Effect of Dietary Coenzyme Q10 Plus NADH Supplementation on Fatigue Perception and Health-Related QoL in ... ME/CFS, 2021, Castro-Marrero et al.

Effect of Dietary Coenzyme Q10 Plus NADH Supplementation on Fatigue Perception and Health-Related Quality of Life in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial

Castro-Marrero et al

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating neuroimmune disease, probably of post-viral multifactorial etiology. Unfortunately, no accurate diagnostic or laboratory tests have been established, nor are any universally effective approved drugs currently available for its treatment.

This study aimed to examine whether oral coenzyme Q10 and NADH (reduced form of nicotinamide adenine dinucleotide) co-supplementation could improve perceived fatigue, unrefreshing sleep, and health-related quality of life in ME/CFS patients.

A 12-week prospective, randomized, double-blind, placebo-controlled trial was conducted in 207 patients with ME/CFS, who were randomly allocated to one of two groups to receive either 200 mg of CoQ10 and 20 mg of NADH (n = 104) or matching placebo (n = 103) once daily. Endpoints were simultaneously evaluated at baseline, and then reassessed at 4- and 8-week treatment visits and four weeks after treatment cessation, using validated patient-reported outcome measures.

A significant reduction in cognitive fatigue perception and overall FIS-40 score (p < 0.001 and p = 0.022, respectively) and an improvement in HRQoL (health-related quality of life (SF-36)) (p < 0.05) from baseline were observed within the experimental group over time. Statistically significant differences were also shown for sleep duration at 4 weeks and habitual sleep efficiency at 8 weeks in follow-up visits from baseline within the experimental group (p = 0.018 and p = 0.038, respectively).

Overall, these findings support the use of CoQ10 plus NADH supplementation as a potentially safe therapeutic option for reducing perceived cognitive fatigue and improving the health-related quality of life in ME/CFS patients. Future interventions are needed to corroborate these clinical benefits and also explore the underlying pathomechanisms of CoQ10 and NADH administration in ME/CFS.

https://www.mdpi.com/2072-6643/13/8/2658

 

I wrote this on another thread

 

This abstract talks about changes within the experimental group but not about comparisons with the placebo group. Why doesn't the abstract mention the placebo arm results? Seems a bit weird if they actually found any differences between the groups and not just from baseline to assessment points in the experimental group.

 

N=1

My expereince of CoQ10 was that it was a robbing Peter to pay Paul supplement.

It could produce short term apparent improvement, but it was never long lasting, and actually repeatedly using the apparent extra resources caused 'issues' (e.g. crashing).

Many supplements I have tried behave like this.

Despite 'feeling' a bit more capable, these were, in my case, non real, non sustainable, effects.

At times a couple of percent increase in cognitive capability is very useful, but it doesn't stick, and encourages overdoing things physically.

I do not think however that I ever tried it with NADH - as everything I read at the time suggested NADH was ill advised for me.

 

Yes, I think it’s important to look at the tables for this one. Any changes look quite minimal.

 

Just why do people still use Fukuda to select patients? At the very least they could screen for PEM - with PEM operationalised properly - and do a separate analysis for participants with and without PEM. Especially in a larger cohort like this.

Using Fukuda like that would help with sorting out if PEM is as relevant as we think it is and, if so, relevant to what areas (e.g. maybe treatment A helps everybody with a specific symptom irrespective of PEM, pointing at common underlying mechanisms, but treatment B only works for one or the other group, pointing at different underlying mechanisms).

Another opportunity missed. Though in this case the results are underwhelming anyway.

[Will put my own experience with CoQ10+NADH into the main CoQ10 thread here https://www.s4me.info/threads/coq10-coenzyme-q10.13640/]

 

I don’t understand how peer reviewers could look at this study, and the conclusions the researchers drew, and let it get published.

 

What's next, resurrecting Acetyl-L-Carnitine? Lipoic Acid? D-Ribose? Good lord we'd know if these things were actually useful by now

 

I agree, this is really misleading, even worse than the abstract of paper on the PRINCE Secondary trial.

I've plotted the primary outcome Fatigue severity (FIS-40 questionnaire) below.


Yet the authors write:

"Overall, these findings support the use of CoQ10 plus NADH supplementation as a potentially safe therapeutic option for reducing perceived cognitive fatigue and improving the health-related quality of life in ME/CFS patients."​

 

If you look at the research done by this group by clicking on the Castro-Marrero tag at the top of this thread, they have suggested other supplement combinations and come up with similar 'findings'.

 

Because it’s pretty clear they found no difference with the placebo group. Both groups showed some improvement almost certainly due to the placebo effect.

Of course, a placebo controlled trial only works if you don’t treat the placebo effect-induced improvement as demonstrating efficacy in the treatment group…

 

Here's a summary of issues I found with this paper:

1) Between-group differences
The authors base their conclusion on significance tests comparing a baseline with a final measurement separately in each group. Bland & Altman described this approach as “conceptually wrong, statistically invalid, and consequently highly misleading.” When comparing the intervention and placebo group directly, there were no significant differences for primary or secondary outcomes. These null results are not mentioned in the abstract.

