Achieving symptom relief in patients with ME by targeting the neuro-immune interface and inducing disease tolerance (2020) Rodriguez et al

So they would have changed their placebo since the older 2014 study for allergic rhinitis... strange?

 

Quite frustrating how the results are reported here.

In the methods section the authors report that "the following measures were recorded for the clinical trial: Fatigue severity scale, SF-36 Physical functioning subscale (PF-10), Hospital anxiety depression scale, EQ5D, as well as VAS." Yet I can't find the data of these questionnaires in the paper. There should have been a table with all these measurements at baseline and post-treatment comparing the treatment to the placebo group. They only report that "We found no significant improvement of the primary outcome measurement, fatigue in this study." That's information that should be mentioned in the abstract.

I think what is reported in the graphs is the ME symptom rating scale, which was used in order to evaluate the degree of disease burden in accordance with the
Canadian Consensus criteria. And even here we don't get the actual scores with standard deviations, only a percentage reduction compared to baseline. The placebo group stopped at 4 weeks so after 8 treatment doses. At that point, the graph suggests that there was approximately a reduction of 20% in the active treatment group (n = 16) and a reduction of 11% in the placebo control group (n = 14). I would like to see the actual data behind this to see if it really was statistically significant if corrections for multiple comparisons are made, given the many other outcomes measures used and the small sample size.

I find the tiny graph with the number of days also to be confusing because, if I understand correctly, the actual RCT only took 28 days (4 weeks) while the graph goes on to 142 days. So only the very first part represents a treatment effect. It's also rather confusing to say you've done an RCT and found a 30% reduction when that 30% reduction is a measurement done weeks after the RCT was finished and without comparing to a control group...

The immune findings are hard to interpret because there's no control group that doesn't have ME.

 

Presumably the idea is that the vibrations that to the body create the impression of turbulent airflow trigger some reaction while sufficiently different vibrations do not. But they don't explain this part well.

 

Interesting. But 30% is a small (and imprecise) effect given how disabling the disease is, despite what the people who promote PACE as the best science ever have to say about the fact that anything that is statistically above the lowest arbitrary threshold = 100%.

I think of this as a preliminary for further research, if funding can be found somewhere. The vagus does appear to be significant but there's a world of difference between it being a therapeutic target and the therapy actually doing the thing it should be doing to target the disease mechanism, again despite the weird beliefs of mind-body ideologies.

One thing that is possible is that it does not target the disease mechanism but still has an impact on autonomic symptoms, which are some of the most significant, however it does not appear to affect fatigue, again normal if it doesn't impact the disease mechanism, but if it does provide symptomatic relief this is still worth pursuing.

Must be weird to have this cognitive dissonance of something providing symptomatic relief without affecting fatigue from a model that views fatigue as the only relevant symptom. Oh well.

 

I see the same way as any other distraction technique bloody useless long term .

 

Intranasal mechanical stimulation....

Hmmmmmm

I thought that this was a family-friendly website....

 

Regarding HR, they say

Regarding the results

1 of the authors is founder of the company that creates the "INMEST" device.

The bottom graph is the length of the treatment (2months, 16 treatments). The top graph is the outcomes, which are recorded after treatment cessation.

I believe the conclusion meant to be found is that had the study just lasted longer, the placebo group would have met the treatment group, having started the treatment later. I'm a little skeptical of this, since this is the exact conclusion a null finding with a vested interest would want to find. If the device were working, I would expect the placebo group to start to match the treatment group by the end.

 

Note, they state their trial failed to have an effect on their initially specified primary outcome measure.

I was about to say the same thing. None of the PROM data is directly reported, no objective outcomes were used. They don't even explain where the "relative symptom" score comes from. Data on other aspects such as the Seahorse testing is not provided either (probably because their sample sizes of n=3 was too small to be statistically meaningful).

But most of all, it still surprises me that researchers conduct "placebo controlled" trials, without asking participants whether they have guessed which arm they are in...

As such, it is hard to interpret the rest of the immunological findings (that are claimed to be associated with treatment) that may well just be the result of natural variation.

 

That last suggestion would be interesting. If every patient were asked whether they received a placebo or active treatment, the results could be very telling. Maybe something other researchers could consider?

 

https://twitter.com/user/status/1231879561555709955


Note the information in the picture.

What is confusing however is that fatigue did not improve. Is it not very likely that fatigue is closely related to metabolism? At least I think of it that way.

 

I hit the Twitter link, but myst have hit # metabolism directly which led to this .
Thoughts?

https://www.embopress.org/doi/10.15252/embr.201949113
https://twitter.com/user/status/1228592695813312512

 

@strategist

Thanks for posting that twitter thread (click on it for full thread).

Tweet number 7 indicates that the paper probably wasn't really read.

Here is the paper.

Bit of an echo chamber on twitter.

 

Why didn't the authors conduct a full crossover design?? Did they run out of budget for the second placebo arm (sarcasm intended).

@Michiel Tack is correct--the analysis should be conducted at week 4, treatment 8. This is when the RCT ends. (For whatever they were measuring that wasn't fatigue).

14 authors on this paper. I'm guessing this study cost at least $200,000.

N.B. I haven't read the immune portion of the paper--beyond me, might be great stuff.

N.B. This is a preprint, so it's within the realm of possibility that it might get cleaned up during review (although if expt. design is bad, this is usually fatal), but even though it's a preprint, it needs to be in *much* better shape before posting.

 

They didn't validate the metabolism findings as their sample size was too small. (n=3)

I daresay a manuscript published in a mainstream journal would read quite differently...

They're suggesting that increased HRV in turn suggests there are actual autonomic changes occurring, but this is speculative.

It is merely unjustified hype that lower than normal HRV is "bad" or somehow pathogenic. HRV is a very non-specific measure and anyone who gives too much credence to HRV measurements in this illness is probably a quack.

 

@Hutan @Trish @Andy @ScottTriGuy

A main concept discussed in this paper by Dr Brodin namely glucokinase, identified since March 2018 using Machine Learning. The PDF was sent to several ME researchers starting from 2017 :

 

The actual posted date regarding glucokinase is October 2017 :

http://algogenomics.blogspot.com/2017/10/glucose-metabolism-fmo3-and-foxo1.html

 

Now published
https://academic.oup.com/ooim/advance-article/doi/10.1093/oxfimm/iqad003/7126430

 

It seems they are now suggesting that they were stimulating the trigeminal nerve rather than the vagus?