Ari J Green1, Jeffrey M Gelfand2, Bruce A Cree2, Carolyn Bevan2, W John Boscardin3, Feng Mei4, Justin Inman2, Sam Arnow2, Michael Devereux2, Aya Abounasr2, Hiroko Nobuta5, Alyssa Zhu2, Matt Friessen6, Roy Gerona6, Hans Christian von Büdingen2, Roland G Henry7, Stephen L Hauser4, Jonah R Chan4. 1. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: agreen@ucsf.edu. 2. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. 3. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. 4. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Program in Neuroscience, University of California, San Francisco, San Francisco, CA, USA. 5. Department of Pediatrics and Neurosurgery and Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA. 6. Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, CA, USA. 7. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA; Bioengineering Graduate Group, University of California, Berkeley, and San Francisco, San Francisco, CA, USA.
Abstract
BACKGROUND: Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis. METHODS: We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298. FINDINGS: Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported. INTERPRETATION: To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage. FUNDING: University of California, San Francisco and the Rachleff Family.
RCT Entities:
BACKGROUND:Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis. METHODS: We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298. FINDINGS: Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported. INTERPRETATION: To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage. FUNDING: University of California, San Francisco and the Rachleff Family.
Authors: Clara M Bacmeister; Helena J Barr; Crystal R McClain; Michael A Thornton; Dailey Nettles; Cristin G Welle; Ethan G Hughes Journal: Nat Neurosci Date: 2020-05-18 Impact factor: 24.884