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This information collection is a core HTA, i.e. an extensive analysis of one or more health technologies using all nine domains of the HTA Core Model. The core HTA is intended to be used as an information base for local (e.g. national or regional) HTAs.

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

Immunoglobulins (IGG) compared to placebo, not doing anything or Usual supportive care in the treatment of Alzheimer’s disease in elderly 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.

(See detailed scope below)

HTA Core Model Application for Pharmaceuticals (2.0)
Core HTA
Published
Tom Jefferson (Agenas - Italy), Marina Cerbo (Agenas - Italy), Nicola Vicari (Agenas - Italy)
Alessandra Lo Scalzo (Agenas), Anna-Theresa Renner (GOG), Antonio Migliore (Agenas), Ingrid Wilbacher (HVB), Luca Vignatelli (ASSR RER), Luciana Ballini (ASSR RER), Nadine Berndt (CEM), Nicola Vicari (Agenas), Plamen Dimitrov (NCPHA), Susanna Maltoni (ASSR RER), Ricardo Ramos (INFARMED), Tom Jefferson (Agenas)
Agenas - Agenzia nazionale per i servizi sanitari regionali
AAZ (Croatia), ASSR RER (Italy), Avalia-t (Spain), CEM (Luxembourg), GÖG (Austria), HAS (France), HVB (Austria), IER (Slovenia), INFARMED (Portugal), ISC III (Spain), NCPHA (Bulgaria), NIPH (Slovenia), NSPH (Greece), NSPH MD (Romania), SBU (Sweden), SNHTA (Switzerland), THL (Finland), UTA (Estonia).
13.1.2014 12.32.00
30.11.2015 11.18.00
Jefferson T, Cerbo M, Vicari N [eds.]. Use of Intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment [Core HTA], Agenas - Agenzia nazionale per i servizi sanitari regionali ; 2015. [cited 19 September 2021]. Available from: http://corehta.info/ViewCover.aspx?id=267

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

<< Description and technical characteristics of technologyClinical Effectiveness >>

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.

TechnologyImmunoglobulins (IGG)
Description

Naturally occurring proteins produced by the body’s immune system to combat foreign antigens

Intended use of the technologyTreatment

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. 

Comparisonplacebo, 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

TopicIssue RelevantResearch questions or rationale for irrelevance
C0001Patient safetyWhat kind of harms can use of the technology cause to the patient; what are the incidence, severity and duration of harms?yesWhat 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?
C0002Patient safetyAre the harms related to dosage or frequency  of applying the technology?yesDo 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?
C0008Patient safetyHow safe is the technology in relation to the comparator(s)?yesWhat 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?
C0007Patient safetyAre there special issues in the use of the technology that may increase the risk of harmful events?yesDo IVIG interfere with or are affected by other treatments used in patients with Mild Cognitive Impairment or in patients with Alzheimer’s disease?
C0004Patient safetyHow does the frequency or severity of harms change over time or in different settings?noNo 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)
C0005Patient safetyAre there susceptible patient groups that are more likely to be harmed through use of the technology?noPatients 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.
C0060Safety risk managementHow does the safety profile of the technology vary between different generations, approved versions  or products?yesDoes 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?
C0061Safety risk managementCan different organizational settings increase or decrease harms?noIVIG 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
C0062Safety risk managementHow can one reduce safety risks for patients (including technology-, user-, and patient-dependent aspects)?noBetter in TECH domain
C0063Safety risk managementHow can one reduce safety risks for professionals (including technology-, user-, and patient-dependent aspects)?noWe consider that risks for professionals are quite low, comparable to those of every product to be administered through a parenteral route
C0064Safety risk managementHow can one reduce safety risks for environment (including technology-, user-, and patient-dependent aspects)noSame risks as every other biological waste
C0020Occupational safetyWhat kind of occupational harms can occur when using the technology?noOccupational harms are supposed to be those related to IV drugs, not specific for IVIG
C0040Environmental safetyWhat kind of risks for public and environment may occur when using the technology?noSame 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 24th 2014 and an update was carried out close to the release of the report on December 16th 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 24th 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 16th 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 16th 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

Result card for SAF1: "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?"

View full card
SAF1: 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?
Method
Result

Importance: Critical

Transferability: Completely

Result card for SAF2: "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?"

View full card
SAF2: 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?
Method
Result

Importance: Critical

Transferability: Completely

Result card for SAF3: "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?"

View full card
SAF3: 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?
Method
Result

Importance: Critical

Transferability: Completely

Result card for SAF4: "Do IVIG interfere with or are affected by other treatments used in patients with Mild Cognitive Impairment or in patients with Alzheimer’s disease?"

View full card
SAF4: Do IVIG interfere with or are affected by other treatments used in patients with Mild Cognitive Impairment or in patients with Alzheimer’s disease?
Method
Result

Importance: Important

Transferability: Completely

Safety risk management

Result card for SAF5: "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?"

View full card
SAF5: 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?
Result

Importance: Optional

Transferability: Not

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.

