Have we thrown the baby out with the bath water?

Who are two of the most original and deep thinkers in the field of MS?

Do you want to know about some of the ideas of Thing1 (MD1) and Thing2 (MD2)?

Two of the most original and deep thinkers in the field of MS are my scientific partner David Baker (aka as the MouseDoctor) and Gareth Pryce (aka MouseDoctor2), David’s research assistant. Together they pioneered the field of cannabinoid research in MS. They showed that the CB1 agonist THC, which happens to be the main psychoactive ingredient in cannabis, has both anti-spastic and neuroprotective effects in their animal model of progressive MS. Their work led to the CUPID study below, which unfortunately was negative. Does this mean THC is not neuroprotective in MS? 

No!! Definitely not!

When you look at the design of the CUPID study wearing rose-coloured spectacles and a new worldview shaped by recent insights, which have surfaced in the last 4-5 years, we think the CUPID study was designed to be negative. Why? 
  1. CUPID enrolled too many pwMS who were EDSS 6.0 or 6.5 (78%), i.e. 78% of the trial population had lost too much lower limb function for the EDSS to report out in a reasonable point of time. When you have lost so much lower limb function it is difficult to show a treatment effect, in other words, the therapeutic window had shut. One way around this would have been to look at upper limb function, but this was not included in the CUPID study.
  2. Using the EDSS as the primary outcome; pwMS spend too much time at EDSS 6.0 and 6.5 and hence were less likely to worsen enough during the trial to be informative. This is called the ceiling effect and is a well-described problem with the EDSS.
  3. The study was a fixed-duration study and not an event-driven trial. The two positive trials in progressive MS (ocrelizumab in PPMS (ORATORIO) and siponimod in SPMS (EXPAND)) were both event-driven. In other words, these trials continued until enough progression events happened to give us an answer (please note I am on the steering committee of both these studies and hence I am conflicted).
  4. The CUPID study was a monotherapy trial. We know that THC is not an anti-inflammatory DMT. It should have been combined with an anti-inflammatory. This seems so obvious to us. We have been discussing combination-therapy trials for so long within Barts-MS that we assume the whole field agrees with us. This is not the case. MS-SMART and STAT2 trials were monotherapy neuroprotection trials. At least the ongoing high-dose biotin and opicinumab trials are being done as combination therapy trials. At least Pharma is listening. 
I am not sure if you are aware that in a post-hoc (after the event) analysis of the CUPID trial limiting the analysis to the population with a baseline EDSS < 6.0, THC was shown to significantly delay disease progression on the EDSS. In other words, THC was neuroprotective in this population. We now know that the reason for THC working in this population is based on the length-dependent axonopathy hypothesis. These study subjects had some reserve in their neuronal pathway subserving the legs and hence would report out earlier on the EDDS than the more advanced patients. CUPID would have been positive it had studied a less disabled population.

The great tragedy is that we have thrown out the baby with the bathwater. We think THC is neuroprotective in MS, but because of the trial design, the MS community now thinks it is not. What can we do about it? I propose we do a CUPID-2 study. Only this time it needs to be (1) event-driven, (2) focus on patients with reserve capacity, either EDSS < 6.0 or to use the 9-HPT as the primary outcome and (3) make it a combination therapy trial. 

Do you think the MS community has the appetite to do this? We owe it to people with more advanced MS and we owe it MD1 & MD2; they did all this ground-breaking research on THC and CB1-agonists as potential neuroprotective therapies in MS only to have their lives work destroyed by poor trial design. 

Zajicek et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol. 2013 Sep;12(9):857-865.

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.

CoI: multiple

4 thoughts on “Have we thrown the baby out with the bath water?”

  1. ProfG, a very informative blog. Yes you are involved with these trials but you give an insight which is not available on the published results document. Trials are deemed to have failed for all sorts of reasons but all I know is that it failed to achieve its primary end point.So the trial failed but it probably succeeded in telling the researchers a really useful piece of information. In order to investigate that they have to grovel, beg or borrow money to test a new hypothesis as a result of the original research.Developing a new drug to treat MS (MND, dementia or Hodginkins as well for that matter) seems to be like playing the National Lottery but it is us the people with the disease who are really suffering.

  2. I would love to see another study done in this area. Thank you MD1 & MD2!Is it possible to do a study with this as a mono therapy today?

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