Now we come to the Phase III trial, the last in the Eisai evidence development plan submitted to regulators.

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There are four main phases of clinical trials – Phase 1 trials are the earliest phase trials, and Phase 3 are later phase trials that compare new treatments with the best currently available treatment to find out which treatment works better,  more about the adverse effects and should include an assessment of quality of life. 

Study 301 is “A randomized, double-blind, parallel-group trial conducted at 235 study centers in Japan and other countries to evaluate if lecanemab was superior to placebo in terms of slowing disease progression in patients with early AD (target sample size, approximately 1,766 subjects)”.

The duration, including the OLE phase, was 60 months.

Eisai Ltd used a single schedule of 10mgs/Kgs twice a week, presumably as this was shown in Phase II as the less toxic regime. They also changed the MAB commercial name to BAN2401, probably to suit the US market. So, the official study number is BAN2401-G000-301.

The study protocol – dated 29 Jan 2019, reports the Primary Objective as follows:

To evaluate the efficacy of BAN2401 in subjects with early Alzheimer’s disease (EAD) by determining the superiority of BAN2401 compared with placebo on the change from baseline in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months of treatment.

So, no more ADCOMS? 

The 132-page protocol is not an easy read. It includes a mishmash of analyses. For example, page 129 reports:

MMRM means Mixed model for repeated measures 

We counted 27 other objectives in the protocol, divided into key secondary, other secondary, biomarker objectives, exploratory, extension phase primary and exploratory objectives. So, that means that 28 outcomes were analysed alone or in combination for 6-time points (3 in the blinded phases and 3 in the OLE phase). This multiple testing ensures that at least one analysis in 20 will yield significance by chance alone. 

The main outcomes are:

CDR-SB Clinical Dementia Rating-Sum of Boxes. 

This is the primary outcome of study BAN2401-G000-301. Its use is recommended by Cedarbaum et al. in a US NIH-funded review, which concluded that “The CDR-SB has psychometric properties that make it attractive as a primary outcome measure that comprehensively assesses both cognitive and functional disability in AD patients. It may prove particularly useful for studies in early predementia stages of AD”. 

Some authors belonged to commercial enterprises included in the “Alzheimer's Disease Neuroimaging Initiative” such as Cytokinetics, Inc., South San Francisco, CA, USA, and Elan Pharmaceuticals, South San Francisco, CA, USA. Global R&D Partners, LLC., San Diego, CA, USA and several departments of the University of Toulouse, France. The paper was published in the JOURNAL OF THE ALZHEIMER SOCIETY. The Society did well in 2023:

Eisai is the number one contributor. All others must have skin in AD products currently on the market or in the pipeline. So lots more to come, folks. 

ADCOMS = Alzheimer’s Disease Composite Score is next. As we have shown in Episode 3, Eisai also mainly funded its development.

 ADAS-cog14 score = Alzheimer’s Disease Assessment Scale-Cognitive subscale with 14 tasks. 

Well, this one is different, as Biogen funded its development (see Cohen et al.), and Helios Medical Communications and MediTech Media, Ltd. ghosted the paper.

Next comes ADCS-MCI-ADL = Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment. A study by Potashman et al. validated this. Five of the seven authors are or were employees of Biogen who funded the study.

MMSE = Mini-Mental State Examination. This test did not impress the authors of the relevant Cochrane review: “Our review did not find evidence supporting a substantial role of MMSE as a stand-alone single-administration test in the identification of MCI patients who could develop dementia. Clinicians could prefer to request additional and extensive tests to be sure about the management of these patients. An important aspect to assess in future updates is if conversion to dementia from MCI stages could be predicted better by MMSE changes over time instead of single measurements. It is also important to assess if a set of tests, rather than an isolated one, may be more successful in predicting conversion from MCI to dementia.”

PET-SUVr  = Positron emission tomography - Standard uptake value ratio. There does not appear to be a direct commercial influence in this (apart from the manufacturers of PET machines, but that’s OK).

There are so many secondary outcomes, but by this stage, the two old geezers are tired old geezers; our readers should be punch drunk and get the point. 

Multiplicity is one of the ruses that pharma companies use to guarantee success, and it’s one of several reasons clinical trial outcomes fail to translate into patient benefit. 

This post was written by two old geezers who would not recognise 758 thousand banknotes if they hit them in the face. 

Readings

Heneghan C et al. Why clinical trial outcomes fail to translate into benefits for patients. Trials 1. Trials 18, 122 (2017). https://doi.org/10.1186/s13063-017-1870-2

Cedarbaum, J.M., Jaros, M., Hernandez, C., Coley, N., Andrieu, S., Grundman, M., Vellas, B. and (2013), Rationale for use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer's disease clinical trials. Alzheimer's & Dementia, 9: S45-S55. https://doi.org/10.1016/j.jalz.2011.11.002

S. Cohen, J. Cummings, S. Knox, et al. Clinical Trial Endpoints and Their Clinical Meaningfulness in Early Stages of Alzheimer’s Disease. J Prev Alz Dis 2022;3(9):507-522; https://doi.org/10.14283/jpad.2022.41

Potashman M, Pang M, Tahir M, Shahraz S, Dichter S, Perneczky R, Nolte S. Psychometric properties of the Alzheimer's Disease Cooperative Study - Activities of Daily Living for Mild Cognitive Impairment (ADCS-MCI-ADL) scale: a post hoc analysis of the ADCS ADC-008 trial. BMC Geriatr. 2023 Mar 6;23(1):124. doi: 10.1186/s12877-022-03527-0. PMID: 36879199; PMCID: PMC9990271.

S. Cohen, J. Cummings, S. Knox, et al. Clinical Trial Endpoints and Their Clinical Meaningfulness in Early Stages of Alzheimer’s Disease. J Prev Alz Dis 2022;3(9):507-522; https://doi.org/10.14283/jpad.2022.41

Arevalo-Rodriguez I, Smailagic N, Roqué-Figuls M, Ciapponi A, Sanchez-Perez E, Giannakou A, Pedraza OL, Bonfill Cosp X, Cullum S. Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2021 Jul 27;7(7):CD010783. doi: 10.1002/14651858.CD010783.pub3. PMID: 34313331; PMCID: PMC8406467.