR "gamimune" OR "flebogamma dif" OR "intravenous ig" OR "iveegam" OR "immunoglobulins iv" OR "immunoglobulins ivig" OR "immunoglobulins ivigs" OR "iv immunoglobulin" OR "iv immunoglobulins"[All Fields]	15230
3	1 OR 2	15230
4	"Mild Cognitive Impairment"[Mesh]	1647
5	"Alzheimer Disease"[Mesh]	64256
6	“Mild Cognitive Impairment"[title/abstract] OR dementia*[Title/Abstract] OR Alzheimer*[Title/Abstract] OR MCI[Abstract/Title]	137580
7	4 OR 5 OR 6	144293
8	3 AND 7	82	24

* search re-run with the same date limit in February 18 2015, in order to capture references previously not indexed  with Mesh terms.

 

Database: EMBASE

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	‘immunoglobulin'/exp/dd_iv	22907
2	'endobulin':ab,ti OR 'ivig':ab,ti OR 'alpha globin':ab,ti OR venoglobulin:ab,ti OR sandoglobulin:ab,ti OR 'intraglobin':ab,ti OR 'globulin n':ab,ti OR 'privigen':ab,ti OR 'gamunex':ab,ti OR 'gammagard':ab,ti OR 'gamimmune':ab,ti OR 'gamimune':ab,ti OR 'flebogamma dif':ab,ti OR 'intravenous ig':ab,ti OR 'iveegam':ab,ti OR 'immunoglobulins iv':ab,ti OR 'immunoglobulins ivig':ab,ti OR 'immunoglobulins ivigs':ab,ti OR 'iv immunoglobulin':ab,ti OR 'iv immunoglobulins':ab,ti OR 'intravenous antibodies':ab,ti OR 'intravenous antibody':ab,ti OR 'intravenous immunoglobulin':ab,ti OR 'intravenous immunoglobulins':ab,ti AND [embase]/lim	14395
3	1 OR 2	31178
4	'dementia'/de OR 'alzheimer disease'/exp OR 'mild cognitive impairment'/exp	173965
5	3 OR 4	359	42

 

Database: Cochrane Central Register of Controlled Trials

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	MeSH descriptor: [Immunoglobulins, Intravenous] explode all trees	616
2	('endobulin':ab,ti or 'ivig':ab,ti or 'alpha globin':ab,ti or venoglobulin:ab,ti or sandoglobulin:ab,ti or 'intraglobin':ab,ti or 'globulin n':ab,ti or 'privigen':ab,ti or 'gamunex':ab,ti or 'gammagard':ab,ti or 'gamimmune':ab,ti or 'gamimune':ab,ti or 'flebogamma dif':ab,ti or 'intravenous ig':ab,ti or 'iveegam':ab,ti or 'immunoglobulins iv':ab,ti or 'immunoglobulins ivig':ab,ti or 'immunoglobulins ivigs':ab,ti or 'iv immunoglobulin':ab,ti or 'iv immunoglobulins':ab,ti or 'intravenous antibodies':ab,ti or 'intravenous antibody':ab,ti or 'intravenous immunoglobulin':ab,ti or 'intravenous immunoglobulins':ab,ti)	2379
3	1 OR 2	2467
4	MeSH descriptor: [Alzheimer Disease] explode all trees	2065
5	MeSH descriptor: [Mild Cognitive Impairment] explode all trees	65
6	Alzheimer or "mild cognitive impairment" or "mild cognitive impairments"	5163
7	4 OR 5 OR 6	5198
8	3 AND 7	10	5

 

Database: Lilacs, Ibec, Medcarib

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	tw: immunoglobulin* AND (alzheimer* OR dementia OR ”mild cognitive impairment”)	11	0

 

