Oxaloacetate Treatment For Mental And Physical Fatigue In (ME/CFS) and Long-COVID fatigue patients, 2022, Cash and Kaufman

This thread is a reminder of the value of this forum. Over on twitter someone posted the paper and all the responses were unquestioning excitement, ooh those results are impressive... where can I get some... how much does it cost. ..This sort of reaction seems to drown out the few who question anything.
 
I was a patient of Kaufman from 2015-2017 and his fees were much much lower than cited above at that time. It seems after cci (both Jen and Jeff were his patients) his waiting lists got much longer and his fees much higher. I find the situation very sad.
 
Hi,
I haven't read this full thread, but I wanted to chime in as someone who participated in the study, here are my notes, apologies if some of the points have already been covered:

1. I was in the ME/CFS arm of the study. I dropped out due to an adverse event. Neither my dropping out or the adverse event were reported in the paper. I emailed the paper authors about this and was told this was a mistake. Somehow my data accidentally got dropped. They said this wouldn't have changed the overall results (likely true), but it is concerning and indicates a lack of carefulness. Also, I would argue, that it is a significant omission if the difference is 0 vs 1 adverse event w/ such a small sample size.

2. Alan Cash, who owns the company selling oxaloacetate was apparently the only one doing data analysis. This raises huge red flags for me.

3. To be accepted into the study, you had to fill out various questionnaires. In order to determine who to accept, they put a cutoff score.
This raises a couple of issues for me:
- First, it increases the odds of accepting someone into the study that is in a temporary flare when they fill out the first questionnaire, which will resolve on its own without oxaloacetate supplementation
- Second, Oxaloacetate is expensive. If, someone wanted to try it, but wasn't sure if they would meet the cutoff for the study, there is an incentive to maybe inflate the scores a little bit on this first questionnaire, just to make sure they get in. This incentive is removed after you have been accepted into the study for the two follow up questionnaires, hence creating an automatic improvement in symptom scores.

These are reasons why you need a proper control group. I don't have a good idea of the magnitude of these effects, but I imagine they could be quite large.

4. I'm not sure / don't remember what time periods all of the questionnaires were asking about? In some studies, I've seen, one questionnaire asks about 2 weeks of symptoms whereas another asks about 6 weeks of symptoms, making them not comparable (yet the study does, directly compare them). Can someone confirm if there is evidence that they did *not* do this? I wouldn't be surprised if the first questionnaire asked about 4 weeks of symptoms whereas the second two each asked about 2 weeks of symptoms, which again, could given an easy improvement (more likely to experience any symptom given 4 weeks vs with 2 weeks).

5. https://psblab.org/?p=618 - Interesting read, claiming oxaloacetate can't work the way it is claimed to work. Would be interested to hear someone w/ knowledge of this kind of thing chime in on accuracy.
 
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cassava7 said:
This being said, according to the trial registration, the cut-off value of 4 on the bimodal Chalder fatigue scale was listed as an inclusion criterion:

“4.1.3 Have significant fatigue complaints, defined as a bimodal score of 4 or greater on the Fatigue Questionnaire.”

It is strange, though, that the company could not supply rice flour capsules as a placebo control. They would certainly have been less expensive than the oxaloacetate capsules, and having patients on a cheap placebo pill means less patients on oxaloacetate (i.e. less costly).

Also, while “4.2.3 Participants may not be receiving any other investigational agents” is an exclusion criterion, it was not asked of patients to refrain from initiating (or stopping) other medications, therapies, or other interventions during the trial. Given that the patients agreed to enroll in a trial of a supplement, that may well have been the case and tainted the results of the trial.
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Oxaloacetate is super acidic.
To do this properly, I imagine you would also need to use a super acidic placebo.
Although maybe most people wouldn't notice?
Agree though that they really need a proper placebo control.
 
It seems to me that oxaloacetate is aimed at raising the rate of production of ATP via the citric acid cycle. Yet it probably is not a critical treatment point that I can see. Other things might be better. It certainly is not working as an energy source, the only value is to increase substrate in the cycle, which is then modified by other factors. That might have an impact but its hard to be sure without lots more research than I have seen.

In any study of this kind I want to see objective outcome markers. I am increasingly of the view that questionnaires should be used strictly for secondary (and subjective) outcome markers.

