Killing CUPID Again

Ball S, Vickery J, Hobart J, Wright D, Green C, Shearer J, Nunn A, Gomez Cano M, MacManus D, Miller D, Mallik S, Zajicek J. 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.
Health Technol Assess. 2015;19(12):1-188.

BACKGROUND:The 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.

OBJECTIVES:There 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.
DESIGN:The 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, Economic evaluation were undertaken.
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 Δ9-THC (maximum 28 mg/day) or matching placebo.
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. Performance of MS-specific rating scales as measurement instruments were examined 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. 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.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.

This study reiterates what was presented before in that CUPID trial failed and tetrahydrocannabinol (CNS) had no neuroprotective effect in MS and contrasts with the mounting biological evidence in a variety of experimental studies. 

This is rather disappointing as it probably kills off any hope of developing this further. Rather that saying further studies are warranted the contents rather says bin this approach. 

What is more disturbing is the data on which the trial was actually based does not repeat. There was no symptomatic benefit of THC treatment and therefore rather suggests that the view that THC is good for symptom control is questioned. However, as there have been a number of recent symptom trials that come to a different conclusion, may ask questions is this the right clinical trial process

So again, like the lamotrigine trial, side effects determine if you take the drug or not. If you don’t take the drug the trial is doomed, but we showed that if you actually took the sodium channel blocker worked.  Until Neuros work out how to do trials, how many more science ideas will be canned.   We will need repetition of some of these  agents once trial design is improved, will this happen. It doubt it.

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  • What was wrong with the trial design? It was double blind placebo controlled. Unless you're thinking they should have been measuring progression in individual systems as per Prof G's 'asynchronous progression; hypothesis. Seems like the biggest problem here is that the subjects as a whole did not progress as predicted and therefore they couldn't show a big enough difference between the placebo and treatment arm. Was it not powered correctly? Or maybe the natural course of the disease is changing? Or maybe the results are simply true and THC is not effective??

    • The trial was powered on the expected rate of progression, which did not happen (is this a giant placebo effect) in this group of MSers tested. You don't add more than the power dictates because of cost and also you expose people to harm (if the drug had a side effect for example).

      If I were planning the trial, I would have wanted to enrich the trial with people with EDSS 4-6, which is a score that rapidly progresses due to the nature of the EDSS and would give you the best opportunity to see a difference. So it is of interest that the planned subgorup analysis indicated a treatment effect in this cohort. Was this real or a fluke? We will probably never know.

      One also has to appreciate that there are practicalities to get studies done. E.g. I would like to see a highly active DMT used at onset to see if MS was stopped. Practically this is a difficult study to do and maybe MSers would not want to volunteer for such a study because of the risks of treatments. If you can't recruit to a study should we be trying.

    • As someone with new onset MS I'd happily put myself forward for a highly active DMT study. I cant imagine you'd have any problems recruiting at all. If you do run one please let me know where to sign up.

    • New onset MS the the hight active DMT are lemtrada and possibly Tysabri. However if you are PPMS then yes you would want some option but in relation to cannabinoids who is going to pay to do this trial. Crowd sourcing but can you raise £2 million pounds assuming you get free drug. If it takes years to raise this amount then will it happen. There is a perceived failed trial so no-one will touch it?
      Maybe one could get a registry in the legalised medical marijuana states verses the non medical marijuana states and with big numbers you may see a difference, but if you talk to the dubious medical marijuana suppliers who attend a meeting I used to go to,, who try a bit too much of their own product, it is the aspirin of the 21st centuary and it cures everything.

    • As ProfG says its a shame when a nasty fact ruins a good idea. Thanks for your citation but based on our own work we can't repeat these findings, despite despite many attempts.Although we can show some neuroprotective effect, I wonder if any cannabinoid is much is going to be developed as there is nothing to patent. How is the evidence going to be obtained

      Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids.
      Pryce G, Riddall DR, Selwood DL, Giovannoni G, Baker D. J Neuroimmune Pharmacol. 2014 Dec 24. [Epub ahead of print]

      Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells.
      Maresz K, Pryce G, Ponomarev ED, Marsicano G, Croxford JL, Shriver LP, Ledent C, Cheng X, Carrier EJ, Mann MK, Giovannoni G, Pertwee RG, Yamamura T, Buckley NE, Hillard CJ, Lutz B, Baker D, Dittel BN. Nat Med. 2007;13:492-7.

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