Database: Isi web of Knowledge

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	Topic=(Venimmun OR "modified immune globulin" OR "ivig" OR "endobulin" OR "alpha globin" OR venoglobulin OR sandoglobulin  OR "intraglobin" OR "globulin n" OR "privigen" OR "gamunex" OR "gammagard" OR "gamimmune") OR "gamimune" OR "flebogamma dif" OR "intravenous ig" OR "iveegam" OR "immunoglobulins iv" OR "immunoglobulins ivig" OR "immunoglobulins ivigs" OR "iv immunoglobulin" OR "iv immunoglobulins" OR "intravenous antibodies" OR "intravenous antibody" OR "intravenous immunoglobulin" OR "intravenous immunoglobulin" OR "intravenous immunoglobulins")
2	Topic=(mci[title/abstract] OR "Mild Cognitive Impairments"[title/abstract] OR "Mild Cognitive Impairment"[title/abstract] OR dementia*[Title/Abstract] OR alzheimer*[Title/Abstract])
3	1 AND 2	138	30

 

Clinical Registers

ALOIS: a comprehensive register of dementia studies

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunlobulin*	7	0

 

metaRegister of Controlled Trials (mRCT), including ISRCTN (International Standard Randomised Controlled Trial Number Register)

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	(immunoglobulin*) and (Alzheimer or dementia or “mild cognitive impairment”)	2	0

 

ClinicalTrials.gov

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	(alzheimer* OR dementia* OR "mild cognitive impairment") AND ( immunoglobulin*)	51	21

 

NIH Clinical research studies

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunoglobulin* and Alzheimer	0	0

 

EU Clinical Trials Register website

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunoglobulin* and Alzheimer	4	0

 

International Clinical Trials Register Platform (ICTRP)

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunoglobulin* and Alzheimer	4	0

Appendix 7

Use of Intravenous immunoglobulins for Mild Cognitive Impairment and Alzeheimer’s disease - PROTOCOL

Costs and economic evaluation

Authors: Anna-Theresa Renner, Neill Booth, Esther Kraft, Ingrid Rosian-Schikuta, Matthias Schwenkglenks

Summary

In the absence of any discernible difference against placebo, no estimates of a trade-off between costs and benefits can be made at present

Introduction

In principle, economic evaluations of medical interventions provide one basis for decisions which involve the distribution of scarce resources. However, an economic evaluation is not the only relevant input to informed decision making and itself relies on other evidence (see, e.g., Strech D., 2007 {1}. Prior to considering costs and efficiency, it is usually regarded as appropriate and useful to incorporate evidence from two other forms of evaluation:

• Efficacy (“Can it work?”)
• Effectiveness (“Does it work?”)

(From: Drummond et al., {2} )

Of these two forms of evaluation, evaluation of efficacy, including related safety considerations, is generally considered as a prerequisite for undertaking economic evaluation. Without reliable evidence as to the (potential) effect of an intervention, spending scarce resources on an intervention can be seen as being economically irrational.

Given the lack of available data and lack of published evidence on the efficacy and/or the effectiveness of the intervention, the researchers (and internal reviewers) of this ‘Costs and economic evaluation’ -domain agreed that it would not be prudent to undertake research into costs or undertake an economic evaluation. At this stage in the development of the intervention, we therefore refrained from producing (necessarily incomplete) assessment elements in this domain.

Methodology

Frame

The collection scope is used in this domain.

Technology	Immunoglobulins (IGG) Description Naturally occurring proteins produced by the body’s immune system to combat foreign antigens
Intended use of the technology	Treatment Treatment of Alzheimer’s disease Target condition Alzheimer’s disease Target condition description Alzheimer's disease (AD) or Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. Target population Target population sex: Any. Target population age: elderly. Target population group: Patients who have the target condition. Target population description AD is diagnosed mostly in people over 65 years of age, although there is an early-onset form that can occur much earlier. According to Wikipedia in 2006, there were 26.6 million sufferers worldwide.
Comparison	placebo, not doing anything or Usual supportive care Description There is no MA for IGGs for AD yet and there is no other intervention licensed for use in AD so the comparison would have to be against placebo or best supportive care
Outcomes	Description of aims of technology (TECH) Regulatory status (CUR) Cognitive function (EFF) Harms (SAF) Cost effectiveness compared to alternatives (ECO) Potential impact on plasma derivative market (ORG/Medico-legal) Impact on family and carers (SOC) Appropriateness of use in relation to solidity of evidence(ETH)

