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

[Barry]

Yes but that's the nature of self-reports.

The phase III rituximab trial also relied on subjective reports but people were generally happy with the design because the treatment was blinded.

This is a preliminary study so there isn't a placebo. However, the results help inform the investigators in future trials.

I don't think we should get too hung up about what we perceive as flaws in this research. Yes there is a patent pending but nothing is being sold off the back of this initial study. Let's see what happens in the future.

Sorry, yes I agree with you. I'd dropped into a more general comment, and drifted somewhat from the specifics of this thread. I was really meaning it's a problem if not properly accounted for ... but only said half of what I should have.

 

[Valentijn]

The phase III rituximab trial also relied on subjective reports but people were generally happy with the design because the treatment was blinded.

I would have preferred the objective measurements be the primary ones, but there was at least one objective secondary outcome.

This is a preliminary study so there isn't a placebo. However, the results help inform the investigators in future trials.

There might be a placebo effect. We don't know, because it's subjective outcomes with no control group.

My concern is not with the preliminary study failing to use objective outcomes, but with the author's seeming lack of intent to use objective outcomes in the future, combined with his belief that fatigue is actually the most relevant outcome:

thanks, once again, for constructive remarks.

Fatigue is a subjective feeling which is extremely hard to objectivate. Exhaustion, lactic acid accumulation, sleep disturbance etc. can be measured, but the feeling of fatigue can only be estimated by using questionnaires. Patients expressing that they were clearly less tired, and could resume their activity, and in whom the FSS was decreased by at least 15%, were considered responders.

I repeat that the prime purpose of treating patients with fatigue is to make them feel better, to increase their "energy" so that they can resume their "normal" professional and familiy life, albeit often with limitations. In general, this is the purpose of medicine.

And responding to our ongoing methodological concerns by claiming that we're just focusing on ourselves, and that he's the expert, does not inspire any faith regarding the use of more rigorous methodology in the future:

when reading further comments, I notice that everyone is looking at his own story. I have given general recommendations based om my clinical experience in a rather important number of patients, many of whom I follow and try to help since several years.

I always appreciate it when a researcher is interested in a biomedical approach, but I must object when they embrace the same methodological flaws which have allowed psychosomatic researchers to make ridiculous claims over the years. It won't harm public perception of our disease if his research is ever publicized, but the poor methodology means that his research will not be useful to patients until he fixes it.

 

[Scarecrow]

There might be a placebo effect. We don't know, because it's subjective outcomes with no control group.

Yes, there may well have been a placebo effect but there was no placebo. Therefore, the effect can't be determined. That's for future trials.

My concern is not with the preliminary study failing to use objective outcomes, but with the author's seeming lack of intent to use objective outcomes in the future, combined with his belief that fatigue is actually the most relevant outcome:

He hasn't commented on objective outcomes in the future so we can't assume he has a lack of intent. Yes, I'd prefer it if the emphasis on fatigue was de-emphasised.

I always appreciate it when a researcher is interested in a biomedical approach, but I must object when they embrace the same methodological flaws which have allowed psychosomatic researchers to make ridiculous claims over the years. It won't harm public perception of our disease if his research is ever publicized, but the poor methodology means that his research will not be useful to patients until he fixes it.

This is a preliminary study. It is not a trial. It's to inform the researcher for the future trials he intends to conduct yet it has been judged completely inappropriately and the researcher has been lectured to.

 

[Trish]

And another nutriceutical pilot study, this time from Australia.

Mitochondrial Modifying Nutrients in Treating Chronic Fatigue Syndrome: A 16-week Open-Label Pilot Study
https://www.sciencedirect.com/science/article/pii/S2212958817300915

Abstract
Introduction
Recent evidence suggests that mitochondrial dysfunction may play a role in the pathophysiology of chronic fatigue syndrome (CFS). We undertook a pilot investigation of a combination of nutraceutical nutrient compounds which are involved in mitochondrial function and energy generation, to assess their efficacy in improving symptoms of CFS. An open-label design was employed as CFS is largely treatment-resistant with limited placebo-response.

