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Fluge, Mella 2019. B-Lymphocyte Depletion in Patients With ME/CFS. (The final report on the Rituximab trial!)

Murph

:)
Messages
1,799
B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial
Øystein Fluge, MD, PhD; Ingrid G. Rekeland, MD; Katarina Lien, MD; Hanne Thürmer, MD, PhD; Petter C. Borchgrevink, MD, PhD; Christoph Schäfer, MD; Kari Sørland, RN; Jörg Aßmus, PhD; Irini Ktoridou-Valen, MD; Ingrid Herder, MD; Merethe E. Gotaas, MD; Øivind Kvammen, MD; Katarzyna A. Baranowska, MD, PhD; Louis M.L.J. Bohnen, MD; Sissel S. Martinsen, RN; Ann E. Lonar, RN; Ann-Elise H. Solvang, RN; Arne E.S. Gya, RN; Ove Bruland, PhD; Kristin Risa, MSc; Kine Alme, MSc; Olav Dahl, MD, PhD; Olav Mella, MD, PhD
Article, Author, and Disclosure Information


FULL TEXT
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.
 
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Murph

:)
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1,799
We knew this trial failed but we didn't know by how much. What we see is a really bad result. More people in the placebo group got better than in the treatment group.

:(

At least the result is clear. Very little room for doubt.
 

Gingergrrl

Senior Member
Messages
16,171
@Murph Thank you for posting this and I have some questions for you (or for anyone else who might know the answers). I am very interested in this study and want to learn more about the final results.

Is what you posted more of a summary (with a longer article to be published later?) or was this the complete article and it was just very short?

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).

I had read that in Phase 1 & 2 (earlier trials) each subject received one gram (1000 mg) of Rituximab per infusion and that they did not follow the BSA (body surface area formula) for dosing. But it seems as if they changed the protocol for the Phase 3 trial and each subject DID receive dosing based on the BSA formula for the first two infusions BUT then each subject received a FIXED dose of 500 mg for the remainder of the infusions (regardless of their body surface area).

For my own Rituximab infusions (not part of any study), my dose is 600 mg per infusion based on the BSA formula. I would imagine if there were men in the study (or women who were taller and/or weighed more than I do), that they should have received higher than 500 mg per infusion. It also seems strange to me that the Rituximab dosing was REDUCED for the Phase 3 portion of the trial. I had read "conspiracy theories" about this, and assumed they were 100% false, but now it seems that the infusion dosing for Phase 3 actually was reduced (per this article). Does anyone know why?

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.

I was also confused by this and want to clarify... were all outcome measurements done by self-reported fatigue questionnaires? I may not be understanding this correctly, but if so, it seems like a weak measurement system that is solely based on self-reporting. Were any other types of outcome measurements taken that were more objective like: 2-Day CPET Testing, Tilt Table Testing, 6-minute walk test, cognitive testing, measuring hours slept per night, spirometry or pulmonary function tests, viral titers or autoantibody blood testing, etc?

Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group

This clearly is a horrible result but I am still curious if the 26% of responders in the Rituximab group were followed over time (after the study ended) and if any of them remain in remission? I would still want to study that group of people and figure out why they were responders and if they really had ME/CFS, or if they had additional co-morbid diagnoses, or if they were completely misdiagnosed?

B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS.

I am also curious (and it may just not be stated) but were the subjects all given the Lymphocyte Subset Panel (or another panel) to measure that their B-cells were indeed at zero for the course of the study? Did they just assume that 500 mg dosing depleted each subject's B cells or was this definitively tested after the initial infusion and again prior to each subsequent infusion?
 
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Murph

:)
Messages
1,799
@Murph

Is what you posted more of a summary (with a longer article to be published later?) or was this the complete article and it was just very short?

This is the only one of your questions I know the answer to! This is just a summary. The complete paper is behind a paywall.

I can't get round it yet but at some point it should become available at this link (nb this is sci-hub, a site that makes scientific papers available in breach of copyright laws.): http://www.sci-hub.tw/10.7326/M18-1451

We may learn more from the full paper to answer your questions.
 

Gingergrrl

Senior Member
Messages
16,171
This is just a summary. The complete paper is behind a paywall.

