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  • 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?
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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?

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

Internal reviewers: Gerardo Atienza, Lavinia Panait

The same methodology was used as described in section for the whole domain.

MCI

There are no data for patients with MCI.

AD

Placebo-controlled trials

Data from three RCTs (one multiple dose study {Arai 2014}, one phase 2, dose-finding study, {Dodel 2013}, and one phase 3 study {NCT00818662}) were available for analysis. See a synopsis of results on Table 4.

In Arai 2014, the proportion of participants who experienced any AEs was similar in IVIG and placebo group: 10/12 (83%) and 4/4 (100%), respectively. A total of 33 treatment-emergent AEs occurred, 26 in IVIG group and 7 in placebo group. Most AEs in the IVIG group were mild or moderate. No deaths occurred in this trial. The most common AEs in the IVIG group were nasopharyngitis (16.7%, three events in two subjects),  injection-site swelling and erythema (16.7%, two events in two subjects). In the placebo group, the incidence of nasopharyngitis was reported to be 25.0% (one event in one subject), and no events of injection-site swelling or erythema occurred. The incidence of any AE did not significantly differ between the IVIG group and the placebo group or between the IVIG 0.2 g/kg and IVIG 0.4 g/kg groups.

Four SAEs were observed in three patients: one event (cataract) in the IVIG 0.2 g/kg group, and three events (patella fracture, radius fracture, and pneumonia) in two subjects in the placebo group. All these SAE were classified by the investigator as being unrelated to the study drug. There were no significant differences between the IVIG groups and the placebo group or between the IVIG 0.2 g/kg and IVIG 0.4 g/kg groups. The incidence of adverse drug reactions occurring in the IVIG group was 33.3% (nine events in four subjects) and 0 in the placebo group. However only one event (rash on the extremity and the trunk with mild elevations in aspartate amino transferase, alanine amino transferase, and lactose dehydrogenase) in one patient was considered ‘possibly associated’ to IVIG treatment. This patient was the only one that missed one infusion of the study drug because of that event. The other eight events (one event each for sinusitis, oral herpes, decreased neutrophil count, white blood cell count decreased, decreased neutrophil percentage, monocyte percentage increase, lymphocyte percentage increase, and erythema) were assessed as ‘unlikely associated’. No microhaemorrhages were registered at MRI in both treatment groups.

The authors of the above mentioned RCT concluded that IVIG treatment is generally safe and well tolerated at doses of 0.2 and 0.4 g/kg in Japanese patients with mild to moderate AD. 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, the proportion of participants who experienced any AEs was similar in IVIG and placebo group: 25/42 (60%) and 9/14 (64%), respectively (p=0.75). Ten SAEs were observed in eight patients with higher proportion (not statistically significant) in the placebo group (4/14, 29%) versus IVIG group (4/42, 10%), p=0.078. Most AEs in the IVIG group were mild or moderate. No deaths occurred in this trial. The incidence of AEs leading to study discontinuation was higher with IVIG then with placebo; three patients on IVIG did not completed the study because of AEs. One 68-year-old women in the high-dose treatment group had a SAE, ischaemic stroke (middle cerebral artery infarction). One patient was removed from the study due to 14 new microbleeds at week 12 seen on MRI scan, without clinical symptoms. For the 3rd patient the specific AE that led to study discontinuation was not reported in the article nor was visible in trial registers. Authors did not record any changes in white matter (amyloid-related imaging abnormalities) nor aseptic meningitis and meningoencephalitis. No microbleeds were registered for patients treated with placebo whilst 6/42 (14%) patients treated with IVIG experienced microbleeds but were asymptomatic. 3/42 and 2/42 patients treated with IVIG experienced headache and hypoaestesia, respectively, versus no patient in the placebo arm. The following AEs were listed with a frequency of 2% or more in experimental arm: chills, influenza-like illness, tremor, muscle spasm, procedural hypertension, actinic keratosis, hyperkeratosis, pruritus, blood pressure fluctuation, impaired hearing, increased AST, increased LDH, dyspepsia, haematuria, fatigue, pyrexia, falls, infusion site extravasation. The authors of the above mentioned RCT concluded that IVIG has acceptable safety profile for patients with mild-to-moderate AD but stated limitations like small sample size in each group and short duration of treatment (only 6 months).

In NCT00818662 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. No deaths occurred in placebo group. The incidence of AEs leading to study discontinuation was higher with IVIG then with placebo (7.3% vs 5.8%). Reasons were not reported. 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%).

