The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis
Authors: Ball Susan , Vickery Jane , Hobart Jeremy , Wright Dave , Green Colin , Shearer James , Nunn Andrew , Gomez Cano Mayam , MacManus David , Miller David , Mallik Shahrukh , Zajicek John 
Published: February 2015

BackgroundThe Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ9-tetrahydrocannabinol (Δ9-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS.ObjectivesThere were three objectives in the CUPID study: (1) to evaluate whether or not Δ9-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ9-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS.DesignThe CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ9-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken.SettingTwenty-seven UK sites.ParticipantsAdults aged 18–65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0–6.5.InterventionsOral Δ9-THC (maximum 28 mg/day) or matching placebo.Assessment visitsThree and 6 months, and then 6-monthly up to 36 or 42 months.Main outcome measuresPrimary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs).ResultsEffectiveness– recruitment targets were achieved. Of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. Primary outcomes: no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active–placebo) –0.9 points (95% CI –2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects.Safety– at least one serious adverse event: 35% and 28% of active and placebo patients, respectively.RMT analyses– scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect.Economic evaluation– estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs.ConclusionsThe CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection.Trial registrationCurrent Controlled Trials ISRCTN62942668.FundingThe National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full inHealth Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.