Insights into globalization: comparison of patient characteristics and disease progression among geographic regions in a multinational Alzheimer's disease clinical program

Abstract

Background: Globalization of clinical trials has important consequences for trial planning and interpretation. This study investigated heterogeneity in patient characteristics and outcomes among world regions in the global idalopirdine Phase 3 clinical program.

Methods: Data were pooled from three 24-week randomized controlled trials in patients aged ≥ 50 years with mild-to-moderate Alzheimer's disease (AD) (n = 2506). Patients received idalopirdine (10, 30, or 60 mg/day) or placebo, added to cholinesterase inhibitor treatment. Patients were categorized into the following regions: Eastern Europe/Turkey (n = 759), Western Europe/Israel (n = 709), USA/Canada (n = 444), South America/Mexico (n = 361), Asia (n = 134), and Australia/South Africa (n = 99). For each region, operational characteristics, baseline demographic and clinical characteristics, adverse events, and mean change from baseline to week 24 in clinical rating scale scores (placebo group only) were summarized using descriptive statistics.

Results: Completion rates were 0.86-0.90 in all regions. Heterogeneity among global regions was evident. Protocol deviations were twice as common in South America/Mexico as in USA/Canada (2.64 vs 1.35 per patient screened). Educational level ranged from 9.2 years in South America/Mexico to 13.4 years in USA/Canada. APOE ε4 carriage was 80.6% in Australia/South Africa, 63.1% in Western Europe/Israel, and < 60% in other regions. Screening Mini-Mental State Examination scores were higher in Eastern Europe/Turkey (18.0) and USA/Canada (17.5) than in other regions (16.9-17.1). Baseline AD Assessment Scale-Cognitive subscale (ADAS-Cog) scores ranged from 24.3 in USA/Canada to 27.2 in South America/Mexico. Baseline AD Cooperative Study-Activities of Daily Living, 23-item version (ADCS-ADL23) scores ranged from 58.5 in USA/Canada to 53.5 in Eastern Europe/Turkey. In the placebo group, adverse events were 1.6-1.7 times more common in Western Europe/Israel, USA/Canada, and Australia/South Africa than in Eastern Europe/Turkey. On the ADAS-Cog, Australia/South Africa and Western Europe/Israel showed the most worsening among patients receiving placebo (1.56 and 1.40 points, respectively), whereas South America/Mexico showed an improvement (-0.71 points). All regions worsened on the ADCS-ADL23, from -3.21 points in Western Europe/Israel to -0.59 points in Eastern Europe/Turkey.

Conclusions: Regional heterogeneity-in terms of study conduct, patient characteristics, and outcomes-exists, and should be accounted for, when planning and conducting multinational AD clinical trials.

Trial registration: ClinicalTrials.gov, NCT01955161 . Registered on 27 September 2013. ClinicalTrials.gov, NCT02006641 . Registered on 5 December 2013. ClinicalTrials.gov, NCT02006654 . Registered on 5 December 2013.

Keywords: Activities of daily living; Alzheimer’s disease; Clinical trial; Cognitive decline; Cognitive dysfunction; Dementia; Disease progression; Globalization; Humans; Patient selection.

Conflict of interest statement

Ethics approval and consent to participate

All studies were conducted in accordance with the International Conference on Harmonisation Good Clinical Practice Guideline and the Declaration of Helsinki. Local ethics committees approved all aspects of study design. Eligible patients or their legal representatives provided written informed consent prior to the start of the studies.

Consent for publication

Not applicable.

Competing interests

JLC reported serving as a consultant to AbbVie, Acadia, Actinogen, Adamas, Alzheon, Anavex, Astellas, Avanir, Avid, Axovant, Boehringer Ingelheim, Bracket, Eisai, GE Healthcare, Genentech, Intra-Cellular Therapies, Lilly, H. Lundbeck A/S, MedAvante, Merck, Neurocog, Novartis, Orion, Otsuka, Pfizer, Piramal, QR Pharma, reMYND, Resverlogix, Roche, Suven, Takeda, Toyama, and Transition; receiving research support from Avid and Teva; owning stock options in Prana, Neurokos, Adamas, MedAvante, and QR Pharma; and owning the copyright of the Neuropsychiatric Inventory and all its derivatives. JLC is supported by Keep Memory Alive and a COBRE grant from the NIGMS (P20GM109025).

AA reported receiving honoraria for consulting, participating in independent data safety monitoring boards, providing educational lectures, programs, and materials, or serving on advisory boards for Allergan, the Alzheimer’s Association, Axovant, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, Lundbeck, Merck, Roche/Genentech, Sunovion, and Suven; receiving book royalties from Oxford University Press; and having institutional contracts or receiving investigational clinical trial-related funding from the American College of Radiology, AbbVie, Avid, Biogen, Lilly, Lundbeck, Merck, and vTV.

CB reported receiving research grants from Acadia and H. Lundbeck A/S; and receiving honoraria from Acadia, Bristol-Myers Squibb, Heptares, Lilly, H. Lundbeck A/S, Novartis, Orion, Otsuka, and Roche.

NB and LLR are full-time employees of H. Lundbeck A/S.

LF reported receiving honoraria for consulting, providing educational lectures, materials, and programs, or serving on advisory boards for Avid–Eli Lilly & Co, Avraham Pharmaceuticals, Axon Neuroscience, Boehringer Ingelheim, GE Healthcare, H. Lundbeck A/S, Merck Sharpe & Dohme, Novartis, Nutricia, Pfizer, Piramal Imaging, Schwabe Pharma, TAD Pharma, and Takeda.

JLM reported receiving honoraria for consulting, providing educational lectures, or serving on advisory boards for ABL, Axovant, Boehringer Ingelheim, Eli Lilly & Co, Fujirebio, GE Healthcare, H. Lundbeck A/S, Merck Sharpe & Dohme, Novartis, Pfizer, Piramal Imaging, Roche, and Roche Diagnostics.

PNT reported receiving consulting fees from Abbott Laboratories, AbbVie, AC Immune, Auspex, Boehringer Ingelheim, Clintara, CME Inc., Corium, GliaCure, INSYS, and T3D; receiving consulting fees and research support from AstraZeneca, Avanir, Cognoptix, Lilly, H. Lundbeck A/S, Merck and Company, and Takeda; receiving research support from Elan, Functional Neuromodulation, Genentech, Novartis, Roche, Targacept, the National Institute on Aging, and the Arizona Department of Health Services; owning stock options in Adamas; and being listed as a contributor to a patent owned by the University of Rochester.

No other disclosures were reported.

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Figures

Fig. 1

Normalized observed decline from baseline to week 24 across regions in placebo group. 100%, maximal decline on the scale observed across regions; 0%, minimum decline/maximum improvement observed on the scale across regions. ADAS-Cog Alzheimer’s Disease Assessment Scale—Cognitive subscale, ADCS-ADL23 Alzheimer’s Disease Cooperative Study—Activities of Daily Living, 23-item version, ADCS-CGIC Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change, MMSE Mini–Mental State Examination, NPI Neuropsychiatric Inventory