Methods
A 16-week open-label trial of a nutraceutical combination (primary nutrients: Coenzyme Q10, Alpha lipoic acid, Acetyl-l-carnitine, N-acetyl cysteine, B Vitamins, in addition to co-factors) was undertaken in Ten patients with CFS. Fatigue symptoms, mood and general health were assessed at each 4-week time point over 16 weeks. Of the ten patients (7 female, 3 male) with a mean age of 36.3, eight completed the trial.

Results
Linear mixed model analysis demonstrated a significant improvement in fatigue symptoms across treatment period on the Chalder Fatigue Scale (p < 0.001). Specific improvements were found in tiredness, weakness, feeling sleepy or drowsy, as well as in sleep, and clinician-reported symptom-improvement. No benefit was observed in mood or other functional domains. No serious adverse events were noted.

Conclusion
These preliminary findings suggest that a combination nutraceutical compound of mitochondrial agents may improve CFS symptoms. Further investigation is warranted in a larger double- blind RCT.
.....................................

Any comment, @ME/CFS?

I do not have access to the full paper.

My main concern with this pilot is the use of the Chalder Fatigue Scale as outcome measure. As we have discussed in the past, particularly in relation to the PACE trial, this scale is nonsensical as a measure of ME symptoms both type and severity. It is both subjective and makes almost now allowance for changes in severity of symptoms, being simply a list of rather vague descriptors of different aspects of fatigue.

I tried the Chalder F S myself and scored the same now when I'm mostly bedbound and need help with showering etc, as I would have done when I was mildly effected and still able to work part time as a teacher.

 

[adreno]

primary nutrients: Coenzyme Q10, Alpha lipoic acid, Acetyl-l-carnitine, N-acetyl cysteine, B Vitamins, in addition to co-factors

These are supplements that we have been trialing for years. Nothing new here.

 

[arewenearlythereyet]

And another nutriceutical pilot study, this time from Australia.

Mitochondrial Modifying Nutrients in Treating Chronic Fatigue Syndrome: A 16-week Open-Label Pilot Study
https://www.sciencedirect.com/science/article/pii/S2212958817300915

Abstract
Introduction
Recent evidence suggests that mitochondrial dysfunction may play a role in the pathophysiology of chronic fatigue syndrome (CFS). We undertook a pilot investigation of a combination of nutraceutical nutrient compounds which are involved in mitochondrial function and energy generation, to assess their efficacy in improving symptoms of CFS. An open-label design was employed as CFS is largely treatment-resistant with limited placebo-response.

Methods
A 16-week open-label trial of a nutraceutical combination (primary nutrients: Coenzyme Q10, Alpha lipoic acid, Acetyl-l-carnitine, N-acetyl cysteine, B Vitamins, in addition to co-factors) was undertaken in Ten patients with CFS. Fatigue symptoms, mood and general health were assessed at each 4-week time point over 16 weeks. Of the ten patients (7 female, 3 male) with a mean age of 36.3, eight completed the trial.

Results
Linear mixed model analysis demonstrated a significant improvement in fatigue symptoms across treatment period on the Chalder Fatigue Scale (p < 0.001). Specific improvements were found in tiredness, weakness, feeling sleepy or drowsy, as well as in sleep, and clinician-reported symptom-improvement. No benefit was observed in mood or other functional domains. No serious adverse events were noted.

Conclusion
These preliminary findings suggest that a combination nutraceutical compound of mitochondrial agents may improve CFS symptoms. Further investigation is warranted in a larger double- blind RCT.
.....................................

Any comment, @ME/CFS?

I do not have access to the full paper.

My main concern with this pilot is the use of the Chalder Fatigue Scale as outcome measure. As we have discussed in the past, particularly in relation to the PACE trial, this scale is nonsensical as a measure of ME symptoms both type and severity. It is both subjective and makes almost now allowance for changes in severity of symptoms, being simply a list of rather vague descriptors of different aspects of fatigue.

I tried the Chalder F S myself and scored the same now when I'm mostly bedbound and need help with showering etc, as I would have done when I was mildly effected and still able to work part time as a teacher.

Perhaps they would like to discuss new scales for the RCT here? I am also concerned about the Chalder scale but would also welcome some hard facts on these supplements. It would be good to be able to offer some suggestions for improvement in the design. The other point I guess is dose soecificity and interactions between the different nutrients and co factors? I suspect this will be quite specific for each subject under test, so some more preliminary work to establish dose variation amongst a wider group may be in order?