Assessment elements

	Topic	Issue	Relevant	Research questions or rationale for irrelevance
E0001	Resource utilization	What types of resources are used when delivering the assessed technology and its comparators (resource-use identification)?	yes	What types of resources are used when delivering IGG and its comparators (resource-use identification)?
E0002	Resource utilization	What amounts of resources are used when delivering the assessed technology and its comparators (resource-use measurement)?	yes	What amounts of resources are used when delivering IGG and its comparators (resource-use measurement)?
E0009	Resource utilization	What were the measured and/or estimated costs of the assessed technology and its comparator(s) (resource-use valuation)?	yes	What were the measured and/or estimated costs of IGG and its comparator(s) (resource-use valuation)?
E0005	Measurement and estimation of outcomes	What is(are) the measured and/or estimated health-related outcome(s) of the assessed technology and its comparator(s)?	yes	What is(are) the measured and/or estimated health-related outcome(s) of IGG and its comparator(s)?
E0006	Examination of costs and outcomes	What are the estimated differences in costs and outcomes between the technology and its comparator(s)?	yes	What are the estimated differences in costs and outcomes between IGG and its comparator(s)?
E0010	Characterising uncertainty	What are the uncertainties surrounding the costs and economic evaluation(s) of the technology and its comparator(s)?	yes	What are the uncertainties surrounding the costs and economic evaluation(s) of IGG and its comparator(s)?
E0011	Characterising heterogeneity	To what extent can differences in costs, outcomes, or ‘cost effectiveness’ be explained by variations between any subgroups using the technology and its comparator(s)?	yes	To what extent can differences in costs, outcomes, or ‘cost effectiveness’ be explained by variations between any subgroups using IGG and its comparator(s)?
E0012	Validity of the model(s)	To what extent can the estimates of costs, outcomes, or economic evaluation(s) be considered as providing valid descriptions of the technology and its comparator(s)?	yes	To what extent can the estimates of costs, outcomes, or economic evaluation(s) be considered as providing valid descriptions of IGG and its comparator(s)?

Result cards

Resource utilization

Measurement and estimation of outcomes

Examination of costs and outcomes

Characterising uncertainty

Characterising heterogeneity

Validity of the model(s)

References

1. Strech D., 2007 Four levels of value judgments in the medical outcome assessment--a systematic approach to the analysis of implicit normativity in evidence based medicine. Zeitschrift fur arztliche Fortbildung und Qualitatssicherung. 2007;101(7):473-80)
2. Drummond et al., 2005 Methods for the Economic Evaluation of Health Care Programmes

Ethical analysis

Authors: Plamen Dimitrov, Anelia Koteva

Summary

IVIG assessment in patients with early Alzheimer’s disease complies with the fundamental ethical principles, as already mentioned. Identified and discussed are the challenges that the use of this technology may provoke for both the patients themselves and their families, on the one hand as well as for the medical staff and the healthcare system management, on the other hand. Part of the problems related to the protection of human dignity of dementia patients could be regulated by some European and international legal documents such as the Charter of Fundamental Rights of the European Union and the Convention for the Protection of Human Rights and Biomedicine, while others, associated with a fair and balanced distribution of health resources for society as a whole, should be addressed and regulated at national/ regional level.

 

Introduction

Due to its prevalence, duration, lack of effective therapy and complex patient care, Alzheimer’s disease has recently become a highly important public health issue. Together with the scientific efforts to clarify the causes of the disease and find the most effective treatment and adequate care for the sick, the researchers seek to better understand the psychological and social impact of the disease on the patients themselves, their families and society as a whole.

