The direct thrombin inhibitor is planned to be evaluated for its effect on the neurodegenerative disease in a trial of 40 to 60 patients with MCI and Alzheimer, led by researchers at the University of Rhode Island.
Paula Grammas, PhD
A research team at the University of Rhode Island (URI) will be undertaking a phase 1 clinical trial evaluating the effects of dabigatran (Pradaxa, Boehringer Ingelheim) on the vascular system’s role in Alzheimer disease.1
The study, dubbed BEACON (NCT03752294), will take place at Alzheimer research clinics in Rhode Island, which study director Paula Grammas, PhD, the executive director of URI’s George & Anne Ryan Institute for Neuroscience, where the team is based, called an important point to the researchers. She said that the state has a "world-class and closely-linked community of researchers and clinicians, which enables us to pull together resources and make progress quickly.”
Results of the trial are anticipated to read out in late 2020. John Stoukides, MD, the medical director of the Rhode Island Mood and Memory Research Institute, will be the principal investigator.
"Based on our many years of exploring the cerebral microvasculature in Alzheimer’s disease we believe targeting the production of vascular-derived neurotoxins is a potentially useful strategy for treating AD," Grammas told NeurologyLive. "We hope to see positive trends in cognition and biomarkers in this study although the sample size is small, but even if there are no statistically significant changes, the BEACON Study is an important step forward into exploring new hypotheses for neurodegeneration in Alzheimer disease, and a sign that researchers and funding sources have recognized the need to identify novel targets that could lead to the first disease-modifying therapy for Alzheimer."
Howard Fillit, MD, the founding executive director and chief scientific officer of the Alzheimer’s Drug Discovery Foundation, the study’s funder, said that the foundation is “pleased to work with Dr. Grammas and fund her work using a very novel approach to repurpose an existing drug to treat the vascular abnormalities in Alzheimer’s disease.”
Dabigatran, a direct thrombin inhibitor, is currently indicated for the reduction of the risk of stroke and systemic embolism in patients with non-vascular atrial fibrillation, and the treatment and prevention of deep venous thrombosis and pulmonary embolism.2
“The role of the vasculature in Alzheimer’s disease has been grossly under-recognized until relatively recently. As a result, strategies to develop therapeutics to address this important part of the disease have been lacking,” Fillit said. He told NeurologyLive in December 2018 that his expectation for the future of Alzheimer research would include not only more trials but “further advances in biomarkers—especially blood biomarkers.”
Overall, the study will consist of 2 phases. The first, a double-blind portion of 40 to 60 total patients with either mild cognitive impairment (MCI) probably due to Alzheimer or mild Alzheimer, in which the patients will be randomized to a 150-mg daily dose of dabigatran or placebo, for 10 months. The second phase will be an open-label period in which the placebo group will be given 150-mg daily dabigatran from month 10 to month 21, while the active group continues treatment until month 21.
After month 21, all patients will be taken off treatment and a 3-month follow-up period will be undertaken to assess if the proposed treatment effect can be sustained without treatment.
The final analysis will consist of a difference in the intercept of a generalized growth model between randomization groups during the second phase of the study, using the Cognitive Dementia Rating Scale-Sum of Boxes (CDR-SB) as evidence of effectiveness and justification of further study. As well, the relationships between changes in plasma biomarker levels of over time will be tested with regards to each other and relative to magnetic resonance imaging and cognitive testing.
“If the drug shows some effects on the progression of Alzheimer’s disease, it would be the first time we’ve found evidence of a treatment that could slow the disease,” Grammas said. “But even if the study’s results are less conclusive, this is a vitally important step forward in expanding our knowledge of the multiple factors that cause this complex disease. I’m very excited to see what happens.”
1. Ryan Institute for Neuroscience at URI Receives Approval for Groundbreaking Clinical Trial Targeting the Blood Vessels in Alzheimer’s Disease [press release]. Kingston, RI: URI; Published January 14, 2019. today.uri.edu/news/ryan-institute-for-neuroscience-at-uri-receives-approval-for-groundbreaking-clinical-trial-targeting-the-blood-vessels-in-alzheimers-disease. Accessed January 14, 2019.
2. Pradaxa. FDA Prescribing Information. FDA website. accessdata.fda.gov/drugsatfda_docs/label/2015/022512s028lbl.pdf. Updated November 2015. Accessed January 14, 2019.