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

Abstract

BackgroundGlobalization 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.MethodsData 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.ResultsCompletion 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.ConclusionsRegional 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 registrationClinicalTrials.gov, NCT01955161. Registered on 27 September 2013.ClinicalTrials.gov, NCT02006641. Registered on 5 December 2013.ClinicalTrials.gov, NCT02006654. Registered on 5 December 2013.

Recruitment and retention of participant and study partner dyads in two multinational Alzheimer’s disease registration trials

“…Alternatively, a recent review of an antidepressant clinical trial found no significant difference in dropout between academic and non-academic sites [ 15 ]. Multinational trials are essential to regulatory goals and a thorough understanding of drug safety, but may carry increased risk of variability, including differences in the proportions of enrolled study partner dyad types by geographic region [ 16 , 17 ]. Completion rates also may differ among global geographic regions in multinational trials [ 16 ].…”

Statistical Disease Progression Modeling in Alzheimer Disease

“…Such biomarker-based synchronization of patient's disease stage would enable testing a drug in a more homogeneous population. This would in turn greatly increase the power of clinical trials in AD where it is common to see extreme levels of variability in patient trajectories (Cummings et al, 2018 ; Ballard et al, 2019 ).…”

Diagnosis of Alzheimer’s Disease in Developed and Developing Countries: Systematic Review and Meta-Analysis of Diagnostic Test Accuracy

“…In contrast, the developed countries like the US and Canada have a stable economy and have established funding agencies and research organizations that provide funding for research and conducts epidemiological, clinical, and pre-clinical studies on mental health diseases like AD. It is estimated that AD is one of the most financially costly diseases and managed by federal government funding agencies in developed nations [9]. The total estimated worldwide cost of dementia was US$ 818 billion in 2015, which represents 1.09% of global GDP and by 2018, the global cost of dementia raises above US$ 1 trillion.…”