 

The ethical analysis aims at providing a balance between norms and values through the discussion of social, political, cultural, legal, religious and economic issues arising from the opposition to the generally accepted societal values, healthcare system goals and the application of new technologies.

 

The present domain focuses on the ethical issues associated with the application of the innovative IVIG technology for the treatment of patients with MCI by debating the following areas:

• Improving the quality of life of patients;
• Impaired decision-making competence and freedom of choice/autonomy of patients with MCI;
• Fair and balanced distribution of resources;
• Equal access to treatment;
• Stigmatization.

Methodology

Frame

The collection scope is used in this domain.

Technology	Immunoglobulins (IGG) Description Naturally occurring proteins produced by the body’s immune system to combat foreign antigens
Intended use of the technology	Treatment Treatment of Alzheimer’s disease Target condition Alzheimer’s disease Target condition description Alzheimer's disease (AD) or Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. Target population Target population sex: Any. Target population age: elderly. Target population group: Patients who have the target condition. Target population description AD is diagnosed mostly in people over 65 years of age, although there is an early-onset form that can occur much earlier. According to Wikipedia in 2006, there were 26.6 million sufferers worldwide.
Comparison	placebo, not doing anything or Usual supportive care Description There is no MA for IGGs for AD yet and there is no other intervention licensed for use in AD so the comparison would have to be against placebo or best supportive care
Outcomes	Description of aims of technology (TECH) Regulatory status (CUR) Cognitive function (EFF) Harms (SAF) Cost effectiveness compared to alternatives (ECO) Potential impact on plasma derivative market (ORG/Medico-legal) Impact on family and carers (SOC) Appropriateness of use in relation to solidity of evidence(ETH)

Assessment elements

	Topic	Issue	Relevant	Research questions or rationale for irrelevance
F0100	Beneficence/nonmaleficence	What is the severity level of the condition that the technology is directed to?	yes	What is the severity level of the condition that IGG is directed to?
F0010	Beneficence/nonmaleficence	What are the known and estimated benefits and harms for patients when implementing or not implementing the technology?	yes	What are the known and estimated benefits and harms for patients when implementing or not implementing IGG?
F0011	Beneficence/nonmaleficence	What are the benefits and harms of the technology for other stakeholders (relatives, other patients, organisations, commercial entities, society, etc.)?	yes	What are the benefits and harms of IGG for other stakeholders (relatives, other patients, organisations, commercial entities, society, etc.)?
F0003	Beneficence/nonmaleficence	Are there any other hidden or unintended consequences of the technology and its applications for different stakeholders (patients/users, relatives, other patients, organisations, commercial entities, society etc.)?	yes	Are there any other hidden or unintended consequences of IGG and its applications for different stakeholders (patients/users, relatives, other patients, organisations, commercial entities, society etc.)?
F0005	Autonomy	Is the technology used for patients/people that are especially vulnerable?	yes	Is IGG used for patients/people that are especially vulnerable?
F0004	Autonomy	Does the implementation or use of the technology affect the patient´s capability and possibility to exercise autonomy?	yes	Does the implementation or use of IGG affect the patient´s capability and possibility to exercise autonomy?
F0006	Autonomy	Is there a need for any specific interventions or supportive actions concerning information in order to respect patient autonomy when the technology is used?	yes	Is there a need for any specific IGGs or supportive actions concerning information in order to respect patient autonomy when IGG is used?
F0007	Autonomy	Does the implementation or withdrawal of the technology challenge or change professional values, ethics or traditional roles?	yes	Does the implementation or withdrawal of IGG challenge or change professional values, ethics or traditional roles?
F0009	Respect for persons	Does the implementation or use of the technology affect the user´s moral, religious or cultural integrity?	yes	Does the implementation or use of IGG affect the user’s moral, religious or cultural integrity?
F0008	Respect for persons	Does the implementation or use of the technology affect human dignity?	no	This question is more in the area of legal issues. Implementation of IG do not affect any aspects of human dignity.
F0101	Respect for persons	Does the technology invade the sphere of privacy of the patient/user?	no	Every technology to some extend is dealing with the privacy of the patients. The current one has much less potential to harm privacy comparing with many others
F0012	Justice and Equity	How does implementation or withdrawal of the technology affect the distribution of health care resources?	yes	How does implementation or withdrawal of IGG affect the distribution of health care resources?
F0013	Justice and Equity	How are technologies with similar ethical issues treated in the health care system?	yes	How are technologies with similar ethical issues treated in the health care system?
H0012	Justice and Equity	Are there factors that could prevent a group or persons to participate?	yes	Are there factors that could prevent a group or persons to participate?
F0102	Ethical consequences of the HTA	Does the economic evaluation of the technology contain any ethical problems?	yes	Does the economic evaluation of IGG contain any ethical problems?
F0103	Ethical consequences of the HTA	What are the ethical consequences of the assessment of the technology?	yes	What are the ethical consequences of the assessment of IGG?
F0017	Ethical consequences of the HTA	What are the ethical consequences of the choice of end-points, cut-off values and comparators/controls in the assessment?	no	This intervention may not have various cut-off values and end-points. Therefore no ethical consequences to consider.
F0014	Legislation	Does the implementation or use of the technology affect the realisation of basic human rights?	no	This question falls within the scope of Legal domain. Such intervention by our opinion is far from harming basic human rights stated in the UN Universal Declaration of Human Rights
F0016	Legislation	Can the use of the technology pose ethical challenges that have not been considered in the existing legislations and regulations?	no

