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

full title:
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

Abstract
Background
There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue.

Methods
ME/CFS and Long-COVID patients were enrolled in an open label dose escalating “Proof of Concept” non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection.

Results
76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the “Chalder Fatigue Questionnaire” of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients’ fatigue was significantly reduced by up to 46.8% in 6-weeks.

Conclusions
Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03488-3

 

Is a 5.2% difference, on the chalder fatigue scale, really significant for pwME, given how small it is, and the almost total insensitivity/misattribution of the chalder fatigue scale when it comes to ME?

 

For those who might not have seen it, here is our submission on the problems with the Chalder Fatigue Scale, S4ME: Submission to the public review on common data elements for ME/CFS: Problems with the Chalder Fatigue Questionnaire

 

Their "historical placebo" was from a small 1998 fluoxetine and GET trial using the 14-item Chalder Fatigue Scale at 12 weeks, not the 11-item scale they used in this study at 2 and 6 weeks. So perhaps not the best control.

Interesting that they didn't show significant improvement on the Fatigue Severity Scale, but did on the Chalder and PROMIS Fatigue 7a. Hard to know what's going on here without a real control group.

"Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID."

There was no dose-dependent improvement on the overall average score, but by using a specific cut-off of "Treated % at or Below 4 on Bimodal" they managed to show this supposed dose-dependent relationship, which sure looks like a fishing expedition. The Long Covid scores were even worse, with much less improvement at the higher dose, which probably had something to do with them taking it after having taken the lower dose for 6 weeks, (maybe the placebo effect weakening over time).

It's a range of 22.5% to 27.9% improvement (depending on the dose).

 

Edit: The study was funded by Terra Biological LLC. The lead author, Alan Cash, is the founder and chief science officer of the company (http://terrabiological.com/). Their oxaloacetate supplement is branded as “benaGene” and costs $500 for 6 weeks of treatment (90 capsules of 1000mg, 2x/day: https://benagene.com/products/oxaloacetate-cfs).

The contributions paragraph states: “[DK] provided the ME/CFS patients from his practice and conducted patient evaluations. AC analyzed and interpreted the patient data regarding patient survey responses”.

I am putting this information at the top of my post as it may shed some light on what @LarsSG wrote in his own post, especially in that Alan Cash has an interest in highlighting a dose-dependence relationship, as well as what I wrote below.

—

I am not sure why the authors said that this is a “controlled trial” when the control group was extracted from a small, old trial of a different drug. This seems most dubious: peer review should have flagged this. It does not control for the potential recovery of long Covid patients either, which is why this group may have had better results than the ME/CFS one. This study should only be considered an open-label non-controlled trial.

It should also be noted that 16/43 (37.2%) long Covid patients discontinued the intervention. Since no adverse effects were reported in this group, may this owe to a spontaneous improvement? If so, this further confirms that the control group is not adequate.

Given the flaws of the Chalder fatigue scale, the open-label nature of the study, and the fluctuations in symptoms over time in ME and long Covid, it is difficult to have much faith in the rather small improvements reported here (22.5 to 27.9%) — especially since they were lower and less significant on the PROMIS fatigue scale, and since there were none on the Fatigue Severity Score. Unsurprisingly, the authors did not mention the latter two results in the text abstract, although they are visible in the graphical abstract.

What is surprising, however, is that Dr Kaufman — who specializes in treating ME patients — would use only fatigue scales as outcome measures for this trial. I would assume that he knows the issues with these scales and better measures to use in ME or long Covid. Knowing how much he charges for a consultation, it is not unreasonable to think that most of the patients in this study could afford a smartwatch. He could have asked these patients their weekly averages of daily step count in the surveys.

 

more of having a product need a marketing strategy to boost sales .

 

Wow, this looks pretty bad when you see the author is selling this supplement for $333-$1000 per month at the dosages used in this study. I wonder if participants were paying for it and that's why many dropped out.

And the trial registration was supposed to be placebo-controlled (and different in many ways).

 

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.

 

Oxaloacetate Shenanigans

https://psblab.org/?p=618

 

Dr. Kaufman is considered the Mecca for many ME/CFS patients, he has a certain reputation. A few years ago Ron Davis said that every time he talked to Dr. Kaufman he "was impressed by how much he knows". I have seen patients sell their house or car to see him in a last ditch effort, as he is very expensive. "If Dr. Kaufman can't help me, nobody else can. If this doesn't work out i'm doomed". I wouldn't be surprised if this kind of patient population was more susceptible to placebo, especially if he told them he is coming out with a novel mitochondrial treatment. As for the long COVID patients, they have been ill only for a short amount of time so they have a much higher chance of natural improvement/remission.

