The Rationale and Design of the Reducing Pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR) Trial

Article type: Research Article

Authors: Kehoe, Patrick G.^{a; *} | Blair, Peter S.^b | Howden, Beth^b | Thomas, David L.^{c; d} | Malone, Ian B.^d | Horwood, Jeremy^b | Clement, Clare^b | Selman, Lucy E.^b | Baber, Hannah^b | Lane, Athene^b | Coulthard, Elizabeth^e | Passmore, Anthony Peter^f | Fox, Nick C.^d | Wilkinson, Ian B.^g | Ben-Shlomo, Yoav^h

Affiliations: [a] Dementia Research Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Faculty of Health Sciences, Level 1 Learning and Research>, Southmead Hospital, Bristol, UK | [b] Bristol Randomised Trials Collaboration (BRTC), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK | [c] Leonard Wolfson Experimental Neurology Centre, UCL Institute of Neurology, Queen Square, London, UK | [d] Dementia Research Centre (DRC), Institute of Neurology, University College London, Queen Square, London, UK | [e] ReMemBr Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Faculty of Health Sciences, Brain Centre, Southmead Hospital, Bristol, UK | [f] Institute of Clinical Sciences, Queens University Belfast, Royal Victoria Hospital, Belfast, UK | [g] Division of Experimental Medicine and Immunotherapeutics, School of Clinical Medicine, University of Cambridge, and Clinical Trials Unit, Addenbrookes Hospital, Cambridge, UK | [h] Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

Correspondence: [*] Correspondence to: Patrick Gavin Kehoe, PhD, Professor of Translational Dementia Research, Dementia Research Group, School of Clinical Sciences, Faculty of Health Sciences,University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK. Tel.: +44 117 4147821; E-mail: [email protected].

Abstract: Background:Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer’s disease (AD) pathology and reduce the rate of disease progression. Objective:To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR). Methods:Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables. Results:The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits. Conclusion:This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted.

Keywords: Alzheimer’s disease, clinical trial, hypertension, parental history, renin-angiotensin system, vascular risk

DOI: 10.3233/JAD-170101

Journal: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 803-814, 2018