Objective: The objective of this study was to systematically review and conduct a direct and network meta-analysis of randomized controlled trials that have examined the clinical safety and efficacy of using passive and active immunotherapies in Alzheimer’s disease (AD). (PDF) Safety and efficacy of active and passive immunotherapy in mild-to-moderate Alzheimer’s disease: A systematic review and network meta-analysis. Available from: https://www.researchgate.net/publication/331985667_Safety_and_efficacy_of_active_and_passive_immunotherapy_in_mild-to-moderate_Alzheimer's_disease_A_systematic_review_and_network_meta-analysis [accessed May 09 2020].

1. A systematic review and network meta-analysis of safety and efficacy of active and
passive immunization in mild-to-moderate Alzheimer`s disease
Naghmeh Foroutan 1,2, Robert Hopkins 1, 2, Jean-Eric Tarride 1, 2, Mitchell Levine 1,2
1PATH Research Institute, St. Joseph’s Healthcare Hamilton, Hamilton, ON; 2Department of Clinical Epidemiology & Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, ON
BAC KG RO U N D
Alzheimer`s disease (AD) is caused by the accumulation of β-amyloid (Aβ).
Preventing the formation of Aβ plaques is the central focus of AD management.
Objective: The primary objective of the present study is to systematically review
and conduct a network meta-analysis of RCTs that have examined the clinical
safety and efficacy of using passive and active amyloid- based immunotherapies
in Alzheimer’s disease.
M E T H O D S
A systematic review of published phase 2 and 3 RCTs was performed in
MEDLINE, EMBASE, PubMed and Cochrane library. Two reviewers independently
selected the studies, extracted the data and assessed risk of bias. Study
inclusion criteria were based upon the following PICO description:
 Population: All adults with clinical diagnosis of mild-to-moderate
Alzheimer`s disease (AD) according to standardized diagnostic criteria
 Intervention: Any medicines for active or passive immunotherapy
(Bapineuzumab, Solanezumab, AN1792 (vaccine), Semagacestat, 3APS,
IVIG)
 Comparator(s): Passive and active immunotherapies or Placebo
 Outcome(s): Alzheimer’s Disease Assessment Scale-cognitive subscales
(ADAS-cog), Clinical Dementia Rating scale (CDR) and Mini–Mental State
Examination (MMSE), Amyloid Related Imaging Abnormalities with Edema
(ARIA-E), rate of neoplasms and mortality
Statistical analysis: A direct comparison meta-analysis using a random effects
model and a network comparison were conducted to calculate mean differences
in treatment effects, SUCRA and ranking probabilities for each medicine per
safety and efficacy outcomes.
R E S U LT S
Efficacy Assessment (ADAS-cog, CDR, MMSE): After a sensitivity analysis removing high
risk of bias studies, immunotherapies compared to placebo produced a statistically (not
clinically) significant improvement in ADAS-cog (MD=-0.387, 95% CI -0.42, -0.35, P<0.01)
and MMSE (MD=0.16, 95% CI 0.14, 0.18, P<0.01) from baseline, whereas the overall results
for CDR showed no benefits for the treatment group.
Safety Assessment (ARIA-E, neoplasms, mortality): Rate of ARIA-E was significantly
higher (RR= 9.3, 95% CI, 3.56, 24.35; P<0.01) with monoclonal antibodies than placebo.
There were no significant difference between placebo and immunotherapies in terms of
rates of neoplasms and mortality.
Network ranking results: Solanezumab (monoclonal antibody) and AN1792 (vaccine) were
drugs of choice
C O N C LU S I O N S
ADAS-cog and Mortality forest & network plots
R E S U LT S ( C O N T ’ D )
RCTs characteristics Range
Number of patients
randomized (sample
size)
55- 1331
Follow-up duration 3- 20 month
Study design 6 studies phase 2 and 6
studies phase 3
Risk of bias 1 study with loss of
follow-up>20%
APOE Ꜫ4 carrier % 55- 75 (0 in one study)
Sources of heterogeneity
There is unlikely to be any implementation of immunotherapies in
AD in practice over next 5 years
Drugs recommended for future studies:
Vaccines, IVIG
In terms of efficacy, the review showed a significant improvement in at least two
AD specific scales (ADAS-cog and MMSE) in favor of immunotherapy versus
placebo. AN1792 and solanezumab (active and passive immunotherapies) were
recommended as drugs of choice based on SUCRA results.
AN1792 needs to be improved regarding safety concerns (meningoencephalitis). A
new formulation (ACC-001) is under development and Phase 2 RCTs are ongoing.
Heterogeneity between groups: p = 0.000
Overall (I-squared = 99.1%, p = 0.000)
Dodel
Doody (Expedition2)
Subtotal (I-squared = .%, p = .)
Farlow
Bapz 1mg/kg
Doody (Expedition1)
Salloway (Carrier)
Subtotal (I-squared = 88.9%, p = 0.000)
Solz 400 mg IV
Subtotal (I-squared = .%, p = .)
ID
Subtotal (I-squared = .%, p = .)
Bapz 0.5mg/kg
Gilman
3APS 150 mg BID
IVIG 0.4 g/kg
Aisen
Semagt 140mg
Subtotal (I-squared = .%, p = .)
Subtotal (I-squared = .%, p = .)