I was also thinking we should provide more suggestions and fact based arguments when we discuss these things. If not Chalda scale we should suggest one? Does anybody have any views on this?

I also think if we are dismissive of fatigue ( as we all were earlier in the thread) we should spell out more clearly what are the more important symptoms to monitor/measure. Otherwise it comes across as just quite one sided and combative rather than collaborative.

By way of example Cognitive function as I've discussed earlier probably needs to be broken down into more specific measures (e.g. Short term Memory, coordination, problem solving etc ) along with all the other side effects such as nausea, feeling dizzy, irritable etc.

I can start a new thread to explore this but it may be we have something we can reference in this regard? Welcome people's thoughts on this.

 

[Valentijn]

Perhaps they would like to discuss new scales for the RCT here? I am also concerned about the Chalder scale but would also welcome some hard facts on these supplements. It would be good to be able to offer some suggestions for improvement in the design.

Maybe I'm just being unduly pessimistic, but I'm starting to think that people involved in research which promotes specific supplement blends aren't interested in good trial design any more than the people whose research promotes specific psychosocial therapies I'm very much looking forward to being proven wrong about that.

 

[Trish]

I was also thinking we should provide more suggestions and fact based arguments when we discuss these things. If not Chalder scale we should suggest one? Does anybody have any views on this?

I agree, just criticising is not enough.

@Cheshire has made a list of lots of scales, good and bad, for our library here:
https://www.s4me.info/index.php?threads/questionnaires-and-scales-used-in-me-or-cfs-research.879/

Researchers might find this article helpful:
Fatigue Scales and Chronic Fatigue Syndrome: Issues of Sensitivity and SpecificityLeonard A. Jason
http://dsq-sds.org/article/view/1375/1540

A scale needs to be able to measure levels of severity, not just which on a list of statements is true, as Chalder does. If they are going to use a questionnaire, I'd prefer SF-36 physical activity because it at least gives an indication of what patients think they can actually do, though even that is open to wide variation of interpretation of what the questions mean by 'can do with difficulty'.

I think we also need to encourage researchers to use at least one objective measure such as step counters, as I've said several times in this thread.

And this probably should go in a new thread.???

 

[arewenearlythereyet]

I was also thinking that referring them to the CDC criteria for diagnosis or the Canada Working case definition would be a start to measure these diagnostic symptoms as well as fatigue? I have recently discovered for instance that after taking Coenzyme Q10 and discontinuing it and restarting that this definitely has a big affect on my cognitive function.

Perhaps they are deliberately confounding the design to get a result, but I do like to give everyone the benefit of the doubt.

 

[Trish]

I think it is reasonable to assume unless we hear otherwise that these two pilot studies have been done with good intentions.

However, as we have just seen with Rituximab, promising results in open label pilot studies, and even good results in small double blind trials can be shown to be illusory once a large double blind trial is carried out over sufficient time scale and with sufficient rigour.

I hope both these teams get the funding to carry out such a large rigorous trial. I guess it will be a few years before we see the results.

 

[TiredSam]

I also think if we are dismissive of fatigue ( as we all were earlier in the thread) we should spell out more clearly what are the more important symptoms to monitor/measure. Otherwise it comes across as just quite one sided and combative rather than collaborative.

Not sure that we should have to spoonfeed information already out there and available for any researcher who cares to look. The CCC have been available since 2003 and are hardly a closely guarded secret, the IOM report is available to download for free.

We are entitled to take a view on whether we consider something worthy of collaboration or not, as for example we did with the MEGA proposal. It may be that having considered a matter we don't feel particularly collaborative, in which case coming across as uncollaborative is entirely appropriate. We can also express ourselves forcefully and tear ideas apart if we feel like it, and anyone who doesn't like that can check the name of the forum.

 

[Hoopoe]

My impression is that carnitine, CoQ10, magnesium, B complex are all somewhat effective. I can clearly do more with the carnitine. They can also be too much and lead to increased or new symptoms if the dose is too high.

 

[TiredSam]

My impression is that carnitine, CoQ10, magnesium, B complex are all somewhat effective. I can clearly do more with the carnitine. They can also be too much and lead to increased or new symptoms if the dose is too high.

