Current Landscape of Late-Phase Clinical Trials for Alzheimer’s Disease: Comparing Regional Variation Between Subjects in Japan and North America
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Over the last few decades, numerous late-phase multi-regional clinical trials have been conducted to develop a novel treatment for Alzheimer’s disease (AD), with no effective results.
To inform the design and interpretation of future clinical trials, the aim of this study was first to examine the current landscape of late-phase clinical trials to determine key study design characteristics, and then assess the regional variation between Japan and North America for the most utilized clinical efficacy endpoint in the most targeted stage of the disease.
The study design and the mechanism of action of the interventional drugs tested in the late-phase clinical trials initiated in the last 5 years (2014–2018) were assessed based on the records in ClinicalTrials.gov database. The regional variation of the most utilized clinical efficacy endpoint in the most targeted population was assessed using data from two similarly designed observational studies conducted in Japan (Japanese Alzheimer’s Disease Neuroimaging Initiative, J-ADNI) and North America (Alzheimer’s Disease Neuroimaging Initiative, ADNI). For the most utilized clinical efficacy endpoint, the change from baseline (CFB) at Month 6, Year 1 and Year 2 was estimated using the growth curve model with a random intercept and slope, including gender as a fixed factor and age, apolipoprotein E ε4 genotype and years of education as covariates.
Of 48 Phase III trials that were initiated during the study period, 25 were disease-modifying treatment trials in which individuals with early AD were the most studied (56%) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) was the most frequently utilized primary clinical efficacy endpoint (64%). The baseline characteristics of the early AD population between J-ADNI and ADNI were generally comparable, except for years of education. When comparing CDR-SB in early AD, J-ADNI had generally better baseline scores and the overall progression was similar (CFB at Year 2, ADNI 2.7 and J-ADNI 2.3, p = 0.190), despite slower progression in functional domains (CFB at Year 2, ADNI 1.4 and J-ADNI 1.0, p = 0.031).
Over the years, the target population has shifted toward early stage of the disease, wherein the clinical progression is slower and difficult to measure. Moreover, our results suggest that regional variation could have an impact on functional measurements due to cultural differences in pivotal clinical trials. Therefore, caution should be exercised according to the characteristics of the endpoint used.
For the J-ADNI J-ADNI was supported by the following grants: Translational Research Promotion Project from the New Energy and Industrial Technology Development Organization of Japan; Research on Dementia, Health Labor Sciences Research Grant; Life Science Database Integration Project of Japan Science and Technology Agency; Research Association of Biotechnology (contributed by Astellas Pharma Inc., Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly and Company, Merck-Banyu, Mitsubishi Tanabe Pharma, Pfizer Inc., Shionogi and Co., Ltd., Sumitomo Dainippon, and Takeda Pharmaceutical Company), Japan, and a grant from an anonymous Foundation. For the NA-ADNI Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson and Johnson Pharmaceutical Research and Development LLC.; Lumosity; Lundbeck; Merck and Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
Compliance with Ethical Standards
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of interest
Masashi Kikuchi and Noriaki Adachi are a full-time employees of MSD K.K. Naoki Matsumaru and Katsura Tsukamoto declare no conflicts of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
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