Mercer's Institute for Research on Ageing, St. James's Hospital, Dublin, Ireland.
Department of Medical Gerontology, Trinity College Dublin (TCD), Dublin, Ireland.
PLoS Med. 2018 Sep 24;15(9):e1002660. doi: 10.1371/journal.pmed.1002660. eCollection 2018 Sep.
This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease.
NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid.
The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease.
Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.
本研究报告了首次大规模的、由研究者主导的 III 期临床试验结果，该试验旨在使用二氢吡啶（DHP）钙通道阻滞剂尼伐地平减缓阿尔茨海默病的认知衰退速度。尼伐地平获许可用于治疗高血压，可减少淀粉样蛋白的产生，增加区域性脑血流，并在临床前研究中表现出抗炎和抗 tau 活性，这些特性可能对阿尔茨海默病具有疾病修饰作用。我们旨在确定尼伐地平是否能有效减缓轻度至中度阿尔茨海默病患者的认知衰退速度。
nilvad 是一项为期 18 个月、随机、安慰剂对照、双盲试验，于 2013 年 5 月 15 日至 2015 年 4 月 13 日期间招募参与者。该研究在欧洲九个国家的 23 个学术中心进行。在 577 名筛查参与者中，有 511 名符合条件并被随机分配（258 名接受安慰剂，253 名接受尼伐地平）。参与者每天早餐后服用一次试验治疗胶囊，持续 78 周。参与者年龄大于 50 岁，符合国家神经病学与交流障碍及阿尔茨海默病协会（NINCDS-ADRDA）对可能患有阿尔茨海默病的诊断标准，采用标准简易精神状态检查（SMMSE）评分≥12 且<27。参与者被随机分配至 8mg 缓释尼伐地平或匹配的安慰剂。预先确定的主要结局是改良意向治疗人群（mITT，n=498）中阿尔茨海默病评估量表认知子量表-12（ADAS-Cog 12）的进展，以临床痴呆评定量表总和评分（CDR-sb）作为门控共同主要结局，有资格成为主要终点，前提是对 ADAS-Cog 12 有显著影响。分析集的平均年龄为 73 岁，女性占 62%。治疗组之间的人口统计学和阿尔茨海默病特定特征相似，报告的平均发病时间为 1.7 年，平均 SMMSE 为 20.4。预先指定的主要分析未能显示尼伐地平在共同主要结局上有任何治疗益处（p=0.465）。安慰剂组在 13 周、52 周和 78 周时，ADAS-Cog 12 的基线下降分别为 0.79（95%CI，-0.07-1.64）、6.41（5.33-7.49）和 9.63（8.33-10.93），尼伐地平组分别为 0.88（0.02-1.74）、5.75（4.66-6.85）和 9.41（8.09-10.73）。对计划中的次要结局的探索性分析显示没有实质性影响，包括 CDR-sb 或痴呆症残疾评估。尼伐地平似乎安全且耐受良好。死亡率在两组之间相似（尼伐地平组 3 例，安慰剂组 4 例）；尼伐地平组（1129 例）比安慰剂组（1030 例）的不良事件（AE）更多，严重不良事件（SAE）也更多（146 例比 101 例）。有 14 例因 AE 退出试验。该研究的主要局限性是受试者已患有痴呆症，且由于缺乏脑淀粉样蛋白存在的生物标志物确认，可能包括非阿尔茨海默病受试者。
这些结果表明尼伐地平作为轻度至中度阿尔茨海默病患者的治疗方法没有益处。
Clinicaltrials.gov NCT02017340，EudraCT 编号 2012-002764-27。
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