Trial design for drug trials for ME/CFS - discussion thread

I agree that testing potentially dangerous drugs that have no plausible theory behind them isn't a great idea. But if drugs are being trialled elsewhere already - such as LDN, I could see the value of extending to the UK? Do we have to wait for the current trial to finish?? Perhaps a more pragmatic design trialling the same two drugs - cluster randomizing, via primary care practices?
I meant to stick to asking for ideas of drugs tested in other conditions, such as POTS, because that was what came out of the priority setting partnership exercise (2nd on the list). https://www.jla.nihr.ac.uk/priority-setting-partnerships/ME-CFS/top-10-priorities.htm.
So maybe Ampligen not a great candidate as it's not used for other conditions and has not been tested properly yet.

 

If it looks well set up enough to give clear results, I imagine it'd be good practice to wait? If not, then I guess there's an argument for doing a rigorous trial.

On a personal level, I wouldn't want to sign up to a trial of any of the meds currently under discussion. I'm not sure any of them look like strong enough candidates, especially given that pwME seem prone to drug sensitivities.

But I'm in my mid-60s and that colours my outlook. Obviously it might be different for people who still have a chance of rescuing their career or education, or who're more severely affected.

 

Generally speaking, if a drug works usefully a single well-designed trial shows that clearly. I withdrew from rituximab trials in ME/CFS when I knew Fluge had a good blinded randomised study set up. I would have just wasted more money.

Whether or not a drug is worth trying does not have much to do with whether someone else is trying it and there are unlikely to be reliable 'positive signals' until the formal analysis is done.

'Pragmatic', as emphasised by Chris Burton to me, really means 'not rigorous enough to provide reliable cause and effect results'. Burton did not seem to understand that trialling a drug was trialling its ability to cause an effect! There may be very clever ways of circumventing expectation bias using unconventional trial designs with multiple drugs but unless the drugs have rather similar pharmacodynamics it may be quite tricky to design something that makes sense.

 

Obviously serendipity can play a part e.g. I think that was one of the factors which led to Jonathan's breakthrough in (rituximab) autoimmune arthritis - people treated with rituximab (cancer patients) whose arthritis relapsed.
I'm hoping GWAS DecodeME, and potentially the application of analytical tools like those applied by PrecisioLife (see Simon McGraths blog), can help to find drug targets.
As per comments above, I'm not sure I'd be keen to ask a family member to participate in a trial without some objective evidence that it should work.

 

I think LDN/Mestinon are already so widely used/prescribed that I don't think waiting for the trial results would be necessary in that case. I don't know if UK trials are necessary for NICE approval?

The others I mentioned would definitely be on the basis of positive trial results.

POTS medications might be helpful for a subset of us - ivabradine has really helped me, and I have heard a lot of similar anecdotes.

Edit: Really helped as in borderline very severe to top end of severe, still mostly bedbound, for clarity.

 

Actually that was a fake news story put about by people wanting to have the patent. I had planned to use rituximab well in advance of doing so, on purely theoretical grounds!

 

NICE simply requires positive results from reliable trials and we don't have those for either mestinon or LDN in ME/CFS. Physicians should not be prescribing these until we know they are actually useful. Theconsensus for LDN seems to be that it probably isn't, since it has been around for yonks and not many people have found it helpful in the long run. There will always be a few people who swear by drug, but people swore by the effect of rituximab for ME/CFS and it was almost certainly spurious.

 

POTS medications are the ones mentioned by the James Lind Alliance, so perhaps a 2x2 factorial placebo controlled trial with ivabradine and another potentially helpful medication which could be combined safely with ivabradine would be good. Following the LIFT template, but with input from patients on the primary outcome, how that outcome could be measured objectively, and the minimally important effect size.

 

Thanks for clarifying about NICE. To be clear I meant that it would not be necessary to wait for the results of the LIFT trial to do a UK LDN and mestinon trial.

In that case the OMF trial should hopefully settle the LDN issue once and for all.

 

I would agree.
That said one of my worries is that the dose tried is too high or inflexible for many participants.
I know I am in the minority in this thread but LDN does actually help me. It reduces my pem, just not my ME functioning level. But only at a fraction of the 4.5mg usual max. I'm stable on 1.7mg. When I got up to around 4mg after a slow titer I crashed. Though that could also be partly over exertion as I'd felt so much better on it. it is quite stimulatory when the dose is higher so it's needs to come with a warning to pace to the same level.

 

What about low dose apiprazole (abilify)? There’s been no randomised blinded trial but a retrospective study found results worth investigating further.