Why oxaloacetate is low in some patients is also critical. It might signal a mitochondrial problem at some earlier point. In other words, its after the block. Given suspected problems with complex V, and potential hypoxia, this looks like a potentially irrelevant treatment. Which means that any study needs to be even more careful, and pay attention to objective results.

If there is some other reason why it is low, not due to a citric acid cycle problem, then it needs to be identified. Where is that study?
 
zippymouse said:
5. https://psblab.org/?p=618 - Interesting read, claiming oxaloacetate can't work the way it is claimed to work. Would be interested to hear someone w/ knowledge of this kind of thing chime in on accuracy.
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That looks a fairly good account of why oxaloacetate isn't going to do anything.
It also looks like fairly good account of why this is almost certainly a scam.
 
I’ve always thought there were red flags around Kauffman. On PR, patients of his would report on treatment protocols that seemed very heavy handed for ME patients — I remember one being advised to do both IVIG and rituximab at once. As far as I recall he also relied on iGenex Lyme disease tests that are known to be hyper sensitive and have false positives.
 
I have sent a mail to Prof Francesco Marincola, Editor-in-Chief of the Journal of Translational Medicine, to alert him about two errors:

1) the claim that the trial was controlled even though it was not, which is explicitly acknowledged by the authors in the paper and was reaffirmed by Dr Kaufman at the 2022 IACFS/ME conference

2) the historical placebo group from the RCT of fluoxetine and graded exercise (Wearden 1998) did not improve by 5.9% at 26 weeks as claimed in the paper but by 7.9%, so the reported effectiveness of oxaloacetate supplementation was artificially inflated.

Misleading errors in a Journal of Translational Medicine article

Dear Professor Marincola,

I am writing to you in your capacity as Editor-in-Chief of the Journal of Translational Medicine with regards to the article on oxaloacetate supplementation for ME/CFS and long Covid that was recently published in your journal (Cash and Kaufman 2022; references listed at the end of this mail).

Cash and Kaufman claim that their study was a non-randomized controlled trial. However, there was no control group, as they acknowledge in the Discussion section:
As there was no placebo group (only historical placebo), there was no randomization into a separate group.
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Kaufman reiterated that there was no control group in the trial when he presented the results at the International Association for CFS/ME’s conference on 29 July 2022 (https://twitter.com/s4me_info/status/1553409008832331779).

For this reason alone, the trial simply cannot be said to be controlled and this makes the title of the article misleading. It is unclear why this was not flagged by the peer reviewers.

Further, the authors extrapolated the “historical placebo” data from one of four arms of a 26 week RCT of fluoxetine and graded exercise (Wearden et al 1998 — note that this reference is missing in the paper). This arm, which was assigned “exercise control and drug placebo”, had a mean baseline Chalder fatigue scale score of 34.0 points (95% CI 32.3 to 35.7) and achieved a mean improvement at 26 weeks of -2.7 points (95% CI -5.4 to 0.01 ; see Table 2). This represents an improvement of 7.9% over baseline, but Cash and Kaufman mistakenly reported that this arm achieved a 5.9% improvement, which artificially increases the reported effectiveness of oxaloacetate in their trial.

Note that this error may benefit the first author, Alan Cash, because of his significant financial conflict of interest. He is the founder and CSO of the company that markets the oxaloacetate supplement (Terra Biological LLC, as disclosed in the article) at a price of $500 for 6 weeks of treatment at the recommended dose for ME/CFS and long Covid (https://benagene.com/products/oxaloacetate-cfs).

Consequently, could you please ask the authors to:

1) remove all claims that their trial was controlled, including in the title, and instead mention that the historical placebo data was used solely as a comparator;

2) correct / recalculate their results in light of the error on the historical placebo improvement in Wearden et al 1998 (7.9% instead of their reported 5.9%);

3) add a reference to Wearden et al 1998 for the historical placebo data?

Yours sincerely,


References

Cash A, Kaufman DL. Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial. J Transl Med. 2022;20(1):295. Published 2022 Jun 28. https://doi.org/10.1186/s12967-022-03488-3

Wearden AJ, Morriss RK, Mullis R, et al. Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome [published correction appears in Br J Psychiatry 1998 Jul;173:89]. Br J Psychiatry. 1998;172:485-490. https://doi.org/10.1192/bjp.172.6.485 (Full text accessible at https://www.researchgate.net/profil...ded-exercise-for-chronic-fatigue-syndrome.pdf)
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Edit: I have sent the same mail to Dr Monica Panelli, editor of the section Illnesses of Unknown Etiology in which the paper was published.
 
