A Novel Nutriceutical Treatment of ME/CFS, 2017, Comhaire

Thanks for the update, @ME/CFS. I look forward to reading the paper when it is published.

You will be aware that we treat all papers published about ME treatments with careful scrutiny, but I hope fairly.

We have been burned so often by the BPS believers use of unblinded trials with subjective outcome measures to make unjustified claims about the effectiveness of CBT/GET therapies.

We therefore treat other trials, of whatever treatment, that also use this approach with equal scepticism.

We have been very disappointed recently to hear that the Phase 3 large, double blind trial of Rituximab did not demonstrate that it was better than placebo, despite the earlier phases of open label trials looking so promising with high rates of improvement in the treatment group.

We all have the same aim - to find treatments that are proven to be effective by rigorous scientific trials. And that means large double blind trials.

The other thing that leads to some scepticism is that many ME sufferers try nutritional therapies and experience apparently significant improvement for a few weeks or months, only to relapse back again. I would therefore be very cautious about a trial of only a few months duration.

I have not come across sodium dichloroacetate. Would you care to tell us what it's biomedical function is, and what its role in ME is likely to be and why you decided to use it? And are you willing to reveal the list of other ingredients you used? I assume in order to publish, you will have to reveal the details of the composition, dosage etc.

Do let us know when the paper is published.

Edit to add: I've just looked it up:

''sodium dichloroacetate
The sodium salt of dichloroacetic acid with potential antineoplastic activity. Dichloroacetate ion inhibits pyruvate dehydrogenase kinase, resulting in the inhibition of glycolysis and a decrease in lactate production. This agent may stimulate apoptosis in cancer cells by restoring normal mitochondrial-induced apoptotic signaling.''

Further interesting information on Wikipedia:
https://en.wikipedia.org/wiki/Dichloroacetic_acid
 
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Indigophoton said:
@ME/CFS Would you mind letting us know the patent number?
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The formulation is fully protected during 12 months while the "novelty" is being checked. During that period "provisional protection" completely covers the intellectual property-rights of the inventor. The complementary ingredients of the nutriceutical are: Vitamin B1, alfa-lipoic acid, acetyl-l-carnitine, and ubiquinone Q10, which all act in synergy with the sodium dichloroacetate. Thanks to this synergy the dose of sodium dichloroacetate can be reduced to far below the level of potential toxicity. By inhibiting the pyruvate dehydrogenase kinase, sodium dichloroacetate has been proven to activate the Kreb's cycle of aerobic metabolism, since the enzymatic activity of pyruvate dehydrogenase is increased. This enhances the production of ATP, the carrier-molecule of cellular energy. Once again, I wish to underscore that many so-called "cases of ME/CFS" are not primarilly due to an enzymatic problem causing poor mitochondrial function, but are "cases of secundary syndromes of fatigue" caused by another disease (as exemplified in my previous paper, and detected by me in ever more patients). Finally, please take into consideration that English is not my "mother-tongue", which explains liguistic errors.
 
ME/CFS said:
A pragmatic trial is, by definition, not blinded, since it is an open-label, prospective, real life trial. Please look up the definition of "pragmatic trial" via internet.
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I looked up pragmatic trials and found a good review in NEJM. It says:

It is only after phase 3 drug trials that we have any real understanding of whether the treatment is beneficial, who might benefit most, the potential adverse effects, and the most cost-effective implementation. The ideal time to perform a pragmatic trial would be during the implementation stage of a complex intervention or the postmarketing phase of drug evaluation, to help provide an understanding of what the effect of introducing the new technology might be on overall public health.

That does not seem to have much to do with early proof of concept studies. Also it says:

In many situations, the need to avoid reporting bias will override purist pragmatic considerations, making blinding the optimal approach. In complex intervention trials, in which blinding the intervention is often impossible, it is usually possible to blind the assessment of outcomes.36 In any trial, the advantages and disadvantages of blinding must be considered; blinding is particularly important when the reporting of key end points or safety events could be biased in an open trial.
 
ME/CFS said:
The beneficial effect of the treatment has persisted for up to 7 months in the patients who were included in the initial trial.
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Is this only in regards to a fatigue questionnaire again?

ME/CFS said:
A pragmatic trial is, by definition, not blinded, since it is an open-label, prospective, real life trial.
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Will you be conducting a more probative trial in the future, with controls, blinding, and objective outcome measurements? A successful treatment for ME/CFS would be groundbreaking, and the extra expense and hassle of such a trial would certainly be worthwhile.
 
