Conferencia»Association of British Neurologists Annual Meeting 2012. Published in: Journal of Neurology, Neurosurgery & Psychiatry. 2012;83(Suppl 2):A36
Cannabinoids have been shown to reduce MS-related symptoms, as well as potentially having a longer-term beneficial effect. This potential disease modifying effect is supported by in vitro evidence for neuroprotection. This led to the development of the current CUPID trial, a 30 centre, 493 patient parallel group randomised, placebo controlled trial over a 3-year treatment period. Patients with primary or secondary progressive MS, deemed to be deteriorating by their treating neurologists, with an Expanded Disability Status Score (EDSS) of between 4.0 and 6.5, were allocated to either oral Δ9 tetrahydrocannabinol, or placebo in a 2:1 ratio over the period May 2006-July 2008. An initial dose titration phase was used to optimise dosage whilst minimising side effects. Patients were followed up at 6 monthly intervals for 3 years before coming off medication. Primary outcome measures were reduction in time to EDSS progression maintained for at least 6 months (physician measure), and overall mean change from baseline to the end of the study in the MSIS-20 V.2 (patient-orientated measure). Secondary outcome measures included the Multiple Sclerosis Functional Composite, MSWS-12, symptom measures, SF-36, MSSS-88, and MRI outcomes in just over half of all patients. The study was powered to allow for 15% loss to follow-up, which was the eventual drop-out figure. This is the only non-commercial large multicentre controlled trial to have been conducted for progressive MS in the UK, and results will be presented.
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.
Conferencia»Association of British Neurologists (ABN) joint meeting with the Royal College of Physicians (RCP), London, UK; 2013. Published in: Journal of Neurology, Neurosurgery & Psychiatry. 2013;84:e2
Introduction In progressive Multiple Sclerosis (MS), there is no proven therapy for preventing accumulation of irreversible disability. The pathological substrate of irreversible disability in MS is neuroaxonal loss, and brain tissue volume loss on MRI can infer such pathology. There is experimental evidence to suggest that cannabinoids may have a neuroprotective and anti-inflammatory effect, although in a recent UK clinical trial (CUPID), oral cannabinoid did not slow the development of disability in progressive MS compared with placebo. Aims Using serial MRI brain scans obtained during the CUPID trial, we compared oral Delta 9-tetrahydrocannabinol (Δ9-THC) versus placebo for the following: (i) rates of new T2 hyperintense and new T1 hypointense lesions, and (ii) rate of brain atrophy. Methods A subset of progressive MS patients from the CUPID trial, who were randomised to either Δ9-THC or placebo, were followed up for 3 years with MRI scans at 4 time points: baseline, and years 1, 2 and 3. MRI sequences included axial dual echo, fast (turbo) spin echo proton density and T2 weighted scans, as well as a conventional T1 weighted spin echo scan. 46 contiguous 3 mm thick axial slices were performed for each acquisition. Scans from each time point were compared with the immediately preceding scan. New T2 lesions and new T1 lesions were marked by review of the electronic data using imaging software application JIM 6.0. If a scan had been missed, comparison was made with the last scan performed. Normalised brain volume (NBV) was estimated with SIENAX. Two-time-point percentage brain volume change (PBVC) was estimated with SIENA for three time-point pairs: baseline to year 1, year 1 to year 2, and year 2 to year 3. Results 273 patients were entered into the sub-study. 182 (67%) received active treatment, and 91 (33%) received placebo. 45 subjects missed one or more scan. Those that only had the baseline scan were excluded from all further analyses. Losses to follow up were 27 at 1 year, 18 at 2 years, and 18 at 3 years. 32 patients did not have a baseline NBV. There was no evidence of an association between treatment group and number of new T1 lesions or T2 lesions, at any of the three time-point pairs (new T1 lesions: baseline to year 1 p=0.99, year 1 to year 2 p=0.17, year 2 to year 3 p=0.90; new T2 lesions: baseline to year 1 p=0.55, year 1 to year 2 p=0.076, year 2 to year 3 p=0.90). Mean baseline NBV was 1420ml (SD 89.02) for all subjects, with no significant difference between the arms (p=0.7). At each of the three time-point pairs, there was no evidence of a difference in mean PBVC between active and placebo arms (baseline to year 1: active -0.60%, placebo -0.59%, p=0.93; year 1 to year 2: active -0.58%, placebo -0.65%, p=0.62; year 2 to year 3: active -0.88%, placebo -0.76%, p=0.39). Conclusion Δ9-THC was not better than placebo at reducing the rates of new T1 or T2 lesions or brain atrophy in patients with progressive MS.
BACKGROUND: The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS.
OBJECTIVES: There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS.
DESIGN: The CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-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.
SETTING: Twenty-seven UK sites.
PARTICIPANTS: Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5.
INTERVENTIONS: Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo.
ASSESSMENT VISITS: Three and 6 months, and then 6-monthly up to 36 or 42 months.
MAIN OUTCOME MEASURES: Primary 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).
RESULTS: Effectiveness - 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.
CONCLUSIONS: The 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 REGISTRATION: Current Controlled Trials ISRCTN62942668.
FUNDING: The 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 in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.