 

Table 4. Summary of adverse events (AE) in one published RCTs on patients with mild-moderate AD

 

N = 12

N = 4

 

N = 42

N =14

 

N=262

121

 

Any AE

10 (83.3%)

4 (100%)

not reported

25 (60.0)

9 (64.0)

0.75 (not reported)

not reported

not reported

not reported

Serious AEs

1 (8.3%)

3 (75.0%)

not reported

4 (10.0)

4 (29.0)

0.078 (not reported)

53 (20.2)

26 (21.5)

not reported

Non Serious AEs

not reported

not reported

not reported

not reported

not reported

not reported

230 (87.8)

103 (85.1)

not reported

AEs leading to discontinuation

1 (8.3%)

0

not reported

3 (7.14)

0 (0)

not reported

not reported

not reported

not reported

Abbreviations: AEs=Adverse events

*Please note that patients had to have been taking a stable dose of an approved AD drug for at least 3 months before screening; use of acetylcholinesterase inhibitor or memantine as reported in Table 1 of Dodel 2013: 36/42  (88%) patients randomised to IVIG and 11/14  (79%) patients randomised to placebo.

 

 

Table 5. Description of Serious AEs, most frequent AEs and AEs leading to discontinuation of treatment.

 

Arai 2014

IVIG all doses (N = 12) vs Placebo

(N =4)

Dodel 2013

IVIG all doses (N = 42) vs Placebo

(N =14)

NCT00818662

IVIG all doses (N = 262) vs Placebo

(N =121)

Description of Serious AEs (No more than 1 or 2 per group) (MedDRA 12.0)

 

 

n (%)

n (%)

Microcytic anaemia

not reported

not reported

2 (0.8%) vs 0

Coronary Artery Disease

not reported

not reported

2 (0.8%) vs 0

Gastral antral vascular ectasia

not reported

0 vs 1 (7%)

not reported

Nausea / Vomiting

not reported

1 (2%) vs 0

1 (0.4%) vs 0

Chest pain

not reported

not reported

3 (1.1%) vs 0

Multi­Organ Failure

not reported

not reported

2 (0.8%) vs 0

Anaphylactic Reaction

not reported

not reported

1 (0.4%) vs 0

Subdural Haematoma

not reported

not reported

2 (0.8%) vs 0

Cerebral infarction

not reported

1 (2%) vs 0

not reported

Cerebral haemorrhage

not reported

not reported

1 (0.4%) vs 0

Convulsion

not reported

0 vs 1 (7%)

not reported

Partial seizures

not reported

not reported

2 (0.8%) vs 0

Dementia Alzheimer's progression

not reported

1 (2%) vs 0

not reported

Delirium

not reported

1 (2%) vs 0

not reported

Agitation

not reported

not reported

1 (0.4%) vs 2 (1.6%)

Confusional state

not reported

not reported

2 (0.8%) vs 0

Aggression

not reported

0 vs 1 (7%)

not reported

Knee arthroplasty

not reported

0 vs 1 (7%)

1 vs 0

Spinal laminectomy

not reported

1 (2%) vs: 0

not reported

Cataract

1 (8.3%) vs 0

not reported

not reported

Patella fracture

0 vs 1 (25.0%)

not reported

not reported

Radius fracture

0 vs 1 (25.0%)

not reported

not reported

Pneumonia

0 vs 1 (25.0%)

not reported

1 (0.4%) vs 1 (0.8%)

Description of most frequent AEs (above 5%)

n (%)

n (%)

n (%)

Eye disorders

2 (16.7%) vs 0

not reported

2 (0.8%) vs 0

Microbleeds / Cerebral Microhaemorrhage

not reported

6 (14%) vs 0

9 (3.4%) vs 4 (3.3%)

Dizziness

not reported

0 vs 1 (7%)

29 (11.1%) vs 12 (9.9%)

Paresthesia

not reported

0 vs 1 (7%)

not reported

Hypoaesthesia

not reported

2 (5%) vs 0

not reported

Increased CSF white-blood-cell count

not reported

0 vs 1 (7%)

not reported

Atrial fibrillation

not reported

0 vs 1 (7%)

2 (0.8%) vs 2 (1.6%)

Agitation

not reported

0 vs 1 (7%)

19 (7.3%) vs 10 (8.3%)

Bradycardia

not reported

not reported

5 (1.9%) vs 8 (6.6%)

Diarrhoea

not reported

not reported

37 (14.1%) vs 15 (12.4%)

Nausea

not reported

not reported

27 (10.3%) vs 10 (8.3%)

Vomiting

1 (8.3%) vs 0

not reported

28 (10.7%) vs 5 (4.1%)

Chills

not reported

not reported

25 (9.5%) vs 3 (2.5%9

Fatigue

not reported

not reported

23 (8.8%) vs 12 (9.9%

Infections and infestations

3 (25.0%) vs 2 (50.0%)

not reported

86 (32.8) vs 57 (47.1%)

Infusion site extravasation / swelling

2 (16.7%) vs 0

not reported

38 (14.5) vs 21 (17.4%)

Erythema

2 (16.7%) vs 0

not reported

not reported

Oedema peripheral

1 (8.3%) vs 0

not reported

12 (4.6%) vs 6 (5%)

