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).

Findings: 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).

Interpretation: 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.

Funding: UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.

Figure 1

Trial profile PEP=primary endpoint of expanded disability status scale score progression. *Nine patients initially did not fulfil entry criteria, but did so on subsequent re-screening.

Figure 2

Kaplan-Meier estimates of the probability of EDSS score progression Only EDSS score progression events that were confirmed 6 months after the first observation were included in the Kaplan-Meier analysis; plot shows timings of first events, not 6 month confirmations. Numbers accompanying the numbers at risk in parentheses are the cumulative number of censored observations. +=patients who were lost to follow-up during the trial. ×=time of last follow-up in those patients who reached the end of the trial (ie, were followed up for 3 years) without progressing. EDSS=expanded disability status scale.

Figure 3

EDSS score progression by subgroup Hazard ratio (unadjusted) of EDSS score progression in the dronabinol group compared with the placebo group. EDSS=expanded disability status scale. PPMS=primary progressive multiple sclerosis. SPMS=secondary progressive multiple sclerosis.

Figure 4

Change in MSIS-29-PHYS score over time Datapoints show mean MSIS-29-PHYS score; vertical lines show 95% CI. MSIS-29-PHYS=29-item multiple sclerosis impact scale, physical impact subscale. n=number of patients with total scores calculated at each visit. *If deterioration was noted at 36 months, a final follow-up visit was done at 42 months to confirm progression; if a patient went on to have an assessment at 42 months, data from this visit were used; if not, data from the assessment at 36 months were used.

Figure 5

Cumulative PBVC over time Datapoints show cumulative PBVC (%) measured at yearly MRI visits; vertical lines show 95% CI. n=number of patients with cumulative PBVC calculated at each visit. PBVC=percentage brain volume change.