Thank you for explaining and it seemed like there must be a much longer paper with the actual details of the study but I was not certain. If you ever find out that it is released from the paywall (or however sci-hub works?) please let me know!

We may learn more from the full paper to answer your questions.

:thumbsup:
 

geraldt52

Senior Member
Messages
602
I think this really hammers home how unreliable patient reports of "improvement" are, and how badly a biomarker is needed if any progress is to be made. It's hard to conclude from those results that any of the "improvements" were due to Rituxan. The most curious result to me is the almost 19% of the placebo arm that had serious adverse events, nearly as high as the 26% in the arm than received Rituxan...
 

Gingergrrl

Senior Member
Messages
16,171
I think this really hammers home how unreliable patient reports of "improvement" are, and how badly a biomarker is needed if any progress is to be made.

I agree that patient self reports on questionnaires about fatigue seem to be inaccurate (and I would think that this study now proves that point)?

The most curious result to me is the almost 19% of the placebo arm that had serious adverse events, nearly as high as the 26% in the arm than received Rituxan...

I have thoughts on this (but have no idea if they are relevant until the full paper is released). In my own case, I had an extremely adverse event to IV saline in 2014. It was just saline and magnesium (which would seem benign) but I ended up with pulmonary edema from the fluid and being rushed to the ER. It was due to a reaction to the saline being infused too quickly (and getting third spacing of fluid b/c I had MCAS) and I also had a reaction to the magnesium (b/c it was too high of a dose and b/c of an autoantibody that no one yet knew that I had).

So the reaction was totally unexpected but it happened to me. Yet three years later in mid 2017 when I started Rituximab (which I am still doing now), I have never had any negative reaction like I did with the saline. This is because, in my case, the infusion speed was VERY slow for the Rituximab (and there was no magnesium which we now know is dangerous for me).

My second thought is that I am very curious what "pre-meds" the subjects in the Fluge and Mella study received prior to getting Rituximab? There is a very high risk for allergic reaction to Rituximab, and since the study was double-blinded, I would assume that ALL subjects received the pre-meds (whether they received Ritux or saline) and that the nurses did not know who received which. Therefore, if the pre-med was IV Benadryl, or an IV steroid, etc, there are many patients who could have a negative reaction to the pre-med. Therefore, I find it very plausible that some percentage reacted to the pre-med (especially if it was a steroid) or to the infusion speed being too fast, or any number of potential factors.

But of course this is all speculation until we see the full paper.
 
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But it seems as if they changed the protocol for the Phase 3 trial and each subject DID receive dosing based on the BSA formula for the first two infusions BUT then each subject received a FIXED dose of 500 mg for the remainder of the infusions (regardless of their body surface area).
This is correct. I did participate in this study.

I had read "conspiracy theories" about this, and assumed they were 100% false, but now it seems that the infusion dosing for Phase 3 actually was reduced (per this article). Does anyone know why?
I don't know why they chosed the dosing regime they did. They (Fluge & Mella) are very professional and respected researchers and clinicians. They knew this study was always going to be highly scrutinised, so it would surprise me if they did make any "junior" mistakes in the design of the study. But I can't know for sure.

I was also confused by this and want to clarify... were all outcome measurements done by self-reported fatigue questionnaires?
No, it was a combination of self-reported fatigue and symptom scores, and objective measurement by electronic SenseWear armband. The SenseWear armband were deployed for one full week some time before the first infusion of Rituximab/placebo and then again for one full week some time after the last infusion (12+ months). It measured among others: energy expenditure [joules], number of steps, time lying down, sleep duration.

This clearly is a horrible result but I am still curious if the 26% of responders in the Rituximab group were followed over time (after the study ended) and if any of them remain in remission?
All participants were followed for an additional 12 month period after their last infusion. So the total time of study, from first infusion (month 0) to last session of self-reporting of fatigue/symptoms (month 24) were two years. I don't think any participants have had any more formal follow-ups after month 24. Not that I know of. I could be wrong.

I would still want to study that group of people and figure out why they were responders and if they really had ME/CFS, or if they had additional co-morbid diagnoses, or if they were completely misdiagnosed?
I don't know. I think they recorded co-morbid diagnosis for all participants prior to study inclusion. Like hypothyroidism, depression etc.

