New research: what should MND clinical trials look like?

Inforgraphic showing suggestions for future trials in MND

Nov 2021: Our systematic review of over ten years of clinical trials in MND has informed what trials should look like in the future to maximise the chances of success.

As every person with MND knows, the last 25 years of clinical trials in MND have mostly failed to identify effective drugs to treat the condition. It is difficult to conduct effective trials in MND because of the usually rapid progression of the condition and variability among individuals. But can anything be done to improve trial design to maximise the chances of finding an effective treatment? This is the research question that has been addressed by one of our clinical PhD fellows, Dr Charis Wong.

Charis Wong is working with the CAMARADES group at the Centre for Clinical Brain Sciences, University of Edinburgh, who specialise in taking a scientific and systematic approach to assess research quality. In her study, Charis and team analysed 125 MND trials published between 2008 and 2019. Collectively, these trials had evaluated 76 drugs and recruited more than 15,000 people with MND. None of these drugs has been approved in the UK. 90% of trials used traditional fixed trial designs, investigating just one drug compared with a placebo (dummy drug).

The team identified problems with some of the trials.  Many drugs were tested in multiple trials, with 10 drugs tested in at least 3 trials, and lithium tested in 10 trials. This suggests that many trials were unable to test whether a drug was effective in a definitive manner. In addition the methodology used in some of the trials proved to be a barrier for some people with MND, such as requiring invasive procedures or the requirement to travel long distances or swallow oral tablets or capsules. Some trials used a very small number of participants - too small for a drug effect to be meaningful statistically - and some used a very restricted set of criteria for participation, meaning that any finding would be unlikely to apply broadly across all people with MND. Overall the team estimated that only 5% of people with MND had the opportunity to take part in a clinical trial.

Taking all these factors into consideration, in their recent publication Charis and the team made some recommendations. They recommended that trials should be designed in such a way to give definitive answers on whether drugs work or not. They recommend 'platform' trials that can evaluate more than one drug at a time, especially if they are adaptive, meaning that drugs can be added or removed from the trial according to the emerging evidence. These types of trial design allow for more efficient and rapid evaluation of drugs. Along with more efficient designs, they recommend that trials should include as many people with MND as possible, and should follow a protocol that makes it straightforward for people to participate, such as using liquid medicines and conducting appointments by phone or video call. Drug choice should take into account the very latest scientific knowledge about the biology of MND. If all these factors come together, many more people will have the chance to take part in a clinical trial and the trial will have the best chance of showing a beneficial effect.

Fortunately, adaptive large-scale clinical trials are now emerging in MND, such as the UK-wide Euan MacDonald Centre trial MND-SMART, the Healey ALS Platform Trial in the USA, and the pan-European TRICALS trial.

Related links

Read the scientific article in Brain Communications: Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective by Wong et al.

Dr Charis Wong's profile on the Anne Rowling Regenerative Neurology website

MND-SMART clinical trial website

CAMARADES team website at the University of Edinburgh

This article was published on: Tuesday, November 30, 2021