Safety and efficacy of losartan for the reduction of brain atrophy in clinically diagnosed Alzheimer's disease (the RADAR trial): a double-blind, randomised, placebo-controlled, phase 2 trial,The Lancet Neurology

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Safety and efficacy of losartan for the reduction of brain atrophy in clinically diagnosed Alzheimer's disease (the RADAR trial): a double-blind, randomised, placebo-controlled, phase 2 trial
The Lancet Neurology ( IF 48.0 ) Pub Date : 2021-10-20 , DOI: 10.1016/s1474-4422(21)00263-5
Patrick Gavin Kehoe ₁ , Nicholas Turner ₂ , Beth Howden ₂ , Lina Jarutyte ₃ , Shona Louise Clegg ₄ , Ian Brian Malone ₄ , Josephine Barnes ₄ , Casper Nielsen ₄ , Carole Hélène Sudre ₅ , Aileen Wilson ₆ , Ngoc Jade Thai ₆ , Peter Sinclair Blair ₂ , Elizabeth Coulthard ₃ , Janet Athene Lane ₂ , Peter Passmore ₇ , Jodi Taylor ₂ , Henk-Jan Mutsaerts ₈ , David Lee Thomas ₄ , Nick Charles Fox ₉ , Ian Wilkinson ₁₀ , Yoav Ben-Shlomo ₂ ,

Affiliation

Dementia Research Group, University of Bristol, Bristol, UK.
Translational Health Sciences, Population Health Sciences, University of Bristol, Bristol, UK; Bristol Trials Centre, University of Bristol, Bristol, UK.
Dementia Neurology Research Group, University of Bristol, Bristol, UK.
Dementia Research Centre, University College London, London, UK; UCL Queen Square Institute of Neurology, University College London, London, UK.
MRC Unit for Lifelong Health and Ageing at UCL, and Centre for Medical Image Computing, University College London, London, UK; School of Biomedical Engineering and Imaging Sciences, Kings College London, UK.
Faculty of Health Sciences, Bristol Medical School, Clinical Research Imaging Centre, University of Bristol, Bristol, UK.
Institute of Clinical Sciences, Queens University Belfast, Royal Victoria Hospital, Belfast, UK.
Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, Netherlands.
Dementia Research Centre, University College London, London, UK; UK Dementia Research Institute, University College London, London, UK; UCL Queen Square Institute of Neurology, University College London, London, UK.
Clinical Pharmacology Unit, School of Clinical Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK.

Background

Drugs modifying angiotensin II signalling could reduce Alzheimer's disease pathology, thus decreasing the rate of disease progression. We investigated whether the angiotensin II receptor antagonist losartan, compared with placebo, could reduce brain volume loss, as a measure of disease progression, in clinically diagnosed mild-to-moderate Alzheimer's disease.

Methods

In this double-blind, multicentre, randomised controlled trial, eligible patients aged 55 years or older, previously untreated with angiotensin II drugs and diagnosed (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) with mild-to-moderate Alzheimer's disease, and who had capacity to consent, were recruited from 23 UK National Health Service hospital trusts. After undergoing a 4-week, open-label phase of active treatment then washout, participants were randomly assigned (1:1) oral over-encapsulated preparations of either 100 mg losartan (after an initial two-dose titration stage) or matched placebo daily for 12 months. Randomisation, minimised by age and baseline medial temporal lobe atrophy score, was undertaken online or via pin-access service by telephone. Participants, their study companions, and study personnel were masked to group assignment. The primary outcome, analysed by the intention-to-treat principle (ie, participants analysed in the group to which they were randomised, without imputation for missing data), was change in whole brain volume between baseline and 12 months, measured using volumetric MRI and determined by boundary shift interval (BSI) analysis. The trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN93682878) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2012–003641–15), and is completed.