A pilot, open label, proof-of-principle, pragmatic trial is the first step in a sequence of validation. For the patients who benefit from the treatment, the effect is what counts. In my view of medicine (which I practice since 54 years), the feeling of health and happiness of the patients is what is of pivotal importance.
In addition, there is a remarkable fact namely that the probability can be predicted that a particular patient will or will not benefit from treatment. This prediction is based on a mathematical formula that is derived from the result of the regression analysis with stepwise elimination (area under the ROCcurve= 0.91).
 
ME/CFS said:
A pilot, open label, proof-of-principle, pragmatic trial is the first step in a sequence of validation. For the patients who benefit from the treatment, the effect is what counts.
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Could you clarify if you will be going on to a second step of validation, with objective outcomes, a control group, and blinding? The effect does indeed count, but we need better trial design to know if there actually is an effect or not.
 
ME/CFS said:
A pilot, open label, proof-of-principle, pragmatic trial is the first step in a sequence of validation. For the patients who benefit from the treatment, the effect is what counts. In my view of medicine (which I practice since 54 years), the feeling of health and happiness of the patients is what is of pivotal importance.
In addition, there is a remarkable fact namely that the probability can be predicted that a particular patient will or will not benefit from treatment. This prediction is based on a mathematical formula that is derived from the result of the regression analysis with stepwise elimination (area under the ROCcurve= 0.91).
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I am not sure I really agree with that, having been heavily involved in devising and executing trials at all stages. My understanding from NEJM is that the term pragmatic was invented to deal with late stage assessment of practical implications in a real clinical setting after pilot and proof of concept trials had been done to establish efficacy. And pilot trials are more or less by definition not proof of concept trials because 'pilot' means preliminary, implying preliminary to a formal demonstration of efficacy, which is what a proof of concept trial does.

My impression is that you are as far as a pilot open study. That is fine in terms of establishing tolerability and feasibility of doing a full study of efficacy but it does not allow conclusions about efficacy to be drawn.
 
As argued before, this is an open-label, proof of principle or proof of concept pilot trial performed in real life circumstances and, therefore, it may be called pragmatic. The message that I have transmitted is that a foodsupplement, that inhibits Pyruvatedehydrogenase kinase and that stimulates energy production by the Kreb's cycle does, indeed, siginificantly improve the health situation of some patients suffering from long-lasting so-called refractory ME/CVS. I am aware of the fact that additional studies are necessary, and I have quite some experience in the field of clinical research.
 
ME/CFS said:
In addition, there is a remarkable fact namely that the probability can be predicted that a particular patient will or will not benefit from treatment. This prediction is based on a mathematical formula that is derived from the result of the regression analysis with stepwise elimination (area under the ROCcurve= 0.91).
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Hi @ME/CFS I am confused by this claim. Are you really saying that, on the basis of a small open label proof of concept pilot trial, you can predict with such a level of certainty which patients will respond?

Surely such a claim cannot be made until much later in the process when you have double blind data that confirms that the response you are finding is more than placebo effect. Only then would you have valid data from which to calculate your regression equation. You would then need a whole new batch of double blinded patients whose data has not been used to derive the equation to test whether it works as a reliable predictor.

There seems to be something I'm not quite getting here from your comments. I guess I'll have to wait for the published paper to see how you did the calculations.

ME/CFS said:
a foodsupplement, that inhibits Pyruvatedehydrogenase kinase
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In my limited on-line reading, sodium dichloroacetate it is described as a prescription only drug being tested for use in some cancers which can have neurological and other side effects, not a food supplement. Can you clarify this?

Please don't think I'm just dismissing your work, or nit picking. I genuinely want to understand, as, like all ME sufferers, I'd love there to be a treatment that works, at least for some of us. And I'd love it to be one based on something that can be administered in a simple pill at not too great cost and with minimal side effects. That would be truly wonderful.

On face value, a mix of supplements that support mitochondrial activity with a chemical with pyruvate dehydrogenase activity seems to chime well with some of the preliminary metabolomics studies we have heard about recently. So you may be on to something useful. That's why I continue to take an interest in what, on the face of it , seem to be overblown claims for a pilot study.

But we have had our hopes dashed recently with Rituximab, and went through the same process of very hopeful early stage open label trials, only to have the early promise contradicted once the large double blind trial was completed. Placebo effect is a very powerful thing.

