Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) study

Introduction: The CUPID study investigated the usefulness of cannabinoids (chemical compounds found in the cannabis plant) or THC slowing progression in MS.

Aims: The study set out to investigate the following:-
1. Does THC have any value in slowing progressive MS over a three year period?
2. Is THC safe over a three year period?
3. Can clinical trial design and conduct be improved by using newer methodology such as patient-based assessments (e.g. MS-specific questionnaires) rather than traditional testing or examination by doctors?

Participants and treatments: 493 MSers with primary or secondary progressive MS were recruited to the study from 27 centres across UK between May 2006 and July 2008. It was a requirement for participants entering the trial that their walking was affected by their MS but that they could still walk, with aids if necessary. Participants were randomly assigned to receive THC capsules or placebo (dummy) capsules, to be taken by mouth over a period of three years. 329 people were allocated to receive the THC capsules and 164 were allocated to the placebo group. For each participant, the first four weeks of the trial were devoted to establishing the best tolerated dose of study treatment. For the remainder of the study period, participants remained on a stable dose of trial treatment, as far as possible, before the dose was gradually reduced to zero at the end of the treatment period. The study was ‘double-blind’, meaning that neither the participants nor the doctors and nurses involved at the study sites knew which treatment group they were in. This is widely recognised as the ‘gold standard’ way to produce the most unbiased results in clinical trials.

Methods: The two ‘primary’ measures of treatment effectiveness used in the CUPID study were the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Impact Scale (MSIS-29). The MSIS-29 is a self-completion questionnaire specifically designed for MSers. Participants were asked to complete this every 6 months either in a paper-based form sent through the post, or via a web-based system on the computer. The study also collected information on a range of ‘secondary’ measures including a timed walk, peg test and number test (PASAT) which took place in the clinic. A variety of questionnaires were also used, to enable participants to provide their own assessment of their MS at regular intervals. At some centres, participants underwent yearly MRI scans to provide additional information.

Results: Overall the study found no evidence that THC has an effect on MS progression in either of the main outcomes (the EDSS neurological assessments conducted by doctors at the study clinics or the MSIS-29 questionnaire responses provided by the participants). The EDSS and MSIS-29 scores showed little change over the course of the study and no difference was found between the active and placebo groups. However, there was some evidence that THC might have a beneficial effect in participants at the lower end of the EDSS disability scale (i.e. in those participants whose MS was less advanced). As this benefit was only found in a small group of people rather than the whole study population, further studies will be needed to assess the robustness of this finding.

Interpretation: Although the study found no evidence that THC has an effect on MS progression, most study participants were at the high end of the disability scale at the start of the study and as a whole did not exhibit much change in their MS. There was some evidence from the two main study assessments (EDSS and MSIS-29) that participants with less disability had some slowing of MS progression but the number of people in this category was too small (in statistical terms) to conclude with certainty that THC is effective in slowing MS progression. More research will be needed to investigate these findings. One of the findings of the study was that the population of study participants did not deteriorate at the rate that had been expected. This is obviously good news and reflects well on the care now provided by the NHS for people with MS compared with previously. However, it does make it more difficult to identify any positive effects of trial treatment when the aim of treatment is to slow progression.

Developing treatments for progressive MS is complicated by the difficulty of designing and conducting clinical trials. In relapsing remitting MS, researchers can assess whether a treatment is reducing the number, frequency and severity of relapses, so measuring the effectiveness of treatments is more straightforward. It is much harder to evaluate the effectiveness of a treatment in progressive MS where symptoms worsen slowly over the course of months and years. This is partly because the measurement methods available to us do not necessarily capture disease progression accurately. The CUPID study is hugely important in terms of what MS researchers across the world will learn about conducting trials in progressive disease, so that we can continue to improve study design and the accuracy with which outcomes can be measured in both clinical practice and research.

"Professor Zajicek, colleagues, the MRC and study subjects must be congratulated on the completion of this study. It was a mammoth undertaking. We were hoping this study was going to be positive as it is based on a therapeutic strategy developed by MouseDoctor and MouseDoctor2 in their animal model of MS."

"It is now time to stop doing neuroprotective trials in progressive MS without using the putative neuroprotective agent in combination with an anti-inflammatory agent. PPMS and SPMS are inflammatory, the pathology studies in SPMS and PPMS are clear on this. THC is not anti-inflammatory, therefore this study did not address the inflammatory component of MS. The same criticisms apply to the lamotrigine SPMS study. I have been banging my head against the wall to get combination therapies neuroprotective studies done; may be the community will agree and reviewers' of grants will stop questioning the strategy."

"It would be tragedy if THC in combination with an anti-inflammatory worked in progressive MS. Have we killed THC off as a neuroprotective drug?"


CoI: The Royal London Hospital was a site in this study and I was the local PI

Note from MouseDoctor. 
With this failure we can't just wait for 3-5 year trials to occur, we need novel designs that can speed up this process! 
With this in mind please take the time to do the "MS lumbar puncture" survey which may help get one such design off the ground (Click on Top left)

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