Tocotrienol-rich vitamin E complex in CADASIL (T3CAD): a randomised, double-blind, placebo-controlled trial.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic small vessel disease, causing recurrent stroke and progressive cognitive decline, with no disease-modifying treatment available. Tocotrienols, members of the vitamin E family, have demonstrated neuroprotective effects in preclinical studies. We evaluated the efficacy and safety of a tocotrienol-rich vitamin E complex (HOV12020) in patients with CADASIL. Methods: In this randomised, double-blind, placebo-controlled trial, 51 patients (median age (range): 58 years (43-73 y), male (n = 24, 47%)) with genetically confirmed CADASIL were assigned (1:1) to receive HOV12020 or placebo for 24 months. The primary endpoint was treatment failure, defined as any stroke occurrence, disability progression, or cognitive decline, and was analysed within a Bayesian framework to estimate the probability of treatment benefit. The secondary endpoints included the time to the first failure event, changes in clinical and cognitive scores, and safety. Exploratory MRI endpoints were analysed using quantile regression with Wilcoxon rank-sum sensitivity tests. EudraCT 2019-002867-23; ClinicalTrials.govNCT04658823. Findings: Patients were enrolled in the trial between 15/01/2021 and 11/02/2022. Treatment failure occurred in 68.0% of patients in the HOV12020 group and 61.5% in the placebo group, both exceeding the 40% placebo event rate that was initially expected. Bayesian analysis indicated a low posterior probability of benefit, meeting the predefined futility criteria. No significant differences were observed in the secondary endpoints or exploratory MRI measurements. HOV12020 was well tolerated, with an excellent safety profile and no excess of adverse events. Interpretation: HOV12020 did not reduce clinical progression in CADASIL over 24 months. Bayesian analysis confirmed futility, suggesting that tocotrienol-rich vitamin E is unlikely to confer benefits in the advanced stages of the disease. This rigorously designed trial illustrated the potential of Bayesian randomised studies in a rare, slowly progressive cerebral small vessel disease as CADASIL and provides key information for the development of future preventive strategies in cerebral small vessel disease. Funding: Hovid Berhad (study sponsor).