Salloway
Fleisher
Subtotal (I-squared = .%, p = .)
AN1792 225 mcg
Study
-0.63 (-0.67, -0.59)
4.80 (-0.17, 9.77)
-1.60 (-1.70, -1.50)
0.10 (-0.06, 0.26)
-1.10 (-2.53, 0.33)
-1.30 (-1.40, -1.20)
-0.20 (-0.26, -0.14)
-1.44 (-1.51, -1.37)
0.00 (-0.99, 0.99)
WMD (95% CI)
2.42 (-0.85, 5.69)
1.10 (-1.79, 3.99)
0.10 (-0.06, 0.26)
-0.20 (-0.26, -0.14)
1.10 (-1.79, 3.99)
0.00 (-0.99, 0.99)
2.42 (-0.85, 5.69)
4.80 (-0.17, 9.77)
100.00
0.01
17.36
7.27
0.09
19.19
55.87
36.64
0.18
Weight
0.02
0.02
7.27
55.87
0.02
0.18
0.02
0.01
%
-0.63 (-0.67, -0.59)
4.80 (-0.17, 9.77)
-1.60 (-1.70, -1.50)
0.10 (-0.06, 0.26)
-1.10 (-2.53, 0.33)
-1.30 (-1.40, -1.20)
-0.20 (-0.26, -0.14)
-1.44 (-1.51, -1.37)
0.00 (-0.99, 0.99)
WMD (95% CI)
2.42 (-0.85, 5.69)
1.10 (-1.79, 3.99)
0.10 (-0.06, 0.26)
-0.20 (-0.26, -0.14)
1.10 (-1.79, 3.99)
0.00 (-0.99, 0.99)
2.42 (-0.85, 5.69)
4.80 (-0.17, 9.77)
100.00
0.01
17.36
7.27
0.09
19.19
55.87
36.64
0.18
Weight
0.02
0.02
7.27
55.87
0.02
0.18
0.02
0.01
%
0-9.77 0 9.77
Placebo
Immunotherapies
PRISMA Flowchart
NOTE: Weights are from random effects analysis
.
.
.
.
.
.
Overall (I-squared = 0.0%, p = 0.779)
Bapz 1mg
ID
Doody, 2014
Salloway, 2014 (carrier study)
Gilman, 2005
Aisen, 2011
Salloway, 2014 (non-carrier
Subtotal (I-squared = 0.0%, p = 0.331)
3APS150mg
segamet140mg
Bapz 0.5mg
Subtotal (I-squared = .%, p = .)
solz400mg
Subtotal (I-squared = .%, p = .)
Subtotal (I-squared = .%, p = .)
Subtotal (I-squared = .%, p = .)
Salloway, 2014 (non-carrier
Doody, 2013
Subtotal (I-squared = .%, p = .)
AN1795
Study
1.42 (0.97, 2.07)
RR (95% CI)
1.25 (0.69, 2.28)
1.95 (0.71, 5.32)
0.61 (0.12, 3.07)
3.04 (0.12, 74.44)
1.58 (0.56, 4.47)
1.42 (0.65, 3.08)
3.04 (0.12, 74.44)
0.61 (0.12, 3.07)
2.19 (0.85, 5.65)
1.58 (0.56, 4.47)
0.89 (0.26, 3.02)
2.19 (0.85, 5.65)
1.25 (0.69, 2.28)
70/3595
Treatment
24/1051
15/673
5/305
1/348
7/336
19/1014
1/348
5/305
14/541
7/336
4/341
14/541
24/1051
Events,
46/3477
Control
19/1044
5/437
2/74
0/353
7/531
12/968
0/353
2/74
6/507
7/531
7/531
6/507
19/1044
Events,
100.00
Weight
40.28
14.15
5.45
1.40
13.25
23.74
1.40
5.45
15.88
13.25
9.59
15.88
40.28
%
1.42 (0.97, 2.07)
RR (95% CI)
1.25 (0.69, 2.28)
1.95 (0.71, 5.32)
0.61 (0.12, 3.07)
3.04 (0.12, 74.44)
1.58 (0.56, 4.47)
1.42 (0.65, 3.08)
3.04 (0.12, 74.44)
0.61 (0.12, 3.07)
2.19 (0.85, 5.65)
1.58 (0.56, 4.47)
0.89 (0.26, 3.02)
2.19 (0.85, 5.65)
1.25 (0.69, 2.28)
70/3595
Treatment
24/1051
15/673
5/305
1/348
7/336
19/1014
1/348
5/305
14/541
7/336
4/341
14/541
24/1051
Events,
1.0134 1 74.4
Placebo
Immunotherapies
Records identified through
database searching
(n =956)
Records after duplicates removed
(n = 828)
Records excluded not
meeting inclusion
criteria
(n =792)
Full-text articles
assessed for
eligibility
(n = 36)
Full-text articles
excluded, with reasons
(n = 26)
- Non-RCTs (n=2)
- No reported required
data for primary
outcomes (n=7)
- Trials do not meet
inclusion (PICOS)
criteria (n=14)
- Same study with
multiple articles (n=2)
- Post-hoc analyses
(n=1)
Articles included in
qualitative synthesis
(n =10)
Studies included in
quantitative synthesis
(meta-analysis)
(n = 12)
Records passed title
& abstract screening
(n = 36)
Records identified from
other reviews references
(n =6)