References

Arai H, Ichimiya Y, Shibata N, Nakajima T, Sudoh S, Tokuda T, Sujaku T, Yokokawa S, Hoshii N, Noguchi H, Bille A. Safety and tolerability of immune globulin intravenous (human), 10% solution in Japanese subjects with mild to moderate Alzheimer's disease. Psychogeriatrics 2014;14:165-74.

Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, Guyatt GH. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401-6.

Dodel R, Hampel H, Depboylu C, Lin S, Gao F, Schock S, Jäckel S, Wei X, Buerger K, Höft C, Hemmer B, Möller HJ, Farlow M, Oertel WH, Sommer N, Du Y. Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer's disease. Ann Neurol 2002;52:253-6.

Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Förster S, Winter Y, Bach JP, Popp J, Alferink J, Wiltfang J, Buerger K, Otto M, Antuono P, Jacoby M, Richter R, Stevens J, Melamed I, Goldstein J, Haag S, Wietek S, Farlow M, Jessen F. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol 2013;12:233-43.

EUnetHTA Joint Action WP5. HTA Core Model for Rapid Relative Effectiveness Assessment of Pharmaceuticals. 1 March 2013 – V3.0. Available at http://www.eunethta.eu/outputs/new-application-hta-core-model-hta-core-model-rapid-relative-effectiveness-assessment-pharma; last access February 19th 2014.

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, Norris S, Falck-Ytter Y, Glasziou P, DeBeer H, Jaeschke R, Rind D, Meerpohl J, Dahm P, Schünemann HJ. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011a; 64:383-94.

Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, Montori V, Akl EA, Djulbegovic B, Falck-Ytter Y, Norris SL, Williams JW Jr, Atkins D, Meerpohl J, Schünemann HJ. GRADE guidelines: 4. Rating the quality of evidence—study limitations (risk of bias). J Clin Epidemiol 2011b; 64:407-15

Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, Alonso-Coello P, Djulbegovic B, Atkins D, Falck-Ytter Y, Williams JW Jr, Meerpohl J, Norris SL, Akl EA, Schünemann HJ. GRADE guidelines: 5. Rating the quality of evidence--publication bias. J Clin Epidemiol 2011c; 64:1277-82.

Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, Devereaux PJ, Montori VM, Freyschuss B, Vist G, Jaeschke R, Williams JW Jr, Murad MH, Sinclair D, Falck-Ytter Y, Meerpohl J, Whittington C, Thorlund K, Andrews J, Schünemann HJ. GRADE guidelines 6. Rating the quality of evidence--imprecision. J Clin Epidemiol 2011d; 64:1283-93.

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, Alonso-Coello P, Glasziou P, Jaeschke R, Akl EA, Norris S, Vist G, Dahm P, Shukla VK, Higgins J, Falck-Ytter Y, Schünemann HJ; GRADE Working Group. GRADE guidelines: 7. Rating the quality of evidence--inconsistency. J Clin Epidemiol 2011e; 64:1294-302.

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, Alonso-Coello P, Falck-Ytter Y, Jaeschke R, Vist G, Akl EA, Post PN, Norris S, Meerpohl J, Shukla VK, Nasser M, Schünemann HJ; GRADE Working Group. GRADE guidelines: 8. Rating the quality of evidence--indirectness. J Clin Epidemiol 2011f; 64: 1303-10.

Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P, Atkins D, Kunz R, Brozek J, Montori V, Jaeschke R, Rind D, Dahm P, Meerpohl J, Vist G, Berliner E, Norris S, Falck-Ytter Y, Murad MH, Schünemann HJ; GRADE Working Group. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol 2011g; 64:1311-6

Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, Brozek J, Norris S, Meerpohl J, Djulbegovic B, Alonso-Coello P, Post PN, Busse JW, Glasziou P, Christensen R, Schünemann HJ. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol 2013; 66:158-72.

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Chapter 5:  Defining the review question and developing criteria for including studies; last access February 19th 2014.

Micromedex Drugdex Database, 2014.

National Institute on Aging. AD - Unraveling the Mystery. U.S. Department of Health and Human Services NIH Publication Number: 08-3782; September 2011; available from www.nia.nih.gov/alzheimers, last access 29th January 2014.

National Institute for Health and Clinical Excellence (NICE). NICE technology appraisal guidance 217 Donepezil, galantamine, rivastigmine and memantine for the treatment of AD (review of NICE technology appraisal guidance 111). 2011; available from www.nice.org.uk/guidance/TA217, accessed 2014 Jan 30th.

NCT00299988. Available at http://prsinfo.clinicaltrial.gov/ct2/show/NCT00299988?term=NCT00299988&rank=1; last access December 16th 2014.

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

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

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

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

NCT01736579. Available at http://prsinfo.clinicaltrial.gov/ct2/results?term=NCT01736579&Search=Search, last access December 16th 2014.

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Appendices

Appendix 1

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

SAF Figure 1

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

SAF Appendix 7

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