CoQ10 blew my head off.

 

[arewenearlythereyet]

Not sure that we should have to spoonfeed information already out there and available for any researcher who cares to look. The CCC have been available since 2003 and are hardly a closely guarded secret, the IOM report is available to download for free.

We are entitled to take a view on whether we consider something worthy of collaboration or not, as for example we did with the MEGA proposal. It may be that having considered a matter we don't feel particularly collaborative, in which case coming across as uncollaborative is entirely appropriate. We can also express ourselves forcefully and tear ideas apart if we feel like it, and anyone who doesn't like that can check the name of the forum.

I see part of the role of the site as being collaborative and a place for all to discuss ideas backwards and forwards in a scientific way (with facts and evidence). it also requires context. That's all I'm saying

 

[Wonko]

CoQ10 in particular is, eventually, moderately effective for me. It eventually restores just enough cognitive function to allow me to fry myself in short order.

As such it's reserved for special occasions, when the need to be more cognitively functional is important enough to override the need to be able to move without a lead suit.

Of course coz I'm not routinely using it I keep forgetting to start it early enough, but...that's life

 

[Scarecrow]

The CCC have been available since 2003 and are hardly a closely guarded secret

Would that be the same CCC that allows 'Post Exertional Malaise and/or Fatigue'?

 

[TiredSam]

Would that be the same CCC that allows 'Post Exertional Malaise and/or Fatigue'?

Yes, that's the one. Rather helpfully defines PEM/Fatigue as:

Post-exertional malaise and/or Fatigue: There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post exertional malaise and/or fatigue and/or pain and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. There is a pathologically slow recovery period - usually 24 hours or longer.

Is that what the FSS accurately and objectively measures?

Also mentions and defines sleep dysfunction, pain, neurological / cognitive manifestations, autonomic manifestations, neuroendocrine manifestations and immune manifestations.

So a study of 10 patients which measures the following:

After routine clinical and biological investigation, the patients were requested to complete a questionnaire deduced and translated from FSS RAND-36 questionnaire [16] or the Fatigue Severity Scale (FSS) [17]. The results of these questionnaires were calculated as sum of scores given per item divided by the maximum score and expressed (%), and also as average score per 9 items given in the FSS. When applying the latter calculation, the average score of healthy subjects is 3.0 [18].They were given the innovative nutriceutical, and returned after 1 and 3 months to report the effect of treatment and to complete the questionnaire once again.

And where the author refuses to commit to objective outcome measures in future despite friendly and respectful suggestions from the patient community (one-sided and uncollaborative who?) is hard for me to get excited about.

 

[Scarecrow]

Yes, that's the one. Rather helpfully defines PEM/Fatigue as:

Yes, that's right. Within the list, there are a sequence of three symptoms that are 'and/or'

post exertional malaise and/or fatigue and/or pain

It's a little ambiguous because it could be taken to mean either:

• post exertional malaise and/or fatigue and/or pain

or

• post exertional malaise and/or post exertional fatigue and/or post exertional pain

Only one of these makes sense and it's the second. The CCC lists symptoms in categories. The first symptom category is fatigue as a stand alone symptom. The second category are the post exertional symptoms. It would be strange to list fatigue in the first category and fatigue in the second.

Therefore CCC ME/CFS is characterised by fatigue that is persistent or recurrent. The post exertional category is at least one of three symptoms (malaise, fatigue or pain) with others being optional.

 

[ME/CFS]

in a short "proof of principle" pragmatic trial, reported previously, I have referred to a new nutriceututical treatment for ME/CFS.
In a larger trial, 45% of patients reacted favourably to this treatment, which contains - among other ingrediënts - sodium dichloroacetate, and that has now been protected by a patent (which means that it is prohibited by law on intellectual property the use this substance for the treatment of ME/CFS patients, except under licence granted by the patent owner). The beneficial effect of the treatment has persisted for up to 7 months in the patients who were included in the initial trial. In addition, logistic regression analysis with stepwife elimination has revealed that it is possible to predict the probability that a particular patient will benefit or not benefit from the treatment. The full scientific paper is in preparation.

 

[Hoopoe]

In a larger trial, 45% of patients reacted favourably to this treatment

Was it blinded?