As others have said, the trial is unblinded with subjective outcomes (laughable questionnaire). The first author is the founder of a company that sells this supplement for exorbitant prices, and he is the one who
"analyzed and interpreted the patient data regarding patient survey responses".

The theoretical basis for this supplement to work is weak, as @Jonathan Edwards pointed out in a previous thread. Much higher doses would be needed to have a meaningful effect on metabolism. The biology doesn't seem to add up.

I doubt anybody will even try to replicate this finding with a proper study because it would just look like a waste of time and money.

A big problem we have with ME research is that many studies are done so poorly that nobody even bothers to try and replicate them. Just because a study has 30 patients instead of 1000 doesn't mean it can't be done properly with blinding, objective measures etc. If things don't start moving forward from this kind of stuff we will never have a treatment. It has been like this for 40 years.

 

it is massively disappointing that Kaufman is lending his reputation to something like this :/

 

https://twitter.com/user/status/1541878972929163267

 

The Bateman Horne Center is currently running a trial dubbed Restore ME, with objective outcome measures (physical exam, blood tests, daily step count & hours of upright activity) and weekly questionnaires:

https://batemanhornecenter.org/research/

 

Sorry, wrong wording - I meant to say that nobody outside of the small ME field would look at this and think it's worth trying to replicate. Luckily this time Lucinda Bateman is here to bail us out, but wouldn't it be better if we had small but properly executed studies of 20-30 patients that enticed people outside of the very small ME circle of clinicians to think "huh, this looks interesting, maybe we could try to replicate it", instead of making poor studies, then wasting more of our already minuscule resources getting one of the ten ME clinicians worldwide to bail the other out while the rest of the world is laughing?

Last i heard (many years ago) Kaufman was charging something like 600$ for a visit and had a super long wait list. And you also had to pay in the hundreds to simply talk to him on the phone if i remember correctly. If he has such a high standard that nobody in the world can match his expertise and skills why is he publishing such a poor study, and why is he not held accountable for it? Medicine is so messed up, anybody can just do whatever they want.

 

I very much agree with you, @Hubris. Since this supplement has been sold for cancer, I wonder what an academic oncologist looking at this paper would be saying.

I am equally disappointed in Dr Kaufman for allowing this to happen, instead of demanding an actual control group, more reliable outcome measures and involving himself in the analysis of the data. He should also have informed himself about the company and his founder before agreeing to run a trial with, or rather for him.

To me, it seems that non-academic clinicians tend to buy into whatever new treatment option they may be able to offer to their patients rather than appraising the evidence critically, especially for yet non-elucidated diseases such as ME. Not that clinician-researchers are immune to this, far from it, but I would like to believe such a poor study would have them raise an eyebrow. It is all too unfortunate, and it is the patients who suffer the consequences of this situation — I don’t think Dr Kaufman’s reputation as a ME specialist will be affected by this study, even though it should be.

Edit: according to a ME patient’s crowdfunding page, as of May 2021, a consultation with Dr Kaufman costs “approx[imately] $732/hr, and a surcharge of $125 for every 15 minutes past the hour”.

 

Even the Bateman Horne study doesn't look great. Primary outcome: Chalder Fatigue Scale. Secondary outcomes: Adverse events, SF-36, Patient Global Impression of Change Questionnaire.

There is mention of "hours of upright activity, functional capacity (upright activity, steps, cognition, and heart rate variability) and general health status (global change, vitals)" in the description, but none of the objective measures appear to be registered outcomes.

 

Our thread on this is here, USA: RESTORE ME: A RandomizEd Double Blind Placebo Control Trial to Determine the EffectS of OxaloaceTate On ImpRoving FatiguE in ME/CFS

 

https://rationalwiki.org/wiki/CRONaxal

 

From my link above:

They also make an eponymous oxaloacetate formula for Dr. Mitch Ghen D.O.[7] “Dr. Mitch” has twice been disciplined: once by the North Carolina Medical Board, and once by the Florida Board of Medicine.[8].



Mitchell Ghen, D.O., Ph.D.

THE WORLD RENOWN EXPERT IN INTEGRATIVE MEDICINE

Dr. Mitch has been a host and guest on hundreds of television and radio programs as an expert in functional medicine and alternative health, including hosting of the Dr. Mitch Show on SiriusXM and the largest health talk program in South Florida, The Dr. Mitch Show, on WFTL 850 for over 7 years. He was the medical expert on the Andy Dean Show “America Now” and the nationally syndicated morning Sam Sorbo show. Currently, he is hosting one of the largest health TV show on WGGS-16.

https://www.integrativemedconsult.us/mitchell-ghen-d-o-ph-d/