Do you have any indication of when your paper is likely to be published?
 
Trish said:
Hi @ME/CFS I am confused by this claim. Are you really saying that, on the basis of a small open label proof of concept pilot trial, you can predict with such a level of certainty which patients will respond?

Surely such a claim cannot be made until much later in the process when you have double blind data that confirms that the response you are finding is more than placebo effect. Only then would you have valid data from which to calculate your regression equation. You would then need a whole new batch of double blinded patients whose data has not been used to derive the equation to test whether it works as a reliable predictor.

There seems to be something I'm not quite getting here from your comments. I guess I'll have to wait for the published paper to see how you did the calculations.



In my limited on-line reading, sodium dichloroacetate it is described as a prescription only drug being tested for use in some cancers which can have neurological and other side effects, not a food supplement. Can you clarify this?

Please don't think I'm just dismissing your work, or nit picking. I genuinely want to understand, as, like all ME sufferers, I'd love there to be a treatment that works, at least for some of us. And I'd love it to be one based on something that can be administered in a simple pill at not too great cost and with minimal side effects. That would be truly wonderful.

On face value, a mix of supplements that support mitochondrial activity with a chemical with pyruvate dehydrogenase activity seems to chime well with some of the preliminary metabolomics studies we have heard about recently. So you may be on to something useful. That's why I continue to take an interest in what, on the face of it , seem to be overblown claims for a pilot study.

But we have had our hopes dashed recently with Rituximab, and went through the same process of very hopeful early stage open label trials, only to have the early promise contradicted once the large double blind trial was completed. Placebo effect is a very powerful thing.

Do you have any indication of when your paper is likely to be published?
Click to expand...
Trish said:
Hi @ME/CFS I am confused by this claim. Are you really saying that, on the basis of a small open label proof of concept pilot trial, you can predict with such a level of certainty which patients will respond?

Surely such a claim cannot be made until much later in the process when you have double blind data that confirms that the response you are finding is more than placebo effect. Only then would you have valid data from which to calculate your regression equation. You would then need a whole new batch of double blinded patients whose data has not been used to derive the equation to test whether it works as a reliable predictor.

There seems to be something I'm not quite getting here from your comments. I guess I'll have to wait for the published paper to see how you did the calculations.



In my limited on-line reading, sodium dichloroacetate it is described as a prescription only drug being tested for use in some cancers which can have neurological and other side effects, not a food supplement. Can you clarify this?

Please don't think I'm just dismissing your work, or nit picking. I genuinely want to understand, as, like all ME sufferers, I'd love there to be a treatment that works, at least for some of us. And I'd love it to be one based on something that can be administered in a simple pill at not too great cost and with minimal side effects. That would be truly wonderful.

On face value, a mix of supplements that support mitochondrial activity with a chemical with pyruvate dehydrogenase activity seems to chime well with some of the preliminary metabolomics studies we have heard about recently. So you may be on to something useful. That's why I continue to take an interest in what, on the face of it , seem to be overblown claims for a pilot study.

But we have had our hopes dashed recently with Rituximab, and went through the same process of very hopeful early stage open label trials, only to have the early promise contradicted once the large double blind trial was completed. Placebo effect is a very powerful thing.

Do you have any indication of when your paper is likely to be published?
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Reply
this is indeed based on a relatively small number of observations, and is performed a posteriori, by calculating the formula derived from the logistic regression analysis (MedCalc statistical program).
 
What about trial of Ibrutinib
There’s a video on youtube,targeting B cell receptor signalling for anti cancer therapy. It hits on a lot of keywords for me pkc being one
If I develop one of these types of cancer treatment may cure both as per fluge mella I think that’s the only way I would receive something like this
It’s like a static pre cancer
 
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ME/CFS said:
This prediction is based on a mathematical formula that is derived from the result of the regression analysis with stepwise elimination (area under the ROCcurve= 0.91).
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Using what biomarker/predictors?

Claiming you have a strong predictive method, without actually stating the method itself is well, unconvincing.
 
Fatigue with PEM has certainly been the main expression of my illness over the past 34 years.

And the PEM "crashes" mainly involve profound exhaustion.

I don't associate with the "fatigue isn't a problem" proclamations up-thread.

I do care about "fatigue". Very (very) much. In fact, fatigue and brain-fog have the biggest impacts on my quality of life.

For me, it is the #1 top symptom (by far).

Bill
 
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