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

Pre-print, https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1



ETA: Added word, "Pre-print".

 

https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1

 

I believe this is the same study, an earlier thread:

New MRT Imaging Biomarkers and Treatment With Kinetic Oscillatory Stimulation (KOS) in Nasal Cavity for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

 

Very interesting work. 30% may not appear so great but for severely ill patients it can be life changing.


Having experimented with HRV and vagus nerve stimulation i saw immediate results during a very difficult period in my life in terms of induced symptoms. On the other hand i do not understand why there is no single mention on the paper regarding the Liver (Gut-Liver axis) and the connection of the vagus nerve with the brain , the gut and the liver.

 

Intranasal Mechanical stimulation (or INMEST for short) is a novel treatment approach pioneered by prof Jan-Erik Juto during his career as an ENT Medical Doctor and Surgeon at the Karolinska Institute. INMEST is delivered using a soft and pliable catheter that is inserted into a nasal cavity where it gently stimulates the deeply innervated tissues that line part of the cavity.

Interesting

 

That part needs more information.

 

Okay, so I’m probably not reading this right... but the results don’t seem to show a placebo only arm.

And in the graph that was put up on twitter, the treatment does not seem to me to have a clearly different effect size to the placebo. (See my crude arrows on the 2nd graph).

Yes over follow up, the group receiving twice the treatment time, had a better follow up outcome, but is this down to the treatment, or group differences? The group with the placebo first had a small treatment benefit in their one week (EDIT... sorry, not one WEEK, after all, the scale is re the number of treatments, so that is a block of treatments over a period of longer than a week, apologies) of treatment (my arrow C) when compared to the first week (my arrow A) of the group getting treatment x2. Actually even the second week of treatment (B) when the placebo effect should have gone, is still bigger than the treatment week of the group getting placebo first.

Am I mis-interpreting something?

(Edited to expand my question.)

 

Okay.. thinking some more. Perhaps 1st treatment week (edit treatment block, not week) is less, and 2nd week is where real benefit happens?

So effect C actually looks like A minus Placebo effect....

So perhaps it is the second week where the real difference occurs?

I’m still to be convinced.

Edit to add: And that weird up-tick in the first week of the treatment arm. What’s going on there? Does that call into question the reliability of the outcome measures? We don’t see that happening when the placebo-first group gets the treatment in the second week.

 

Or alternatively that word “Active” written in blue, should really read “Placebo”??? Typo?

 

Here is a description of the placebo from a paper by the inventor of the KOS device.

Juto, J. E., & Axelsson, M. (2014). Kinetic oscillation stimulation as treatment of non-allergic rhinitis: an RCT study. Acta oto-laryngologica, 134(5), 506–512. https://doi.org/10.3109/00016489.2013.861927

They also note:

That raises the question of study participants sharing their experiences during the course of the study. If I were a patient receiving the placebo, and that I happened to talk to a patient in the study who told me "oh the vibrations were funny"... I would know I received the placebo.

 

There is something very odd about these graphs. They seem to show the same lines but the point in time give as 16 in the big graph is given as about 60 days in the small graph. Also, the rise in the red line at 4 (?days) might be expected from a single case but if the line is an average for 14 cases it must be a real biological effect - which as @Keela Too says, does not appear on the blue line.

I remain unclear how vagal nerve stimulation could be indistinguishable from no vagal nerve stimulation since it is normally expected to affect heart rate and various other things.

Also, from the description, one would expect the stimulator to hum like the mains and the placebo not.

 

Yes, this is clearly a typo. Should be "placebo", because patients were either assigned active treatment or placebo throughout the whole course of the study (noone swapped groups, see my previous post).

ETA: actually, this was not a typo. See Keela's post below.

Yes, the placebo device does not emit vibrations, so this is the reason the assignment of placebo/active treatment was fixed for all patients during the study (no swap).

ETA: after 8x placebo sessions, patients in the placebo group received active treatment after 8x placebo sessions. See Keela's post below.

You probably picked this up, but in the upper small graph, the x-axis is days while in the bigger graph, the x-axis is number of sessions received (either active or placebo). Patients had a KOS session every... 4 days, judging from the small graph? So this would seem to match. Just the x-axis change is a little weird.

 

Just realised the x axis has a different scale on each of the graphs.
Top graph gives Days, and lower one Number of treatments. So presumably the treatments were not daily? Meaning the lower graph is taking place over more than 2 weeks. Sorry that was my bad, as I talked about that graph as if it were 2 weeks long.

Edit: I’ve now edited my posts above to explain that I misinterpreted each treatment block as happening over a period of a week, when in fact it was longer.

 

You mean the blue word “Active” should actually read “Placebo”?
If so, then why annotate each line twice? And why have the change in background colour just after intervention 8? It is confusing I think.

 

So from the image in the first tweet, it seems there was a cross-over between placebo and active, but not the other way around.... so the word “Active” in blue must be intentional, and not a typo.

 

LOL.. Mind you seems it wasn’t a typo at all. See my post above, where the image clearly shows a cross over in the group that started with placebo. I wonder why.

 

There, I've edited all my posts to mention that there was no typo to begin with. Thank you!

I wonder why they were switched to. Or rather, I wonder if the placebo-turned-active patients' outcome measure was taken into account: does this not introduce serious bias?

 

There now seems to me to be a likely explanation for the shapes of the curves. At the beginning there is no real difference between treatment and placebo. The difference comes later - with no apparent catch up in the placebo group when given treatment. The treatment throughout group might not be able to guess whether or not what they had was real treatment but the placebo group are almost certain realise by treatment 10 that they had placebo first because the active treatment would feel different (buzzing).

 

One of the study authors said otherwise.

 

So one device triggers nerves and the other doesn't but the person cannot tell (that their nerves are triggered or not). I find this reasonably implausible. And if I remember rightly there is no reference to vibrations of the placebo device in the paper?