B-Lymphocyte Depletion in Patients With ME/cfs: A Randomized, Double-Blind, Placebo-Controlled Trial (2019) Fluge et al

M

Milo

Senior Member (Voting Rights)
B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

https://annals.org/aim/article-abst...omyelitis-chronic-fatigue-syndrome-randomized

Abstract
Background:
Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objective:
To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS.

Design:
Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942)

Setting:
4 university hospitals and 1 general hospital in Norway.

Patients:
151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years.

Intervention:
Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n = 74).

Measurements:
Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures.

Results:
Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, −5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, −0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events.

Limitation:
Self-reported primary outcome measures and possible recall bias.

Conclusion:
B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS.
 
article said:
“This study highlights the importance of randomized and blinded clinical trials with a placebo group, especially in diseases that lack specific and sensitive biomarkers, have limited possibilities for objective end points, and rely mainly on self-reported symptom scores,” Fluge and colleagues concluded.
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The 35% response in the placebo group shows how poorly conceived the BPS studies, some of which don't even have good placebo controls, have been.

In an accompanying editorial, Peter C. Rowe, MD, from Johns Hopkins University School of Medicine, wrote that the study by Fluge and colleagues was methodologically sound.

He noted that the heterogeneity of ME/CFS is a significant challenge in performing research on the illness.
“The profound level of impaired function of affected individuals warrants a new commitment to hypothesis-driven clinical trials that incorporate and expand on the methodological sophistication of the rituximab trial,” Rowe concluded.
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Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events.
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I'm curious about the 18.9% in the placebo group that had "serious adverse events." Would this be the so-called "nocebo" effect, and can that actually produce serious adverse events? Or might these events have been part of the disease process itself and unrelated to the study?
 
Forbin said:
I'm curious about the 18.9% in the placebo group that had "serious adverse events." Would this be the so-called "nocebo" effect, and can that actually produce serious adverse events? Or might these events have been part of the disease process itself and unrelated to the study?
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Anxiety related, perhaps? Usually when you give a drug that has the potential to give a reaction, the nurse must advise to let them know if they feel anything such as... flushing, difficulty breathing, chest pain, itchiness, etc... in the case of a placebo control trial, since the nurse would not know which the patient is receiving, caution must be explained to all patients.
 
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Kalliope said:
Link to Peter C Rowe's editorial in Annals of Internal Medicine:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Trial Fails to Confirm Earlier Observations of Rituximab's Effectiveness
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Some PACE comments in the abstract, though I can't access the full paper on scihub yet:

Cognitive behavioral therapy and graded exercise therapy have been recommended enthusiastically by some groups despite only modest effect sizes in trials. A reanalysis of the large PACE trial using the study's prespecified outcomes showed only modest, unsustained, short-term improvements in self-reported symptoms in the groups receiving cognitive behavioral therapy and graded exercise therapy—and no true “recovery” of healthy function (3), in clear contrast to the original trial claims.
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Forbin said:
I'm curious about the 18.9% in the placebo group that had "serious adverse events." Would this be the so-called "nocebo" effect, and can that actually produce serious adverse events? Or might these events have been part of the disease process itself and unrelated to the study?
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It`s probably worsening due to activity imo, and the authors thought it was too.
 
I’d be interested to look at those individuals in the rituximab group who did improve. Were there any genuine responders even though overall there was no difference in the groups? Might there be an auto-immune subset or am I clutching at straws?
 
Daisybell said:
I’d be interested to look at those individuals in the rituximab group who did improve. Were there any genuine responders even though overall there was no difference in the groups? Might there be an auto-immune subset or am I clutching at straws?
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But then, the researchers followed the plan, did what they said they would do. They did not know who had Rituximab and who had the placebo until unblinding. Many patients believed they were responders despite receiving the dummy IV. This is the essence of the trial, that regardless whether you received the real drug or the placebo, some got better and some didn’t.

You could go on a try Low Dose Naltrexone against a placebo. With patient self report only, we may well arrive to the same kind of results, some believing they have improved, others not. If the placebo generates similar answers than the drug it means that the drug has no impact on the mechanism of illness. Then we might as well save ourselves time and money.

Their conclusion remains that we are in need of biomarkers and mechanism of illness.

This was a very long trial due to the way Rituximab works. i hope the next drug will have a shorter action so we can move trough the process much quicker. Then we are still waiting for the Cyclophosphamide paper.
 
Daisybell said:
Might there be an auto-immune subset or am I clutching at straws?
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It has always seemed to me likely that a small proportion of people diagnosd with ME/CFS have misdiagnosed autoimmune diseases. There will be a few with ANA related disease. However, this trial makes it less likely that any significant prportion do.

The trial does not exclude the possibility of some autoimmune cases that are not rituximab responsive. Fatigue with ANA related autoimmunity often does not respond. But of course that means there is no point in looking for 'hidden responders'. Looking at the people who got beter in this study is I think a waste of time.
 
Øysten Fluge, Kari Sørland, Ingrid G. Rekeland and Olav Mella have written this article at the Kavli Trust's webpage. The Kavli Trust has been an important supporter of their research since 2011.

The article gives a good introduction to the study for lay persons.

No effect of Rituximab treatment in patients with ME/CFS

The sound methodology of the RituxME trial is recognized in a separate editorial in Annals of Internal Medicine, and we believe the trial offers a clear answer to its research question. This is important, and the trial results can help adjust the course for future research into symptom mechanisms, as well as efforts to develop rational therapeutic treatments.

Moreover, the study highlights the importance of performing larger, placebo-controlled trials with double-blind design before drawing firm conclusions. This may be particularly significant in conditions that have no specific biomarkers thus far, and where researchers must rely on self-reported data in order to assess symptom development. Sound methodology and study design are equally important in trials of drug interventions and studies involving other approaches, such as cognitive therapy.
https://kavlifondet.no/en/2019/04/no-effect-of-rituximab-treatment-in-patients-with-me-cfs/
 
Sheesh, some people forgot to read The Memo. :rolleyes:

I mean, how are we going to keep reinforcing the BPS narrative about us being rabid oppressive anti-science activists if we are going to recognise and praise high quality science like this, and fully accept its results, even if negative for us? :bored:

:p
 
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