The effects of rasagiline on cerebral glucose metabolism, cognition, and tau in a double-blind, placebo-controlled Phase II clinical trial in Alzheimer’s dementia

Abstract BackgroundA 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 (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluoro-2-deoxyglucose positron emission tomography (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.MethodsThis 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 as an outcome using prespecified regions of interest and image classification for longitudinal data. 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 Intention-to-Treat (ITT) model.FindingsBetween 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 Controlled Word Association Test (p<0.08) favored rasagiline. Rasagiline treatment was generally well tolerated with low rates of both serious and other adverse events and notably less neuropsychiatric symptoms reported with rasagiline. ConclusionsThese study outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in mild to moderate AD patients. Rasagiline appears to affect neuronal activity in frontostriatal pathways, as observed through changes in glucose metabolism. This study illustrated the benefit of a POC design using biomarkers to characterize a diverse patient population and treatment response. Limitations include the study size and duration. Further investigation of rasagiline as a repurposed treatment in AD is warranted. Trial RegistrationClinicaltrials.gov number NCT02359552, February 10, 2015.