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