Findings

Between July 22, 2014, and May 17, 2018, 261 participants entered the open-label phase. 211 were randomly assigned losartan (n=105) or placebo (n=106). Of 197 (93%) participants who completed the study, 171 (81%) had complete primary outcome data. The mean brain volume (BSI) reduction was 19·1 mL (SD 10·3) in the losartan group and 20·0 mL (10·8) in the placebo group. The difference in total volume reduction between groups was –2·29 mL (95% CI –6·46 to 0·89; p=0·14). The number of adverse events was low (22 in the losartan group and 20 in the placebo group) with no differences between treatment groups. There was one treatment-related death per treatment group.

Interpretation

12 months of treatment with losartan was well tolerated but was not effective in reducing the rate of brain atrophy in individuals with clinically diagnosed mild-to-moderate Alzheimer's disease. Further research is needed to assess the potential therapeutic benefit from earlier treatment in patients with milder cognitive impairment or from longer treatment periods.

Funding

Efficacy and Mechanism Evaluation Programme (UK Medical Research Council and National Institute for Health Research).

中文翻译：

氯沙坦在临床诊断的阿尔茨海默病中减少脑萎缩的安全性和有效性（RADAR 试验）：一项双盲、随机、安慰剂对照的 2 期试验

背景

改变血管紧张素 II 信号的药物可以减少阿尔茨海默病的病理学，从而降低疾病进展的速度。我们研究了与安慰剂相比，血管紧张素 II 受体拮抗剂氯沙坦是否可以减少临床诊断为轻度至中度阿尔茨海默病的脑容量损失，作为疾病进展的衡量标准。

方法

在这项双盲、多中心、随机对照试验中，符合条件的年龄在 55 岁或以上、既往未接受过血管紧张素 II 药物治疗并被诊断为患有轻度从 23 家英国国家卫生服务医院信托基金招募了患有中度阿尔茨海默病且有能力同意的人。在经历了为期 4 周的开放标签阶段的积极治疗后，参与者每天被随机分配（1:1）口服 100 mg 氯沙坦（在最初的两剂滴定阶段后）或匹配的安慰剂的口服过度封装制剂12个月。随机化，按年龄和基线内侧颞叶萎缩评分最小化，是在网上或通过电话通过密码访问服务进行的。参与者、他们的研究同伴和研究人员被蒙蔽到小组分配。通过意向治疗原则分析的主要结果（即，参与者在他们被随机分组的组中进行分析，没有对缺失数据进行插补），是使用容积 MRI 测量的基线和 12 个月之间全脑体积的变化并通过边界移位间隔 (BSI) 分析确定。该试验已在国际标准随机对照试验注册（ISRCTN93682878）和欧盟药品监管机构临床试验数据库（EudraCT 2012-003641-15）注册，并已完成。通过意向治疗原则分析（即，参与者在他们被随机分组的组中进行分析，没有填补缺失数据），是基线和 12 个月之间全脑体积的变化，使用体积 MRI 测量并由边界确定班次间隔（BSI）分析。该试验已在国际标准随机对照试验注册（ISRCTN93682878）和欧盟药品监管机构临床试验数据库（EudraCT 2012-003641-15）注册，并已完成。通过意向治疗原则分析（即，参与者在他们被随机分组的组中进行分析，没有填补缺失数据），是基线和 12 个月之间全脑体积的变化，使用体积 MRI 测量并由边界确定班次间隔（BSI）分析。该试验已在国际标准随机对照试验注册（ISRCTN93682878）和欧盟药品监管机构临床试验数据库（EudraCT 2012-003641-15）注册，并已完成。

发现

2014 年 7 月 22 日至 2018 年 5 月 17 日期间，261 名参与者进入了开放标签阶段。211 人被随机分配氯沙坦（n=105）或安慰剂（n=106）。在完成研究的 197 名 (93%) 参与者中，171 名 (81%) 拥有完整的主要结果数据。氯沙坦组平均脑容量 (BSI) 减少 19·1 mL (SD 10·3)，安慰剂组减少 20·0 mL (10·8)。组间总体积减少的差异为 –2·29 mL（95% CI –6·46 至 0·89；p=0·14）。不良事件的数量很低（氯沙坦组为 22 例，安慰剂组为 20 例），治疗组之间没有差异。每个治疗组有一名治疗相关死亡。