2) Within-group differences
Even if we look at the differences over time in the intervention group only, it is still misleading to speak of significant improvements as the authors did not control for multiple comparisons. They tested differences at 3 timepoints (4, 8, and 12 weeks) on 20 different scales and subscales, meaning that 60 paired t-tests were conducted, inflating the false positivity rate.

When one looks at the size of differences that are reported as statistically significant, it becomes clear that these are small fluctuations that are unlikely to be clinically relevant. When means per group are presented graphically over time for each of the three outcome measures (fatigue, sleep and quality of life) it becomes clear that there were no improvements in the intervention group, no matter how you analyze it.



The paper repeatedly makes claims to the contrary. For example, it states: “Our results show that the CoQ10 plus NADH administration improved the perception of sleep quality.” It also claims that fatigue perception and fatigue severity increased over time and that “our intragroup comparison analysis found that ME/CFS patients supplemented with CoQ10 plus NADH showed significant increases in the physical function domain of the SF-36 at both follow-up visits”. As the graphs above indicate, both statements are incorrect. The trial actually found evidence that CoQ10 plus NADH supplementation is not effective for patients with ME/CFS.

3) No Intention to treat
The paper states “all analyses were performed on the data set using all available information with intention-to-treat (ITT) criteria.” This doesn’t seem correct as ITT requires statistical analysis of all patients that were randomized. In this trial, 207 patients were randomized but analyses were performed on only 144 patients. Patients who abandoned treatment or were lost to follow-up were not included in the analyses.

This leads to contradictory statements. The authors for example report that 9 patients abandoned treatment on their own request and that an additional 8 participants abandoned treatment due to adverse effects. Yet in the paper the authors claim:

“In our study of ME/CFS patients, no relevant treatment-related adverse events were recorded. Our findings demonstrate that oral CoQ10 plus NADH supplementation for eight weeks was safe and potentially well-tolerated by the participants”​

This is because the analysis was not ITT and patients with adverse events were excluded from the analysis.

4) inclusion criteria changed.
The inclusion criteria mentioned in the trial registration say that patients should meet both the Fukuda and Canadian criteria, while the paper doesn’t mention the Canadian criteria. Patients were included if they met the Fukuda criteria only. This change in inclusion criteria was not explained.

5) Power calculation doesn’t make sense
The authors write: “Allowing for an estimated early drop-out rate of 20%, and accepting an alpha risk of 5% and a beta risk of 20% (two-sided test), a total of 121 subjects in each group was considered necessary to find statistically significant differences between groups, expected to be 10% in the placebo group and 25% in the experimental group.”

It is not exactly clear what they mean and I cannot find an explanation that makes sense. Perhaps the authors wanted to detect a difference between groups that corresponds to a 15% increase from baseline (25% for the intervention group – 10% in the control group). If we take the baseline values on the FIS-total scale from the experimental group this corresponds to 134.35 x 0.15 = 20.15 points. The standard deviation in the experimental group was 19.80. So this would correspond to a between-group difference of more than 1 standard deviation. Similarly, if we do the same in the control group, we get a between-group difference of 0.77 standard deviations. To detect such an effect size with a two-sided independent t-test a sample size of only 28 would be needed per group. So it’s unclear what power analysis they performed or what effect size they hoped to detect.

 

Although the authors seem to report this correctly, I think it might be worth highlighting their conflict of interest:

The second author is an employee at VITAE Health Innovation, a company that sells supplements like the ones tested in the trial. The company provided the supplements and placebo pills for the trial. The first author received research support and honoraria from VITAE Health Innovation

 

Funny I have tried all of those and needless to say they didnt do anything. I've tried CoQ10 too and the same story. I havent tried NADH, but I am pretty sure it wont do anything either.

 

I doubt I will change your or some other people’s minds but I’m not convinced one can extrapolate like that to all “energy”/mitochondrial/similar supplements.

Also to explain a particular problem with some personal experience in this area. The trials of L-Carnitine have used 2000mg-3000mg/day. But a lot of supplements are in 100mg or 200mg capsules/tablets and say things like take 1-3 per day. I’m not sure I have ever seen a box suggesting a dosage of 2000mg-3000mg per day. So most people don’t have personal experience of taking those sorts of doses: their personal experience is of something much lower.

Also some people take acetyl l-carnitine and have never tried l-carnitine.

 

The problem with higher doses is that for some people who have tried a lower dose of some supplements that lower dose is already seeming to be over stimulating. Perhaps a much higher dose has a paradoxical effect but I'm not sure how one can know this.

 

If somebody has a problem with side-effects of a lower dose, I generally wouldn't recommend a higher dose alright and haven't heard anyone who had difficulties with a lower dose of l-carnitine, who could deal with a higher dosage.

Though I have seen the odd comment about acetyl l-carnitine, which seems to affect the brain more, in discussions about l-carnitine so not sure one can necessarily extrapolate from experiences of one to the other.