RESUMO
BACKGROUND: Oligodendrocytes (OGs) provide metabolic support to motor neurons (MNs) and are implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). MD1003, or high-dose Pharmaceutical grade Biotin (hdPB), may improve disability in progressive multiple sclerosis patients via augmentation of OG or MN energy levels. Here, we assessed the safety and efficacy of MD1003 in ALS patients. METHODS: This single centre, randomised, double-blind, placebo-controlled trial included patients aged 25-80 years with probable or definite ALS. Patients were assigned (2:1), using a computer-generated randomisation list, to receive oral MD1003 (300 mg/day) or placebo treatment for 24 weeks. The primary outcome, safety, was analysed in all patients who received at least one dose of study drug. This study, registered with ClinicalTrials.gov, NCT03114215, has been completed. FINDINGS: Between June and December 2016, 30 patients were enrolled (MD1003, n = 20; placebo, n = 10). Baseline characteristics were representative of the ALS population. MD1003 and placebo groups were not well balanced at screening, with the MD1003-treated group having a higher rate of ALSFRS-R decline prior to screening versus placebo (-6·0 IQR [-8·5, -5·0] vs. -5·0 IQR [-5·0, -3·0]) and a predominance of ALS with upper limb onset compared to placebo (35% vs. 10%). MD1003 had a favourable safety profile and was well tolerated. The occurrence of adverse events was similar in both groups (60%). Two deaths occurred in the MD1003 group versus 1 in the placebo group. ALSFRS-R median change from baseline to month 6 was not significantly different between the two groups (p = 0·49); the mean difference between groups was -1·6 (SEM=3·3). INTERPRETATION: MD1003 treatment was safe and well tolerated. It was not possible to establish MD1003 efficacy in this relatively small study. Given the favourable safety profile of MD1003 and an imbalance between treatment groups favouring placebo, additional, larger studies in ALS are warranted. FUNDING: MedDay Pharmaceuticals.
RESUMO
BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic connective tissue disorder secondary to pathogenic variants within the COL3A1 gene, resulting in exceptional arterial and organ fragility and premature death. The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality. OBJECTIVES: The authors herein describe the outcomes of a large cohort of vEDS patients followed ≤17 years in a single national referral center. METHODS: All patients with molecularly confirmed vEDS were included in a retrospective cohort study. After an initial work-up, patients were treated or recommended for treatment with celiprolol (≤400 mg/day) in addition to usual care and scheduled for yearly follow-up. vEDS-related events and deaths were collected and recorded for each patient. RESULTS: Between 2000 and 2017, 144 patients (median age at diagnosis 34.5 years, 91 probands) were included in this study. After a median follow-up of 5.3 years, overall patient survival was high (71.6%; 95% confidence interval: 50% to 90%) and dependent on the type of COL3A1 variant, age at diagnosis, and medical treatment. At the end of the study period, almost all patients (90.3%) were treated with celiprolol alone or in combination. More than two-thirds of patients remained clinically silent, despite a large number (51%) with previous arterial events or arterial lesions at molecular diagnosis. Patients treated with celiprolol had a better survival than others (p = 0.0004). The observed reduction in mortality was dose-dependent: the best protection was observed at the dose of 400 mg/day versus <400 mg/day (p = 0.003). During the period surveyed, the authors observed a statistically significant difference in the ratio of hospitalizations for acute arterial events/hospitalizations for regular follow-up before and after 2011. CONCLUSIONS: In this long-term survey, vEDS patients exhibited a low annual occurrence of arterial complications and a high survival rate, on which the overall medical care seems to have a positive influence.