title: Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial.
abstract: BACKGROUND
  Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ(9)-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis.
  
  
  METHODS
  In this multicentre, parallel, randomised, double-blind, placebo-controlled study, we recruited patients aged 18-65 years with primary or secondary progressive multiple sclerosis from 27 UK neurology or rehabilitation departments. Patients were randomly assigned (2:1) to receive dronabinol or placebo for 36 months; randomisation was by stochastic minimisation, using a computer-generated randomisation sequence, balanced according to expanded disability status scale (EDSS) score, centre, and disease type. Maximum dose was 28 mg per day, titrated against bodyweight and adverse effects. Primary outcomes were EDSS score progression (masked assessor, time to progression of ≥1 point from a baseline score of 4·0-5·0 or ≥0·5 points from a baseline score of ≥5·5, confirmed after 6 months) and change from baseline in the physical impact subscale of the 29-item multiple sclerosis impact scale (MSIS-29-PHYS). All patients who received at least one dose of study drug were included in the intention-to-treat analyses. This trial is registered as an International Standard Randomised Controlled Trial (ISRCTN 62942668).
  
  
  RESULTS
  Of the 498 patients randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0·24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0·23 first progression events per patient-year; crude rate); HR for prespecified primary analysis was 0·92 (95% CI 0·68-1·23; p=0·57). Mean yearly change in MSIS-29-PHYS score was 0·62 points (SD 3·29) in the dronabinol group versus 1·03 points (3·74) in the placebo group. Primary analysis with a multilevel model gave an estimated between-group difference (dronabinol-placebo) of -0·9 points (95% CI -2·0 to 0·2). We noted no serious safety concerns (114 [35%] patients in the dronabinol group had at least one serious adverse event, compared with 46 [28%] in the placebo group).
  
  
  CONCLUSIONS
  Our results show that dronabinol has no overall effect on the progression of multiple sclerosis in the progressive phase. The findings have implications for the design of future studies of progressive multiple sclerosis, because lower than expected progression rates might have affected our ability to detect clinical change.
  
  
  BACKGROUND
  UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.
authors.affiliation: Peninsula Clinical Trials Unit, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK. Electronic address: john.zajicek@nhs.net.
authors.forename: John
authors.initials: J
authors.lastname: Zajicek
authors.affiliation: Peninsula Clinical Trials Unit, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Ball
authors.affiliation: Peninsula Clinical Trials Unit, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: David
authors.initials: D
authors.lastname: Wright
authors.affiliation: Peninsula Clinical Trials Unit, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Vickery
authors.affiliation: Medical Research Council Clinical Trials Unit, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Nunn
authors.affiliation: Institute of Neurology, University College London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.affiliation: Peninsula Clinical Trials Unit, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: Mayam Gomez
authors.initials: MG
authors.lastname: Cano
authors.affiliation: Institute of Neurology, University College London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: McManus
authors.affiliation: Institute of Neurology, University College London, London, UK.
authors.forename: Sharukh
authors.initials: S
authors.lastname: Mallik
authors.affiliation: Peninsula Clinical Trials Unit, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hobart
mesh_terms: D000328:Adult; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D018450:Disease Progression; D004311:Double-Blind Method; D013759:Dronabinol / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D063386:Cannabinoid Receptor Agonists; D013759:Dronabinol