The Effects of Rasagiline on Glucose Metabolism and Cognition and Their Relationship to Tau Burden in a Double-Blind, Placebo-Controlled Phase Ii Clinical Trial of Participants with Alzheimer's Dementia

Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a MAO-B inhibitor, in mild to moderate Alzheimer’s disease. The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (FDG PET) compared to placebo. Secondary objectives included use of flortaucipir PET to assess effects on tau pathology and determination of directional consistency of clinical endpoints with FDG PET. Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG PET was analyzed at screening for the presence of an AD-like pattern as an inclusion criterion and longitudinally using prespecified regions of interest and image classification. Participants who completed baseline and 24-week FDG PET scans and passed quality control were included in the primary analysis; secondary clinical outcomes were analyzed using an ITT model. Findings: Between May 19, 2015 and January 26, 2018, 96 participants were screened, 50 randomized, and 43 completed treatment. The study met its primary endpoint, demonstrating favorable change in FDG PET differences in rasagiline vs. placebo in middle frontal (2·5%,95%CI 0·3–4·7%,p<0·025), anterior cingulate (2·2%,0·1–4·3%,p<0·041), and striatal (2·4%,0·2–4·3%,p<0·023) regions. Tau PET cortical region secondary endpoints did not differ between study arms. Clinical secondary endpoint measures of Quality of Life (p<0·04) and COWAT favored rasagiline. Rasagiline was generally well tolerated with low rates of both serious and other adverse events and notably less neuropsychiatric symptoms reported with rasagiine. Interpretation: These study outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in AD, with positive effects on frontostriatal pathways. Strengths are the FDG PET results coupled with the directional consistency of clinical outcomes. This data adds important converging evidence for POC of rasagiline in patients well characterized using FDG and tau PET. Limitations include the study size and duration. Further investigation of rasagiline in AD is warranted. Funding: Alzheimer’s Drug Discovery Foundation (ADDF) Declaration of Interest: Dawn Matthews is an employee of ADM Diagnostics, Inc., which was compensated to provide image analysis for the study. Dr. Aaron Ritter has nothing to disclose. Dr. Ronald Thomas has nothing to disclose. Randolph Andrews is an employee of ADM Diagnostics, Inc., which was compensated to provide image analysis for the study. Dr. Ana Lukic is an employee of ADM Diagnostics, Inc., which was compensated to provide image analysis for the study. Carolyn Revta has received grants from Toyama Pharmaceuticals, Biohaven Pharmaceuticals, and Vivoryon (Probiodrug) during the conduct of the study. Dr. Babak Tousi has received a grant from the Alzheimer’s Drug Discovery Foundation during the study. Dr. James Leverenz has received research support from the Alzheimer’s Association, Avid Radiopharmaceuticals, Department of Defense, GE Healthcare, Lewy Body Dementia Association, Michael J Fox Foundation, National Institute of Health and Sanofi/Genzyme. Dr. Howard Fillit is founding Executive Director and Chief Science Officer of the Alzheimer’s Drug Discovery Foundation which funded the rasagiline clinical trial, and has provided consulting to the following pharmaceutical companies: Axovant, vTv, Lundbeck, Otsuka, Lilly, Biogen (RTI), Roche, Genentech, Merck, Samus, Pfizer, and Alector. Dr. Kate Zhong has nothing to disclose. Dr. Howard Feldman reports a service agreement through UCSD with the Cleveland Clinic for data management and biostatistics during the conduct of this study; grants from Toyama Pharmaceuticals , Biohaven Pharmaceuticals , and Vivoryon (Probiodrug). Dr. Feldman also reports service agreements through UCSD for consulting with Eisai Pharmaceuticals, Merck Pharmaceuticals, Tau RX , Samus Therapeutics, Arkuda Therapeutics, Samumed, Axon Neurosciences Roche/Genentech Pharmaceuticals for DMC and DSMB activities; Tau Consortium for Scientific Advisory Board; Novo Nordisk for Advisory Board. He reports travel expenses Samus, Samumed, Axox and Alion Pharmaceuticals and speaker fees to UCSD from World Events Forum, Optum Health, and Medscape. Dr. Jeffrey Cummings reports grants from National Institute of General Medical Sciences (NIGMS) COBRE grant #P20GM109025, during the conduct of the study; personal fees from Acadia, Actinogen, AgenBio, Alkahest, Alzheon, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cognoptix, Cortexyme, EIP, Eisai, Foresight, Green Valley, Grifols, Idorsia, Karuna, Nutricia, Orion, Otsuka, Probiodrug, QR Pharma, ReMYND, Resverlogix, Roche, Samumed, Samus Therapeutics, Third Rock, Signant Health, Sunovion, Suven, and United Neuroscience pharmaceutical and assessment companies;other from Alzheimer Drug Discovery Foundation; other from ADAMAS, BioAsis, MedAvante, QR Pharma, and United Neuroscience,;personal fees from Neuropsychiatric Inventory (NPI), outside the submitted work; and Dr. Cummings is the Chief Scientific Advisor for CNS Innovations. Ethical Approval: The study was conducted under Institutional Review Board approval.