Anecdotally, behind LDN, it seems to be the drug most people report benefits from.

 

I think anecdotally a lot more people find benefits from LDA than LDN. The LDA FB group has like 5k members. LDA can take you from Bell 30 to Bell 90– see here https://forums.phoenixrising.me/threads/pramipexole-put-my-cfs-me-into-remission.92410/

LDN doesn’t do that.

 

I'm another one who does seem to get a minor benefit from LDN and had that overstimulation-overexertion issue when first going up to a higher dose. I also wonder about what the dosage recommendation is based on, whether bigger studies could look at different doses and ways of taking it.

 

I'm finding an extra low dose combo of both good. LDA helps brainfog and pem but sadly no physical stamina gain, LDN lessens pem and pain. But overexertion possible on both as neither address my underlying problem (or I'm too severe/late stage) and side effects can be difficult especially the insomnia at the start.

 

I understand the reasons for trying meds that don't address the underlying ME, but if they don't, can they be good candidates for the significant investment needed for a large trial?

Maybe the same's not true for a proportion of patients, of course; but if it was, they're arguably no better than the movement-and-CBT treatments for mildly affected pwME. There's a risk they distract from/suppress the symptoms long enough to set up the conditions for a damaging crash.

(I'm only playing devil's advocate, by the way, and don't know enough to have actually made up my mind! )

 

I do get the dilemma. But ME is complex and we need to improve QoL while we wait for science to make more headway as that's going to take years.
So I think on balance given they do seem to at least address pem in severe (just don't increase function / stamina) the quality of life improvement would warrant it. Some Less severe patients (albeit anecdotally) seem to report greater gains.

It may well in any case turn out that we need to use multiple drugs in combination to reverse the process. So then we'd need a trial of proven drug or drug combo a and new drug b (something targeting the underlying pathological cause) .

Its as much about the right trial design. Using an ongoing octopus style platform trial set up would aid trial cost efficiency and make it easier to add in new drug candidates as the scientific understanding improves.

But just my lay patient perspective of course

 

I went to a research presentation recently for ME patients in Oxford organized by Karl Morten. A collaborator of his Dr Pawel Zalewski presented about his research on the effect of cryotherapy (going in a ridiculously cold chamber for a bit...apparently as not as unpleasant as it sounds) on clinical and biological markers of ME/CFS. It seems to show promise and he suggested it might be a good treatment to trial in a less pleasant but more pragmatic way cold bath, shower, cold water swimming, or whatever, in order to do a large and rigorous test of effectiveness on PwME who have been diagnosed properly. And using objective outcomes rather than the Chalder Fatigue scale or similar. I checked and there is a thread about this work https://www.s4me.info/threads/combi...e-ans-in-cfs-2022-kujawski-et-al.28144/page-2.

I am submitting my application for funding for my Trialblazers idea - in short, enabling patients to design trials that they can take part in. Plain language summary attached. I hadn't considered non-drug treatments, because the James Lind prioritized question was to test repurposed drugs. But with the concern about most drugs having unpredictable and potentially dangerous effects, I wonder if cryotherapy could be added to the treatment options?

 

Possibly, but my N=1 experience is that cold water swimming is in part a stimulant therapy—albeit one using drugs manufactured in your body.

Swimming in a boring old corporation pool resulted in less PEM, possibly because it didn't make me tend to do more afterwards due to feeling so exhilarated. But in the seas around northern Britain it was also impossible to focus on the physical feedback that would normally tell me when to stop; they're never less than freezing, so every sense in my body was yelling the whole time.

Shorter and more controlled exposures in a clinical situation might be much less risky, though. Maybe it is worth trialling if the preliminary results look promising? But it's only suitable for mild or moderately ill people, and there might be age limits too. Cold therapy definitely shouldn't be tried by people who're alone at home, and the risk of adverse events increases with age. It can cause stroke and even cardiac arrest in people who had no reason to think they were at risk.

 

I have yet to see anything that suggests that this is serious science. There is no coherent background hypothesis as far as I know and no meaningful trials to date. That leaves us with something of the status of some arbitrary nineteenth century magical cure. If I remember rightly cryotherapy - once claimed to help psoriasis - has been around for at least forty years and maybe even a century or more but never proven to be of any use.

 

Cold water immersion should be filed along with dark chocolate and green tea. My N=1 like Kitty’s is that it’s a stimulant. It temporarily masks fatiguability but not PEM. The exertion bill still has to be paid eventually.