Cleveland Clinic Lou Ruvo Center for Brain Health, 888 W Bonneville Avenue, Las Vegas, NV, 89106, USA.
Banner Sun Health Research Institute, Sun City, AZ, USA.
Alzheimers Res Ther. 2018 Nov 24;10(1):116. doi: 10.1186/s13195-018-0443-2.
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.
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.
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-ADL) 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-ADL, from -3.21 points in Western Europe/Israel to -0.59 points in Eastern Europe/Turkey.
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.
ClinicalTrials.gov, NCT01955161 . Registered on 27 September 2013. ClinicalTrials.gov, NCT02006641 . Registered on 5 December 2013. ClinicalTrials.gov, NCT02006654 . Registered on 5 December 2013.
临床试验的全球化对试验规划和解释具有重要影响。本研究调查了 idalopirdine 全球 3 期临床项目中世界各地区患者特征和结局的异质性。
汇总了来自三项年龄≥50 岁、轻度至中度阿尔茨海默病（AD）患者（n=2506）的 24 周随机对照试验的数据。患者接受 idalopirdine（10、30 或 60mg/天）或安慰剂治疗，联合胆碱酯酶抑制剂治疗。患者被分为以下地区：东欧/土耳其（n=759）、西欧/以色列（n=709）、美国/加拿大（n=444）、南美/墨西哥（n=361）、亚洲（n=134）和澳大利亚/南非（n=99）。对于每个地区，采用描述性统计方法总结了操作特征、基线人口统计学和临床特征、不良事件以及临床评定量表评分从基线到第 24 周的平均变化（仅安慰剂组）。
所有地区的完成率为 0.86-0.90。全球各地区之间存在明显的异质性。南美/墨西哥的方案偏离率是美国/加拿大的两倍（每筛查 1 例患者分别为 2.64 和 1.35）。教育程度从南美/墨西哥的 9.2 年到美国/加拿大的 13.4 年不等。APOE ε4 携带率在澳大利亚/南非为 80.6%，在西欧/以色列为 63.1%，在其他地区则低于 60%。筛查时的简易精神状态检查（MMSE）评分在东欧/土耳其（18.0）和美国/加拿大（17.5）较高，而在其他地区（16.9-17.1）较低。基线 AD 评估量表-认知子量表（ADAS-Cog）评分在美国/加拿大（24.3）和南美/墨西哥（27.2）较高，在其他地区（24.3-27.2）较低。基线 AD 合作研究-日常生活活动量表，23 项版（ADCS-ADL）评分在美国/加拿大（58.5）较高，在东欧/土耳其（53.5）较低。在安慰剂组中，西欧/以色列、美国/加拿大和澳大利亚/南非的不良事件发生率比东欧/土耳其高 1.6-1.7 倍。在 ADAS-Cog 上，澳大利亚/南非和西欧/以色列的安慰剂组患者恶化最明显（分别为 1.56 和 1.40 分），而南美/墨西哥则有改善（-0.71 分）。所有地区的 ADCS-ADL 评分均恶化，从西欧/以色列的-3.21 分至东欧/土耳其的-0.59 分。
在规划和开展多国 AD 临床试验时，应考虑到研究实施、患者特征和结局方面的地区异质性。
ClinicalTrials.gov，NCT01955161。于 2013 年 9 月 27 日注册。ClinicalTrials.gov，NCT02006641。于 2013 年 12 月 5 日注册。ClinicalTrials.gov，NCT02006654。于 2013 年 12 月 5 日注册。
