Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial

Abstract

SummaryBackgroundLaboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ9-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis.MethodsIn 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).FindingsOf 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).InterpretationOur 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.FundingUK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.

Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids

“…Although it been suggested that the influence of CBD on CB 1 R-mediated effects of Δ9-THC are of marginal significance at the concentrations of CBD in typical US of smoked marijuana (Varvel et al 2006), it may be relevant that long-term follow-up in symptom-control trials suggested that oral Δ9-THC but not oral 1:1 CBD:Δ9-THC cannabis extracts (Cannador) containing comparable levels of Δ9-THC, could limit the accumulation of disabilities in MS ). This would be consistent with a neuroprotective effect of Δ9-THC (Carroll et al 2012), which was formally investigated in a recent trial in MS (Zajicek et al 2013).…”

“…This suggests that agonism of the CB 1 R by exogenous delivered cannabinoids should have neuroprotective potential. However, unfortunately, it was reported that daily treatment with oral Δ9-THC had no overall effect on the progression of MS in the progressive phase of MS (Zajicek et al 2013. Fig.…”

A Sativex®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

“…However, to date, there are no clinical studies evaluating Sativex as a disease-modifying agent of progressive MS. The closest clinical study is the CUPID trial, the results of which were recently published (Zajicek et al, 2013). This study showed that dronabinol (Δ 9 -THC) administration to patients with progressive MS did not slow the course of the disease.…”

Cannabinoid signaling in health and disease

“…A brief overview on the important role of endocannabinoid signaling in a few CNS disorders is discussed below. trial failed to show benefits of dronabinol on multiple sclerosis progression, perhaps due to slow progression rate which confounded statistical detection of group differences (Zajicek et al 2013). …”