Pyrexia

not reported

not reported

14 (5.3%) vs 4 (3.3%)

Nasopharyngitis

2 (16.7%) vs 1 (25.0%)

not reported

16 (6.1%) vs 9 (7.4%)

Upper Respiratory Tract Infection

not reported

not reported

16 (6.1%) vs 10 (8.3%)

Urinary Tract Infection

not reported

not reported

20 (7.6%) vs 15 (1..4%)

Contusion

not reported

not reported

22 (8.4%) vs 10 (8.3%)

Fall

not reported

not reported

30 (11.5%) vs 23 (19%)

Laceration

not reported

not reported

12 (4.6%) vs 9 (7.4%)

Blood pressure increased

not reported

not reported

31 (11.8%) vs 9 (7.4%)

Arthralgia

not reported

not reported

19 (7.3%) vs 4 (3.3%)

Back pain

not reported

not reported

23 (8.8%) vs 8 (6.6%)

Headache

not reported

not reported

63 (24%) vs 22 (18.2%)

Tremor

not reported

not reported

13 (5%) vs 5 (4.1%)

Anxiety

not reported

not reported

23 (8.8%) vs 10 (8.3%)

Confusional state

not reported

not reported

18 (6.9%) vs 4 (3.3%)

Depression

not reported

not reported

30 (11.5%) vs 19 (15.7%)

Cough

not reported

not reported

21 (8%) vs 13 (10.7%)

Epistaxis

not reported

not reported

15 (5.7%) vs 3 (2.5%)

Rash

1 (8.3%) vs 0

not reported

40 (15.3%) vs 6 (5%)

Hypertension

not reported

not reported

32 (12.2%) vs 11 (9.1%)

Hypotension

not reported

1 (2%) vs 1 (7%)

9 (3.4%) vs 7 (5.8%)

Description of AEs leading to discontinuation of treatment

 

n (%)

n (%)

Ischaemic stroke

not reported

1 (2%) vs 0

not reported

Microbleeds on MRI scan without symptoms

not reported

1 (2%) vs 0

not reported

Not reported

-

1 (2%) vs 0

19 (7.3%) vs 7 (5.8%)

The overall quality of evidence, assessed according to the GRADE approach, is very low.

 

Table 6. Evidence profile table on adverse events assessed with the GRADE approach (for Arai 2014, Dodel 2013, NCT00818662).

Adverse events

 

 

 

 

 

 

 

 

Frequency of adverse events

2/74

RCT

Arai 2014

Dodel 2013

High1,2

-1

Direct

Limitations for inconsistency

- 1

Limitations (CI NA)

- 1

Limitations

- 1

Small sample size, with small samples in intervention group and very small control group; short duration of treatment

1 RCT: Industry funded and COI;

Evidence of publication bias

Very low

Frequency of serious adverse events

3/457

RCT

Arai 2014

Dodel 2013, NCT00818662

 

High1,2

-1

Direct

Inconsistencies

- 1

Limitations (CI NA)

- 1

Limitations

-1

Industry funded and COI; small sample size, with small samples in intervention group and very small control group; short duration of treatment

Evidence of publication bias

Very low

1 Risk of bias at study level high.

2 High risk of bias at outcome level.

GRADE Working Group grades of evidence:

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: 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 quality: We are very uncertain about the estimate.

 

Active comparator trials

None were published or had visible results in publicly available registers.

 

Studies without comparator

Data from two interventional prospective non-controlled studies { Dodel 2004, Relkin 2009} were available for analysis.

{Dodel 2004}: Despite the fact that authors wrote that no SAE occurred during the study, one patient was admitted to the hospital 2 weeks after IVIG due to confusion that resolved within few days. Headaches was reported in 3 patients, duration less than one day, without any further neurological signs. One patient experienced tooth infection, but according the authors, this AE was not related to the treatment. Authors concluded that IVIG was well tolerated in these 5 patients.

{Relkin 2009}: No SAEs occurred during the study period; five AEs which were judged to be treatment related include one episode each of headache, chills, diaphoresis, fever and transient confusion (symptoms resolved spontaneously without sequelae). Authors stated that there were no AEs incurred during this study that have not been previously reported in association with IVIG therapy in other patient populations.

Table 7. Summary of adverse events (AEs) in two interventional prospective non-controlled studies in patients with mild-to-moderate AD (Dodel 2004, Relkin 2009).

Study (N pts)

Any AE,

n

Treatment related AEs,

n

Serious AEs,

n

AEs leading to discontinuation,

n

Dodel 2004 (N = 5)

5

4

1

0

Relkin 2009 (N = 8)

Not reported

5

0

0

AEs=Adverse events

Critical
Completely
Vignatelli L et al. Result Card SAF1 In: Vignatelli L et al. Safety In: 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 30 October 2020]. Available from: http://corehta.info/ViewCover.aspx?id=267

References