Methodology description

The Ethical domain has been developed in compliance with the fundamental ethical principles, basically following the method of principalism. Consistently presented are ethical arguments related to the autonomy and benefits for the patient as well as possible complications and limitations pertaining to the implementation of the health technology discussed, without aiming to give a definite answer or “ethical prescription”.

 

The domain comprises 19 issues, preliminarily divided into 4 sections, as listed below:

 

• Section 1 – Beneficence/Nonmaleficence;
• Section 2 – Autonomy;
• Section 3 – Respect for Persons;
• Section 4 – Justice and Equity.

 

We have answered 14 issues. The other 5 issues we consider either irrelevant or have marked them as a “skipped issue”. More specifically unanswered are:

 

• Issue 10 (marked as irrelevant);
• Issue 11 (marked as irrelevant);
• Issue 17 (marked as irrelevant);
• Issue 18 (marked as irrelevant);
• Issue 19 (marked as skipped).

 

 

The object of the analysis is the treatment with intravenous immunoglobulins of patients with early-stage Alzheimer’s disease – an innovative immunotherapy, which is still at the experimental stage.

 

The intravenous immunoglobulin infusions by maintaining optimal level of antibodies in the patient’s organism constitute a form of an experimental passive immunotherapy with a potential for reduction of beta-amyloid plaques, where the technology is expected to help completely heal or significantly improve the cognitive status of the treated subjects with all subsequent benefits, i.e. improved social interaction and quality of life.

 

The object of treatment are adults of both sexes, diagnosed with Alzheimer’s disease at the stage of MCI with an estimate of progression of the disease.

 

Alzheimer’s disease, the most common cause of dementia, belongs to the group of neurodegenerative diseases characterized by unknown etiology, hereditary predisposition and gradual progression over many years. The disease is of great medical and social importance with unnoticeable onset and irreversible course, being incurable at present, leading to death.

Result cards

Beneficence/nonmaleficence

Autonomy

Respect for persons

Justice and Equity

Ethical consequences of the HTA

Discussion

As already stated, the analysis is based on different information sources pointing out that the IVIG innovative health technology is still at the experimental stage. Therefore, the future results of the final stage of the experiment are likely to affect all or some of the ethical considerations already debated on the effectiveness and adequacy of the use of IVIG technology in patients suffering from Alzheimer’s disease in the prodromal MCI stage.

