Can we speed up MS clinical trials?

Neuroprotection for MS stops axons, the backbone of neurons, from degenerating as a result of demyelination. There are a number of intricate processes which cause this to happen, and so potentially a lot of different methods of stopping it.

But clinical trials are huge beasts. You need thousands of participants to make them hold any scientific weight and, due to the slow nature of MS progression, you need very long time periods over which to study them. Clinical trials are set up in this way for a reason. Each phase helps determine whether a treatment is safe and ready to progress to a broader trial. So how might we make this process quicker and more efficient, and speed up the process of finding neuroprotective treatments for progressive MS? Emma Gray is head of Clinical Trials at the MS Society, who have funded a huge project to do just that…

Emma - We have to have randomised controlled trials. They're the gold standard in terms of, you know, a patient having confidence that a treatment is safe and effective for the regulators to be able to allow it to be prescribed. So we can't get away from that, but we need to be smart about it. We know that all the trial stages are all required, but they're all done separately. You know, you set them up, you shut them down. You might have to apply for funding for the next stage. You set that up, you shut that down. Surely there must be a better way of doing that. Also, normally in traditional trials, you would trial your potential treatment of interest compared with a placebo or a dummy treatment, or if available, a current existing treatment. So again, that's a really inefficient way of just testing one placebo against one drug.

James - As I understand it, you've been looking at inspiration from other fields of medicine, where there are other methodologies of conducting clinical trials in operation.

Emma - Yeah, we have. And we're hugely inspired by the oncology field, especially prostate cancer, a trial called STAMPEDE. So we thought, we have to be able to do this. So we got some of the statisticians from that trial and said, look, can you come and help us? And so, yeah, so we got the community together and started to design a really exciting, what we call multi-arm, multi-stage trial called Octopus, where you can test lots of treatments at once, but also you merge the stages. So you have one consecutive trial that enables you to, as soon as you find a new treatment, if you're able to, you could add that in. If you find out one of the treatments aren't working, you could remove that. You could change the outcome measures that you're testing within the trial. You can change the cohorts. If you're able to personalise your trial in a certain way for a certain group, you could do that. And you're also, with these trials, able to link it to other data sets to bring new knowledge back in to develop new treatments in the future.

James - You started by talking about the kind of multi-arm phase of the trial, using multiple drugs at once. How is that made possible given the rigours of clinical trials usually and the safety with which they have to be conducted?

Emma - Yeah, it's a really good question. I mean, the short answer is you need very clever statisticians. So what you do, you'd have one placebo group or dummy drug, whatever you want to call it, control arm, against, instead of just having one, you can add in say two or three arms with active treatment in them. So Octopus has started actually with what we're calling repurposed off-patent drugs. So these drugs are used for other things, but we know that they are cheap and could be readily available for the population. So what you need to do is to consider all the possible biological mechanisms that trigger accumulation of disability in people with MS, and then look for drugs that potentially target those mechanisms.

So we did a huge piece of work looking at hundreds of potential drugs, whittling them down, shortlisting them, reviewing them, getting them reviewed by experts, coming up with a shortlist. So we're starting Octopus with two drugs. One is metformin, which is a commonly used drug for diabetes, and alpha-lipoic acid, which is actually kind of more of a food supplement, if anything else. We've got evidence that they are worth testing in MS. We also have other drugs, on a shortlist or a watchlist for the future, as and when the trial would be able to add the new drugs. You need to have the finances in place. You need to have the statistics in place. There's lots of things to do before you can add new drugs in, but there's plenty of things we'd like to test when we get there. I mean, obviously, the development of novel treatments is really, really important, but certainly for a sort of charity academic enterprise, using these drugs, I mean, they're great because you don't have to do the early safety testing of them. So they can go into later stage trial knowing they're safe and effective in people. I mean, we might not know everything about their safety profile in someone with MS, but the trial will do that in a really controlled, safe way.

James - Because you've got multiple drugs working at once and you're analysing on the fly, could you then look to further streamline the process by directing more energy towards treatments that seem to be working and away from those that seem not to be so effective?

Emma - Absolutely. So what we do with these studies is that normally, with a clinical trial, you'd have an outcome measure or a measurement you're looking for at the end of the trial to tell you whether or not that drug is effective. And what we do in these sort of MAMs or these efficient designs is use what we call interim outcomes. You find that you put in a measurement that is telling you something about your ultimate goal. So for MS, we're looking at people, how far they can walk in combination with other measurements like upper limb function. So what we do is we look for an interim outcome that tells us that if we get some signal there, it's worth continuing, doing an MRI scan essentially, halfway through the trial to see if the drug is worth continuing with or not. If it's not, it gets dropped, which frees up the resources to add in a future arm. Or if it is working, then what we do is we then randomise more participants into that arm. So we're able to kind of make that group bigger to give us a clear answer whether that drug is safe and effective or not.

James - So that's it in principle. In practice, how many people have you been able to recruit in the Octopus trial? And how's it been going?

Emma - So we've currently got around 400 people with MS recruited into Octopus. We're going to get to about summer, kind of autumn 2026 to analyse our interim outcome, that MRI scan, to find out if the two drugs are worth continuing with. Then the ones that are, we will then add more participants in, including more participants in the placebo control arm. And then I think we should get to 28, 29 before we have a definitive answer. But in the meantime, we're going to be working on adding in new arms as well. So it becomes this complicated, staggered design. But the idea is that every few years you read out something about the trial, whether it's this drug is worth continuing with, or, you know, we potentially have a new treatment for MS.