MedCheck in English No 27

Supplementary appendix
Sept. 15, 2023
MedCheck Editorial teamTable. List of FailedExperimental Drugs for
Alzheimer’s Disease
Targeting Amyloid-Beta
Accumulation
Table by Pubulic Citizen
Health Research Grouphttps://www.citizen.org/wp-content/uploads/2598.pdf
Referring1) Alavi A, Barrio JR, Werner TJ, et al. Suboptimal validity ofamyloid imaging-based diagnosis and management of
Alzheimer’s disease: why it is time to abandon the approach.
Eur J Nucl Med Mol Imaging. 2020;47(2):225–230. and2) Panza F, Lozupone M, Logroscino G, et al.
A critical appraisal of amyloid-β-targeting therapies for
Alzheimer disease. Nat Rev Neurol. 2019;15(2):73-88.

30% of 5967
Assigned mITT population
39 (898-859) 22 (897-875)

mITT population：randomly assigned
participants who received at least one dose of
lecanemab or placebo and underwent
assessment for the primary end point.
*: At the final evaluation stage, it is possible toLec PL OR LL
PUL
exclude those who have severe adverse events
Discontinued trial
169 140 1.25 0.98 1.60 0.071
and whose symptoms do not seem to improve
Discontinued trial having AE
51 28 1.87 1.17 2.99 0.008
well, from assessment for the primary end point.
Assigned mITT population
39 22 1.81 1.06 3.07 0.027
It leads to an overestimation of efficacy oflecanemab.
AE leading to discontinuation of study agent 62 26 2.48 1.56 3.92 <0.0001

AE leading todiscontinuation oftrial agent
62/898 vs 26/897
OR=2.48 (1.52, 3.73)
P＝0.00008

Macrohemorrhage
5 vs 1

Figure: Proportion of participants who discontinued and the reasons

It is unclear what adverse event
caused the discontinuation.
Differences in overall cognitive function that take into
account the cognitive function of participants corresponding
to the difference (2.6% to 4.0%) have not been reported.
Therefore, there is no evidence that lecanemab delayed theworsening of cognitive function.
mITT population：randomly assigned participants who received at least one doseof lecanemab or placebo and underwent assessment for the primary end point.
*: At the final evaluation stage, it is possible to exclude those who have severeadverse events and whose symptoms do not seem to improve well, from assessment
for the primary end point. It leads to an overestimation of efficacy of lecanemab.

レカネマブの有害事象（AE)、プラセボとの比較
22

AEtrial agent
AE related to
輸注反応（IRR)
IRR (Infusion RelatedReaction)

7

ARIA-H
ARIA-H

814
112

14138

頭痛
Headache

AE leading to discontinuation
中断に至るAEof trial agent

3

脳表ヘモジデリン沈着症
Superficialsiderosis

21176

AEなし
No AE

110

プラセボ
Placebo
Lecanemab
レカネマブ

26

重篤AE
SeriousAE
ARIA-E
ARIA-E

4510AE: Adverse event
ARIA ：Amyloid Related Imaging Abnormality
ARIA-H: ARIA with hemorrhage or siderosis
ARIA-E: ARIA with edema
IRR: Infusion Related Reaction
1820割合（％）

30405

Baseline characteristics are for ｍITT population
What about the baselinecharacteristics of those
excluded, especially theirstatus of dementia ?

What are the results ofthe primary endpoint(cognitive function)
for those excluded?
The results are notreported in this paper.

How is the protocol written?
9.7.1.7.4 of the protocol states thatchanges after 18 months will be
evaluated using CDR-SB, ADCOMS,ADAS-cog-14, and MMSE.
However, what is actually describedin the paper is only for the first
three. MMSE, which is one of themost important outcome measures,
was only listed in the baselinecharacteristics in Table 1.
Wasn’t it because there was no
significant change that MMSE wasnot included as in the reported
outcome measures?

No statistical analysis plan in the Protocol

Statistical Methods
All statistical analyses will be performed by the sponsor ordesignee after the study is completed and the database islocked and released for unblinding. Details of the statisticalanalyses will be included in a separate statisticalanalysis plan (SAP).

No statistical analysis plan
Study EndPoint
Core study
Primary endpoint●Change from baseline in the CDR-AB at 18 months.

In the other part of the protocol, same sentences are repeated
9.7 Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study iscompleted and the database is locked and released for unblinding. Statistical analyses will be
performed using SAS software or other validated statistical software as required. Details of
the statistical analyses will be included in a separate statistical analysis plan (SAP).

9.7.5 Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how therevision impacts the study and how the revision should be implemented. The details of therevision will be documented and described in the clinical study report.

These are not included in the supplementary appendix of the paper.