The therapeutic use of the innovative technology faces several ethical challenges. The major issue concerns the respect for the autonomy of the patients with impaired/reduced decision-making capacity, which requires that the engaged healthcare staff demonstrate more correctness and patience towards the sick ones. Moreover, the early stage of Alzheimer’s disease is difficult to diagnose and may sometimes be carrying the risk of false diagnosis, thus resulting in stigmatization and social isolation of patients and their families, which contradicts the ethical principle of nonmaleficence. The third major ethical problem generated by the application of the very technology is associated with the principle of equitable distribution of resources. The use of immunoglobulins for the treatment of patients with Alzheimer’s disease is likely to create a deficit of the same products by reducing the possible therapeutic options for other groups of patients, for whom there is no other alternative treatment.

We believe that the information discussed in the Ethical domain is therefore sufficient to support the process of assessment and the related decision-making process at national/regional level.

References

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1. Kral, V., “Senescent Forgetfulness: Benign and Malignant”, Journal of the Canadian Medical Association, February, 1962, vol. 86 (6): 257-260, available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1848846/pdf/canmedaj00930-0002.pdf ;

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Organisational aspects

Authors: Pseudo117 Pseudo117, Pseudo451 Pseudo451, Pseudo136 Pseudo136, Pseudo262 Pseudo262

Summary

It is not possible to determine with certainty whether use of Intravenous immunoglobulins for Alzheimer disease including Mild Cognitive Impairment affects significantly organisational aspects.

The current overview can be used as a starting point for further research on the organisational impact of use of Intravenous immunoglobulins for Alzheimer disease including Mild Cognitive Impairment.

Introduction

The most issues of this domain should not be included in the HTA on the “Use of Intravenous immunoglobulins for Alzheimer disease including Mild Cognitive Impairment”.

From a organisational point of view the “Health Problem and Current Use of the Technology” domain, “Description and technical characteristics of technology” domain already includes the use and technical characteristics of technology.

For Mild Cognitive Impairment, and Moderate to Severe there is no available evidence, while for Mild to Moderate Alzheimer disease there is upcoming evidence.

The technology under assessment is still in its early stage of development and evidence based answers to the AEs of ORG domain we selected during the protocol, cannot be given. On the other hand decisions about their use for treating one category of patients or another rise ethical questions related to how to use limited resources (ETH domain).

Methodology

Frame

The collection scope is used in this domain.

Technology	Immunoglobulins (IGG) Description Naturally occurring proteins produced by the body’s immune system to combat foreign antigens
Intended use of the technology	Treatment Treatment of Alzheimer’s disease Target condition Alzheimer’s disease Target condition description Alzheimer's disease (AD) or Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. Target population Target population sex: Any. Target population age: elderly. Target population group: Patients who have the target condition. Target population description AD is diagnosed mostly in people over 65 years of age, although there is an early-onset form that can occur much earlier. According to Wikipedia in 2006, there were 26.6 million sufferers worldwide.
Comparison	placebo, not doing anything or Usual supportive care Description There is no MA for IGGs for AD yet and there is no other intervention licensed for use in AD so the comparison would have to be against placebo or best supportive care
Outcomes	Description of aims of technology (TECH) Regulatory status (CUR) Cognitive function (EFF) Harms (SAF) Cost effectiveness compared to alternatives (ECO) Potential impact on plasma derivative market (ORG/Medico-legal) Impact on family and carers (SOC) Appropriateness of use in relation to solidity of evidence(ETH)

