Abstract
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).
| Original language | English |
|---|---|
| Pages (from-to) | 895-906 |
| Number of pages | 12 |
| Journal | Lancet Neurology |
| Volume | 20 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2021 |
Bibliographical note
Funding Information:PGK reports grants from the National Institute of Health Research (NIHR), during the conduct of the study; being a non-funded co-investigator of the ongoing Alzheimer's Association-funded HEART phase 1b study of telmisartan and its use as an intervention against the renin–angiotensin system in African American people at risk of developing dementia by parental history; and having previously undertaken advisory work for Novartis in their development and intended trialling of dual acting inhibitors of Angiotensin Receptor Blockers and neprilysin (LCZ696) for the treatment of heart failure. NT, BH, LJ, SLB, IBM, CN, NJT, PSB, JAL, PP, JT, DLT, IW, and YBS report grants from the NIHR, during the conduct of the study. JB reports grants from Alzheimer's Research UK, outside the submitted work. CHS reports grants for the Alzheimer's Society, during the conduct of the study. EC reports grants from the NIHR, during the conduct of the study; and received payment from Biogen, Novartis, and Union Chimique Belge for providing educational resources or consultancy around Alzheimer's Disease trials. NCF reports other funding from Roche, personal fees from Biogen, and non-financial support from Lilly and Ionis, outside the submitted work. AW and H-JM declare no competing interests.
Funding Information:
The RADAR Study Investigators thank the various groups of people who made the conduct of this study possible. We thank participants and their study companions who consented to take part and give their time to allow this research question to be addressed. We would also like to thank past and present members of the University College London Dementia Research Centre team who supported the quality assurance review process for all the MRI scans from the RADAR centres, which were crucial to the randomisation process. We thank all current and previous academic and lay members of the Trial Steering Committee for their continuous advice, support, and encouragement throughout the conduct of the study. We also thank the members of the Data Monitoring and Ethics Committee for their time, effort, and helpful advice while monitoring our study. We thank the past and present members of the Wales Research Ethics Committee 2 Cardiff for their guidance and advice at various parts of the study and to members of the Health Research Authority for their guidance to us through the new procedures arising from its formation during the study. We also thank the many members of the various research teams and associated Research and Development Governance teams at individual sites that are as follows: North Bristol NHS Trust (site 10), Bristol, UK; Sheffield Teaching Hospital Trust (site 11), Sheffield, UK; 2gether NHS Foundation Trust (site 12), Cheltenham, UK; Oxford Health NHS Foundation Trust (site 13), Oxford, UK; NHS Tayside (site 15), Dundee, UK; NHS Lothian (site 16), Edinburgh, UK; NHS Borders (site 17), Melrose, UK; NHS Grampian (site 18), Aberdeen, UK; NHS Greater Glasgow and Clyde (site 19), Glasgow, UK; North Staffordshire Combined Healthcare NHS Trust (site 20), Stoke-on-Trent, UK; Torbay and South Devon NHS Foundation Trust (site 21), Torquay, UK; Salford Royal NHS Foundation Trust (site 22), Salford, UK; Norfolk and Suffolk NHS Foundation Trust (site 23), Norwich, UK; Royal Devon and Exeter NHS Foundation Trust (site 24), Exeter, UK; NHS Ayrshire and Arran (site 25), Kilmarnock, UK; NHS Lanarkshire (site 26) Bothwell, UK; Leeds & York Partnership NHS Trust (site 27), Leeds, UK; NHS Forth Valley (site 28), Larbert, UK; NHS Fife (site 29), Kirkcaldy, UK; Newcastle upon Tyne NHS Foundation Trust (site 30), Newcastle, UK; Kent and Medway NHS and Social Care Partnership Trust (site 31), Gillingham, UK; Midlands Partnership NHS Foundation Trust (site 32), Stafford,UK; Belfast Health and Social Care Trust (site 33), Belfast, UK. We acknowledge the contributions of John Starr (University of Edinburgh and NHS Lothian) who died during the study. We also thank past and present members of our sponsor; the Research and Innovation team at North Bristol NHS Trust for their guidance and help throughout the conduct and completion of the study; and the members, past and present, of the NIHR projects management team for their guidance and collaborative support in our efforts to deliver the RADAR study to completion. The RADAR study team would also like to thank the Bristol Trials Centre for its hosting of this study and its support throughout and members of the South West Dementia Brain Bank, University of Bristol, for providing technical assistance and help with the coordination of the retrieval and processing of volunteered research blood samples for the study. The views expressed in this publication are those of the author(s) and not necessarily those of the UK Medical Research Council, National Institute for Health Research, or the Department of Health and Social Care.
Publisher Copyright:
© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
Research Groups and Themes
- Translational Dementia Research Group