Trial Report RESTORE ME: A RCT of Oxaloacetate for Improving Fatigue in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), 2024, Cash et al

forestglip said:
RESTORE ME: A RCT of Oxaloacetate for Improving Fatigue in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Alan B. Cash, Suzanne D. Vernon, Candace Rond, Saeed Abbaszadeh, Jen Bell, Brayden Yellman, David Kaufman

*[Provisionally accepted, full text not yet available]*

Abstract
The energy metabolite oxaloacetate is significantly lower in the blood plasma of ME/CFS subjects. A previous open-label trial with oxaloacetate supplementation significantly reduced ME/CFS fatigue.

In a follow-on trial, 82 ME/CFS subjects were enrolled in a 3-month randomized double blinded controlled trial using 2,000 mg oxaloacetate or control/day. The primary endpoints were safety and a reduction in fatigue from baseline. Secondary and exploratory endpoints reviewed functional capacity, and general health status.

Results: Anhydrous enol-oxaloacetate (oxaloacetate) was well tolerated at the doses tested. Oxaloacetate significantly lowered fatigue from baseline by >25%, whereas the control group was not significant at ~10% reduction. Intergroup analysis of oxaloacetate and control measured shifted fatigue to lower levels in the oxaloacetate group (P= 0.0039), but with no significant shift in the control group. The oxaloacetate group had a higher percentage of subjects achieve a > 25% reduction in fatigue compared to the control group (P< 0.05). A subset of subjects that comprised 40.5% of the oxaloacetate group were "Enhanced Responders" with a 63% average fatigue reduction.

Both physical and mental fatigue were improved by oxaloacetate. Oxaloacetate is well-tolerated and helps to reduce fatigue in ME/CFS.

Link (Frontiers in Neurology)
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I’m only well enough to scan and see if there was a longer term measure so might have missed something on that

but that is what these days I’m looking for having had experience of many things or pints in time where I feel or function a bit more short term only for that to catch up with me whether I stop or it catches up to stop me (it’s probably both as I’m pretty determined and then there’s a point where you realise you are getting worse and can’t do what you did)

I think this always used to be known given that’s surely why people warn stimulants etc don’t actually work

so I’m disappointed this isn’t much longer time points and also having some triangulation measures that ensure people aren’t kidding themselves because in some fatigue = how tired you feel / what you did to feel tired and not just whether you feel dozy or lethargic one day whether you were lucky enough to be lying around for weeks on end or had the peak time at work. And if people cut back and get tenacious about things like starting online groceries or just doing a quick tidy (knowing it will build up) or skipping x that week of getting early nights that matters vs their start point?

it’s one thing too if even if something ‘worked’ it makes you feel more alert for eg your six hours a day vs overall making you less exhausted vs both and you don’t get PEM fir doing more and you don’t crash every fortnight or months in

I don’t know how stuff like this is helpful because we can never really compare what does what even to have something as part of a combination of options to help different people if we don’t test all of these to see what it helps with what it doesn’t etc

I haven’t looked at what was covered by this ‘safety’ priority either but surely a 12month + follow up is also key here to make sure function hasn’t ended up below the start point etc (to at least give warnings or advice about it eg if it is in some but not others)
 
Yates's correction for continuityQuite a few patients scored a value of 0 at baseline or follow-up which seems weird given that these were the completer's analysis, so 0 doesn't indicate missing data.

The abstract writes: 'A greater proportion of subjects in the oxaloacetate group achieved a reduction in fatigue greater than 25% compared to the control group (p < 0.05)'. I could not replicate this and it is unclear what they did with controls who had a baseline value of 0. Setting their percentage difference to 0, I got the following results for 25% reductions in fatigue scores:

upload_2024-12-14_10-48-18.png

Using a chi-square test, this difference was not statistically significant (X-squared = 1.614, df = 1, p-value = 0.2039).
EDIT: It looks like the authors used ITT analysis here so 8/40 responders in the control group and 17/42 in the intervention group. That's how you get the p-value of 0.04. But it is recommended to use 'Yates's correction for continuity' (the default in R) which gives a p-value of 0.07.
 
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The paper says:
During the trial, a patient death occurred, which was classified as a serious adverse event. As a result, the trial was temporarily paused, and the study was unblinded to determine which group the deceased patient belonged to. It was revealed that the patient was in the control group, not the oxaloacetate group. After the pause, new patients were re-randomized using individual randomization numbers. This adjustment was implemented to ensure that if further serious events occurred, unblinding of other participants would not be necessary
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The abstract claims it was a double blinded study. Well, actually it doesn't quite, there's a bit of sleight of hand there
In a follow-on trial, 82 ME/CFS subjects were enrolled in a 3-month randomized double blinded controlled trial
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The subjects were enrolled in a double blinded trial, yes, it's just that it didn't stay double blinded through to the analysis of the data. I wonder if some of the participants became aware of what treatment arm they were in.


ME/CFS Skeptic said:
I assumed nobody would take these results seriously as indicating a real effect but Suzanne Vernon wrote on the Bateman Horne clinic website:
the results clearly show oxaloacetate can help
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We have some commentary about this here:
USA: News from the Bateman Horne Center

I think the Bateman Horne Center directors need to take a careful look at what is happening with the studies they are supporting. I don't think these studies are reputation enhancing, nor do they improve the medical care people with ME/CFS will receive at this clinic and beyond.
 
I'm sure no one will need to tinker round the statistical edges when a treatment's found that actually works. In a real remission, everything's off-the-charts better.

Just imagine it not being a problem to stand in a queue at the bar. And when the craic's still going strong and someone suggests going on to a late-night place, the calculation's only about whether you fancy it, not whether you can.

A thousand little miracles like that.
 
Yep. Though to be fair, a treatment that can improve my functional capacity by something tiny like 5% on a bell scale would be lifechanging. I might be able to tolerate sound again, have short conversation, tolerate humans in my presence, properly wash, listen to music… Like a very small improvement could completely change my life for the better.
 
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