Assessment elements

	Topic	Issue	Relevant	Research questions or rationale for irrelevance
G0001	Health delivery process	How does the technology affect the current work processes?	yes	How does IGG affect the current work processes?
G0100	Health delivery process	What kind of patient/participant flow is associated with the new technology?	yes	What kind of patient/participant flow is associated with IGG?
G0002	Health delivery process	What kind of involvement has to be mobilized for patients/participants and important others?	yes	What kind of involvement has to be mobilized for patients/participants and important others?
G0003	Health delivery process	What is the process ensuring proper education and training of the staff?	yes	What is the process ensuring proper education and training of the staff?
G0004	Health delivery process	What kind of co-operation and communication of activities have to be mobilised?	yes	What kind of co-operation and communication of activities have to be mobilised?
G0012	Health delivery process	How is the quality assurance and monitoring system of the new technology organised?	yes	How is the quality assurance and monitoring system of IGG organised?
G0005	Structure of health care system	How does de-centralisation or centralization requirements influence the implementation of the technology?	yes	How does de-centralisation or centralization requirements influence the implementation of IGG?
G0101	Structure of health care system	What are the processes ensuring access to care of the new technology for patients/participants?	yes	What are the processes ensuring access to care of IGG for patients/participants?
G0006	Process-related costs	What are the processes related to purchasing and setting up the new technology?	yes	What are the processes related to purchasing and setting up IGG?
G0007	Process-related costs	What are the likely budget impacts of implementing the technologies being compared?	yes	What are the likely budget impacts of implementing the technologies being compared?
G0008	Management	What management problems and opportunities are attached to the technology?	yes	What management problems and opportunities are attached to IGG?
G0009	Management	Who decides which people are eligible for the technology and on what basis?	yes	Who decides which people are eligible for intravenous immunoglobulin (IVIG) therapy and on what basis?
G0010	Culture	How is the technology accepted?	yes	How is IGG accepted?
G0011	Culture	How are the other interest groups taken into account in the planning / implementation of the technology?	yes	How are the other interest groups taken into account in the planning / implementation of IGG?

Methodology description

The project scope is applied in this domain.

Result cards

Health delivery process

Structure of health care system

Process-related costs

Management

Culture

Discussion

According to the information available at the time of writing, IVIG are not used for Alzheimer’s disease including Mild Cognitive Impairment in any of the EUnetHTA partners, and is quite difficult to find available information on the organizational aspects.

References

1. White-Reid K, Scherf R. Giving intravenous immunoglobulin. Modern Medicine, 2008; Accessed the 17th of November 2014 from http://www.modernmedicine.com/modern-medicine/content/giving-intravenous-immunoglobulin
2. Silvergleid, A.J, Berger, M. General principles in the use of immune globulin. UpToDate; Accessed 9 of October 2013.
3. Brodaty H, Breteler MM, Dekosky ST, Dorenlot P, Fratiglioni L, Hock C, Kenigsberg PA, Scheltens P, De Strooper B.; The world of dementia beyond 2020; 2011; J Am Geriatr Soc.
4. Department of Health. 2008. Demand Management Plan for Immunoglobulin Use. United Kingdom. Available from http://www.ivig.nhs.uk/documents/Demand_Management_Plan_SECOND_EDITION.pdf ; Accessed the 4th December 2014.
5. National Blood Authority. 2014. Home » Best Practice » Immunoglobulin Product Authorisation and Management » Ig Program. Commonwealth of Australia. Available from http://www.blood.gov.au/Ig-program; Accessed the 4th December 2014.
6. Provincial Health Services Authority. 2014. IVIG Provincial Program [Internet]. BC, Canada. Available from http://www.pbco.ca/index.php/programs/ivig-provincial-program; Accessed the 4th December 2014.
7. National Blood Authority. 2014. Home » Best Practice » Immunoglobulin Product Authorisation and Management » Ig Program. Commonwealth of Australia. Available from http://www.blood.gov.au/Ig-program; Accessed the 4th December 2014.
8. Loeffler DA. Intravenous immunoglobulin and Alzheimer’s disease: what now? J Neuroinflamm 2013, 10:70.

Social aspects

Authors: Alessandra Lo Scalzo, Cristina Mototolea, Ingrid Wilbacher

Summary

In the absence of any discernible difference against placebo the social aspects cannot be defined

Introduction

The technology under assessment is still in its early stage of development and evidence based answers to the AEs of SOC domain we selected during the protocol, cannot be given. The issues of this domain should not be included in the HTA on the “Use of Intravenous immunoglobulins for Alzheimer disease including Mild Cognitive Impairment”. On the other hand decisions about their  use for treating one category of patients or another rise ethical questions related to how to use limited resources (ETH domain).

