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
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)
Disappointing from a professional point of view and disappointing from a MSer point of view. However it does again suggest that trial design is important.
Trial design is critical; the CUPID design was flawed from the outset. It ignored everything we knew about progressive MS at the time.
Re: "However it does again suggest that trial design is important."I suggest we test a novel CB1 agonist on top of an anti-inflammatory using CSF neurofilament levels as an outcome measure in progressive MS. It is too early to discard CB1 agonism as a treatment strategy in MS.
Once again the important point is that you need to treat early, as has finally been realised with the anti-inflammatory trials. THC needs to go in with anti-inflammatory. It's important that a potential neuroprotective agent is not lost to us.
It is all biology….If you do not know you are getting the drug, I would suspect that you are not getting enough, so it is unlikely to be really blinded at effective doses
What anti-inflammatory agent would you recommend be tested in the neuroprotective trials?
Are more neuroprotection trials going on and do they use the same trial design?
As a PPMSer, I'm so disheartened by this news. I have been following the CUPID trials, really hoping this would be the first good news for progressive MS. Alas, it's just anothe failed experiment. I'm so saddened by this report. Even the news on television are reporting on it, saying it is not only disappointing, but also a costly failiure. ITN made it one of their primary new items.The heart sinks. Progressive MS is what it is I guess, and even then I'm not sure we know what it is. Feel like crying.
Wait, wait, wait… the 'I'in CUPID stands for 'inflammatory, yet the scientists forgot to include an anti-inflammotory agent in the trial design? What was the bleeding point?Prof G, I hopoe the drugs you're trialling aren't like this one? I can't beleive that all that money, time and hype went into this and all we're left with is a bunch of bruised egos saying, "well, participants with less disability did kind of okay, so maybe the cannabis is doing something good."Aggh! So annoyed right now. Look, let's not all act cray like me and let's dust ourselves off. Onwards and upwards. Like the bloke above said, the trial design was flawed to begin with. Things can only get better, right?This bad new is making me feel ill… more so.
Anti-inflammatories dont do anything for PPMS on their own. Why will they work differently when paired with THC?
"Are more neuroprotection trials going on and do they use the same trial design?"Maybe. Clinicians do not often think outside the box. However history shows us that the first immunosuppressive trials failed also, you have to learn from the failures. The neuroprotective can be anti-inflammatory
Anti-inflammtories dont do anything for PPMS on their ownImmunosuppressives maybe do not appear to do the trick in PPMS, do not discard anti-inflammatories they are not all immunosuppressives.When we see the actual data we can learn and move on.However this is the reason why trials like the ones Prof G has been proposing need to be done, because we don't want to wait 3-5years to get bad news. We must work out how to speed the process up.
What sad news this is. I had such high hopes. I suppose most of us did.For all those who are upset by this news, of whom there are many, the CUPID results are the first out of the gate. Therefore, I am trying to convince myself that there must be so many compounds in the pipeline that at least one of them will deliver solid results. If not, then we're seriously in bother.This is a tough disease, granted. It hits us at a young age and we're meant to get through life, sufferering. Sod CUPID, it was, allegedly, a flawed trial desighn. Let's look forward to FREEDOMS, let's look to Prof G's PPMS trials and let's keep an eye on Franklin's mad remylineation experiments over in Cambridge University.I do think that some form of personal analysis of today's CUPID results won't go amiss Mousedoc and Prof G.
I can't believe it failed. Heard them talking about this on Radio 4 this morning. Felt so sad.Hope something soon works out for us prog'ers.
"I do think that some form of personal analysis of today's CUPID results won't go amiss Mousedoc and Prof G".Will do but, i can't say anything until we see the data, so we may have to wait until it is published.
Re: "Anti-inflammatories dont do anything for PPMS on their own."This perception is incorrect. The problem is that we have not used very effective anti-inflammatory drugs to date in progressive MS. There is a hint from the rituximab PPMS trial that anti-inflammatory drugs will work. This is the reason why fingolimod, ocrelizumab and natalizumab are being tried in progressive MS. My problem is that these drugs, with the possible exception of fingolimod, simply target the inflammation and don't impact on the slow burn or loss of nerve cells that occurs as part of progressive MS. This is why we have been promoting a combination strategy, an anti-inflammatory with a neuroprotective.
