(Abst.) Effect of dronabinol on progression (PPMS, SPMS)

 
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PostPosted: Sat Jul 20, 2013 5:46 pm    Post subject: (Abst.) Effect of dronabinol on progression (PPMS, SPMS) Reply with quote

From PubMed via MS Discovery Channel, July 19, 2013:

Quote:
Lancet Neurol. 2013 Jul 12.

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

Zajicek J, Ball S, Wright D, Vickery J, Nunn A, Miller D, Cano MG, McManus D, Mallik S, Hobart J; on behalf of the CUPID investigator group.

Peninsula Clinical Trials Unit, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK. Electronic address: john.zajicek@nhs.net.

BACKGROUND:

Laboratory 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.

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.


PMID: 23856559
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agate
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PostPosted: Wed Jul 24, 2013 1:25 pm    Post subject: Review and comment from Journal Watch Neurology Reply with quote

From Journal Watch Neurology, July 23, 2013:

Quote:
SUMMARY AND COMMENT | NEUROLOGY

Dronabinol Ineffective to Reduce Disability in Progressive Multiple Sclerosis

Robert T. Naismith, MD Reviewing Zajicek J et al., Lancet Neurol 2013 Jul 13;

Marijuana extract does not have beneficial effect as a disease modifier in progressive MS.

Delta-9-tetrahydrocannabinol (THC) has a variety of physiologic effects. Some researchers suggest that cannabis and the endocannabinoid system may have a potential role in neuroprotection. To test this hypothesis in patients with progressive multiple sclerosis (MS), investigators conducted a multicenter, randomized, double-blind, placebo-controlled trial, including 498 patients with primary-progressive (PP) or secondary-progressive (SP) MS, randomized 2:1 to dronabinol or placebo. Dose titration was performed over 4 weeks, and final dose was based on weight (up to 28 mg daily).

Demographics were evenly distributed among treatment allocations. The median age was 52, female:male ratio was 3:2, 39% had PPMS and 61% SPMS, and median expanded disability status scale (EDSS) score was 5.9. Of those enrolled, 84% completed 3 years of follow-up; 29% of these discontinued study medication. Treatment had no apparent effect on the rate of progression or scores on an MS impact scale, MS functional composite scale, MS walking scale, or Rivermead mobility index. Magnetic resonance imaging showed no differences in brain volume changes, new or enlarging T2 lesions, or new or enlarging T1 lesions. Subgroup analyses suggested a trend toward worsening disability with treatment for those with EDSS 6.0 to 6.5, and an improvement with treatment for EDSS 4.0 to 5.5. Serious adverse events did not differ between treatment groups, although dizziness, lightheadedness, and cognitive difficulties were reported more frequently with active treatment.

Comment

This multicenter study provides definitive class I evidence that THC does not reduce worsening disability in progressive multiple sclerosis. Although the authors optimistically suggest that a larger trial may be needed and note the post hoc evidence of potential benefit in the lower-EDSS group, no consistent effect was evident in looking at the sum of the data. Now that THC has been shown not to have a clinical benefit as a neuroprotective agent, we should study other therapeutic agents with greater potential to help those with progressive MS.
_________________________________________

Editor Disclosures at Time of Publication

Disclosures for Robert T. Naismith, MD at time of publication:

Consultant / Advisory board
Acorda Therapeutics; Biogen Idec; EMD Serono; Genzyme; Questcor
Speaker's bureau
Acorda Therapeutics; Bayer Healthcare; Biogen Idec; Genzyme
Grant / research support
NIH; Acorda Therapeutics; National Multiple Sclerosis Society
Leadership positions in professional societies
Consortium of MS Centers (Speaker); National Multiple Sclerosis Society (Local Chair of Clinical Advisory Committee; Program Services Committee, Research Advocate, and Research Champion)

Citation(s):

Zajicek J et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): A randomised, placebo-controlled trial. Lancet Neurol 2013 Jul 13.
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