From a micro-sociological point of view (related to the impact of the technology on patients QoL) the EFF domain had included the QoL outcome (D0012 and D0013) and the reader can be referred to this domain. In short, for Mild Cognitive Impairment, and Moderate to Severe there is no available evidence, while for Mild to Moderate Alzheimer disease there is upcoming evidence (ongoing RCT and before and after study by Relkin 2012). For the phase 3 double-blind, placebo-controlled, two dose arm RCT, aiming at testing the safety and effectiveness of IVIG for patients with mild-to-moderate AD whose results were posted on clinical trial register in October 23rd 2014, after completion of this report,  see EFF domain’s comment.  As regard to  outcomes such as activity of daily living (ADCS-ADL) and quality of life (both in patients and caregivers according to QOLAD), EFF domain’s report that there is no difference between IVIG and placebo groups.

Methodology

Frame

The collection scope is used in this domain.

Technology	Immunoglobulins (IGG) Description Naturally occurring proteins produced by the body’s immune system to combat foreign antigens
Intended use of the technology	Treatment Treatment of Alzheimer’s disease Target condition Alzheimer’s disease Target condition description Alzheimer's disease (AD) or Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. Target population Target population sex: Any. Target population age: elderly. Target population group: Patients who have the target condition. Target population description AD is diagnosed mostly in people over 65 years of age, although there is an early-onset form that can occur much earlier. According to Wikipedia in 2006, there were 26.6 million sufferers worldwide.
Comparison	placebo, not doing anything or Usual supportive care Description There is no MA for IGGs for AD yet and there is no other intervention licensed for use in AD so the comparison would have to be against placebo or best supportive care
Outcomes	Description of aims of technology (TECH) Regulatory status (CUR) Cognitive function (EFF) Harms (SAF) Cost effectiveness compared to alternatives (ECO) Potential impact on plasma derivative market (ORG/Medico-legal) Impact on family and carers (SOC) Appropriateness of use in relation to solidity of evidence(ETH)

Assessment elements

	Topic	Issue	Relevant	Research questions or rationale for irrelevance
H0100	Individual	What kind of changes do patients or citizens expect?	yes	What kind of changes do patients or citizens expect?
H0002	Individual	Who are the important others that may be affected, in addition to the individual using the technology?	yes	Who are the important others that may be affected, in addition to the individual using IGG?
H0004	Individual	What kind of changes may the use of the technology generate in the individual's role in the major life areas?	yes	What kind of changes may the use of IGG generate in the individual's role in the major life areas?
H0006	Individual	How do patients, citizens and the important others using the technology react and act upon the technology?	yes	How do patients, citizens and the important others using IGG react and act upon IGG?
H0012	Individual	Are there factors that could prevent a group or persons to participate?	yes	Are there factors that could prevent a group or persons to participate?
H0003	Individual	What kind of support and resources are needed for the patient or citizen as the technology is introduced?	no	The technology doesn not seem to imply any support for patients
H0001	Major life areas	Which social areas does the use of the technology influence?	yes	Which social areas does the use of IGG influence?
H0009	Major life areas	What influences patients’ or citizens’ decisions to use the technology?	yes	What influences patients’ or citizens’ decisions to use IGG?
H0011	Major life areas	What kinds of reactions and consequences can the introduction of the technology cause at the overall societal level?	no	This technology should not have this effect
H0007	Information exchange	What is the knowledge and understanding of the technology in patients and citizens?	no	The use of the technology does not necessarly imply a specific understanding/knowledge
H0013	Information exchange	What are the social obstacles or prospects in the communication about the technology?	no	The use of this technology does not seem to depend on social obastcles

Result cards

Individual

Major life areas

Collection appendices

Appendix 1 - Legal aspects of the technology