Re: "Wait, wait, wait… the 'I'in CUPID stands for 'inflammatory, yet the scientists forgot to include an anti-inflammotory agent in the trial design? What was the bleeding point?"Hindsight is a powerful thing. When the CUPID study was designed it was based on some observations of the CAMMS study, which hinted at THC slowing disease progression. The fact is that we had data at that THC at standard doses was not anti-inflammatory. The CUPID study was not a waste of time. My initial take home messages are:1. 8 years is too long in the life of an MSers to do a trial.2. We need shorter phase 2 studies.3. We need to add neuroprotective therapies on top if anti-inflammatories.4. We need to enrich trials with MSers who are more likely to progress in the next 6-24 months. 5. We need new and better outcome measures for progressive MS. This story will continue to run as more data is made available for review.
Re: "The heart sinks. Progressive MS is what it is I guess, and even then I'm not sure we know what it is. Feel like crying."Please don't get disheartened; there are other trials running. I am confident that one of them will be positive.
Re: "Are more neuroprotection trials going on and do they use the same trial design?"Yes, there are some running and not all use this trial design. Some are early in the course of the disease and some are being done in optic neuritis.
Re: "What anti-inflammatory agent would you recommend be tested in the neuroprotective trials?"I would start by adding onto interferon-beta and glatiramer acetate. There are a large number of MSers with SPMS on these drugs.
Prof G, considering the now understood importance of anti-inflammatory agents in progressive MS trials, will you be combining interferon-beta and glatiramer acetate in the trial design when testing fingolimod and ocrelizumab on PPMS patients?I was on Mitoxantrone 3 years ago for my PPMS and it did nothing to stem my progression, yet it too is anti-inflammatory, is it not?
Re: "I was on Mitoxantrone 3 years ago for my PPMS and it did nothing to stem my progression, yet it too is anti-inflammatory, is it not?"Yes, mitoxantrone is anti-inflammatory. The question is not necessarily whether it stopped your progression, but whether or not it slowed down the rate of progression. Please read the post on our recent survey on this issue: http://multiple-sclerosis-research.blogspot.co.uk/2012/04/survey-results-neuroprotection.html
Re – "… mitoxantrone is anti-inflammatory. The question is not necessarily whether it stopped your progression, but whether or not it slowed down the rate of progression."Trust me when I say it did nothing. I was able to walk unaided 3 years ago and now I need crutches. Even with the crutches I'm struggling.
Dr. G or Mousedoctor:You mentioned that the reasoning behind trying THC was "based on a therapeutic strategy developed by MouseDoctor and MouseDoctor2 in their animal model of MS," and observations from the CAMMS study. Could you elaborate on this? What was seen that led them to try THC for progressive MS?Thanks.
We had shown in 2003 that if you lack the receptor that THC and cannabis work through, mice do very badly when they have an MS-like disease. Likewise we showed that they lose nerves. We were also able to show that if you stimulate the receptor that you could prevent nerve loss. We showed this in a large number of ways. We have other studies yet to be published that further support this. That is the biology and that is why we hoped it would work, if the drug cold be tolerated.Now to the human in the initial symtomatic trial neither cannabis a mix of THC and cannabinol) or THC affected the primary outcome measure called the Ashworth scale. So that failed also (However a smoked cannabis trial showed a positive effect recently and so supports our mouse study in 2000 on symptom control).However when people who were on the CAMMS trial (initially 6 weeks) but were left on the drug were looked at after a year there was an affect on the Ashworth scale and others with THC (but not the cannabis). This suggested either it was promoting plasticity and repair or that it was slowing progression.
Thanks for the reply.Can I ask what mouse model do you use for your research? Is it the traditional model, EAE?So many treatments that have performed great in mice, preventing and stopping disease progression, have not worked or have seen only limited effectiveness in humans. Given this, what is the reasoning behind continuing trying to transfer treatments from mice to humans? Is it a case that we have to try them on animals first, and we don't have a better model right now?
Re: "Can I ask what mouse model do you use for your research? Is it the traditional model, EAE?"The Biozzi or ABH EAE model; this is a rather special model as it has CIS, RR and SP phases. It therefore allows us to interrogate different phases of the disease. In addition, the pathology looks very much like MS.