Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

Ari J Green; Jeffrey M Gelfand; Bruce A Cree; Carolyn Bevan; W John Boscardin; Feng Mei; Justin Inman; Sam Arnow; Michael Devereux; Aya Abounasr; Hiroko Nobuta; Alyssa Zhu; Matt Friessen; Roy Gerona; Hans Christian von Büdingen; Roland G Henry; Stephen L Hauser; Jonah R Chan

doi:10.1016/S0140-6736(17)32346-2

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

Lancet. 2017 Dec 2;390(10111):2481-2489. doi: 10.1016/S0140-6736(17)32346-2. Epub 2017 Oct 10.

Authors

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

Affiliations

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.

PMID: 29029896
DOI: 10.1016/S0140-6736(17)32346-2

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.

Publication types

Randomized Controlled Trial

MeSH terms

Adult
Clemastine / therapeutic use*
Cross-Over Studies
Double-Blind Method
Evoked Potentials, Visual / drug effects
Female
Humans
Male
Multiple Sclerosis / drug therapy*
Remyelination / drug effects
Tomography, Optical Coherence
Treatment Outcome

Substances

Clemastine

Associated data

ClinicalTrials.gov/NCT02040298