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cassava7 said:
I have sent a mail to Prof Francesco Marincola, Editor-in-Chief of the Journal of Translational Medicine, to alert him about two errors:

1) the claim that the trial was controlled even though it was not, which is explicitly acknowledged by the authors in the paper and was reaffirmed by Dr Kaufman at the 2022 IACFS/ME conference

2) the historical placebo group from the RCT of fluoxetine and graded exercise (Wearden 1998) did not improve by 5.9% at 26 weeks as claimed in the paper but by 7.9%, so the reported effectiveness of oxaloacetate supplementation was artificially inflated.



Edit: I have sent the same mail to Dr Monica Panelli, editor of the section Illnesses of Unknown Etiology in which the paper was published.
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thank you @cassava7 I wish that there was more discussion at IACFSME surrounding this presentation but also others in regards to the limitations of their study. Kaufman reported no conflict of interest, it was a question that was asked in the Q&A. Beyond COI though, I wish it had been pointed out to him that this was not a controlled trial, there was no placebo and therefore this is not a strong clinical trial.

I would say as a research community, the experts lack clinical trial training and experience but I am willing to be wrong on this. Compare this field to the fields that have medical specialties dedicated to the disease they serve, and having funded drug trials left and right, I do sense that there is a low bar for success and for clinical trial standards with ME. Of course it doesn't help that we are still relying on self-report outcome measures and the possibility of all kinds of bias, from the patients, from the study design and from the researcher/sponsor point of view.

edit to add: I am sorry, I was venting. it is so frustrating to witness how slow it is to find what's wrong and how to fix it.
 
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Post on the ME Association Facebook page.

"Oxaloacetate - a new treatment for ME/CFS and Long Covid?
I have been at the annual IACFS conference in (virtual) America for the past three days
One of the presentations in a Treatment session on Saturday afternoon came from Dr David Kaufman - who described the non-randomised clinical trial that he and Dr Alan Cash have carried out into the use of a nutritional supplement called oxaloacetate
The results that have been published - reductions in both physical and mental fatigue - are clearly interesting but have to be regarded as very preliminary at this stage
We will need more information from further clinical trials before any conclusions about the use of this supplement can be made
If anyone has tried using an oxaloacetate supplement please let us know
Dr Charles Shepherd - MEA"

https://www.facebook.com/meassociat...4tAmFpiFNHxJsaCKcg3bxDfQaVgVKGKoUxMo5vsWyx76l

I posted a link to this thread in the comments.
 
I also watched the Oxaloacetate trial presentation. I was too exhausted by then to take notes, but several things I remember concerned me.

First, from memory, they used the Chalder fatigue questionnaire bimodal scores as the primary outcome measure, and counted the number who reached less than 4 on the bimodal score as their measure of success, but in the talk didn't report what they bimodal scores were before taking oxaloacetate, and being an unblinded trial, they would inevitably be influenced by hope and wishful thinking. And we all know the problems with CFQ. Yet he praised it as 'a validated measure'.

Second, Bateman Horne Center are now doing a double blind trial but still using CFQ as the primary outcome measure. They are using some better measures as secondary outcomes.

Third, when patients stop taking oxaloacetate any benefit disappeared. So if it does anything, it's a temporary boost, possibly from placebo effect, not a switch back to health.

Fourth. There was a large dropout rate from patients recruited online with Long Covid to try oxaloacetate, so I assume they mostly didn't find it helped. He put this larger drop out rate than for the ME patients down to the fact that the ME patients were from his own clinic so could be more easily followed up.
 
Trish said:
Fourth. There was a large dropout rate from patients recruited online with Long Covid to try oxaloacetate, so I assume they mostly didn't find it helped. He put this larger drop out rate than for the ME patients down to the fact that the ME patients were from his own clinic so could be more easily followed up.
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Could it have been the prohibitive cost? Were the long-covid patients required to purchase it?
Would allegiance to your doctor matters when it comes to participating in a study like this? Long-Covid patients would not have such allegiance or connection with the doctor.
 
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