I am also curious (and it may just not be stated) but were the subjects all given the Lymphocyte Subset Panel (or another panel) to measure that their B-cells were indeed at zero for the course of the study? Did they just assume that 500 mg dosing depleted each subject's B cells or was this definitively tested after the initial infusion and again prior to each subsequent infusion?
I don't know. They drew a lot of blood. Tons before inclusion, and then every 3 months throughout the study, I think. At least for the first 12 months (the complete period of infusions). But I think the blood was going to be part of building a wider bio-bank, to be used beyond this singular study (RituxME phase III). I am not sure they used the bloodwork to measure what you describe. But again, I could be wrong. My brain is messed up and my memory is failing me.
 
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23
My second thought is that I am very curious what "pre-meds" the subjects in the Fluge and Mella study received prior to getting Rituximab?
The pre-med were all oral, no IV pre-meds.

One hour before each infusion we got the following three pre-medications:
1000 mg paracetamol
10 mg cetirizine hydrochloride
8 mg dexamethasone

The infusion speed was administrated very carefully. The speed of infusion started off very slowly and increased according to a specific pre-planned and timed schedule. One infusion session took approx 5-6 hours from start to finish. Also, during each infusion nurses did regular measurements of our heart rate and blood pressure (each hour maybe?). All measurements were recorded.
 

Gingergrrl

Senior Member
Messages
16,171
@robson Thank you so much for your replies and they are very informative.

This is correct. I did participate in this study.
I don't know why they chosed the dosing regime they did. They (Fluge & Mella) are very professional and respected researchers and clinicians. They knew this study was always going to be highly scrutinised, so it would surprise me if they did make any "junior" mistakes in the design of the study. But I can't know for sure.

I totally agree that Fluge & Mella are very professional and respected clinicians. I am just baffled by the discrepancy in dosing between the Phase 2 and Phase 3 studies. If Phase 2 was considered to have statistically significant results re: subjects in remission from Rituximab, yet those subjects all received one gram (1000 mg) of Rituximab per infusion regardless of their body surface area (BSA)... but then in Phase 3, the subjects got 2 doses based on their BSA (which varies per person) and then all subsequent doses at 500 mg (a low dose since my own dose is 600 mg), this literally makes no sense to me.

Did they lower the dose for Phase 3 for financial reasons or clinical reasons? Because they literally cut it in half from 1000 mg to 500 mg (if what you are verifying is correct and I assume it is b/c it matches with the summary that Murph posted above).

The SenseWear armband were deployed for one full week some time before the first infusion of Rituximab/placebo and then again for one full week some time after the last infusion (12+ months). It measured among others: energy expenditure [joules], number of steps, time lying down, sleep duration.

That is good and I am glad that there were some objective measurements beyond self-reports/questionnaires.

All participants were followed for an additional 12 month period after their last infusion. So the total time of study, from first infusion (month 0) to last session of self-reporting of fatigue/symptoms (month 24) were two years.

Do you know if the 26% of subjects who were responders were still in remission at month 24? These are the people I would want to study further to know why they responded?

I don't know. They drew a lot of blood. Tons before inclusion, and then every 3 months throughout the study, I think. At least for the first 12 months (the complete period of infusions). But I think the blood was going to be part of building a wider bio-bank, to be used beyond this singular study (RituxME phase III). I am not sure they used the bloodwork to measure what you describe. But again, I could be wrong.

I would assume if they drew a lot of blood throughout the study that they measured if each subject's B cells were at zero. It would be very strange to assume that every subject achieved full B cell depletion from 500 mg of Ritux without doing labs to verify this.

The pre-med were all oral, no IV pre-meds.

One hour before each infusion we got the following three pre-medications:
1000 mg paracetamol
10 mg cetirizine hydrochloride
8 mg dexamethasone

This is surprising to me that they did not give IV Benadryl as a pre-med since Ritux has such a high rate of allergic reaction (in general for all people), especially with the first two infusions. I personally cannot tolerate Decadron (Dexamethasone) and I would bet that at least some of the adverse infusion reactions were from the Dexamethasone itself (vs. the Ritux or the saline).

I am assuming that all subjects got the same oral pre-meds regardless if they got Ritux or saline? Do you know if that is the case?

The infusion speed was administrated very carefully. The speed of infusion started off very slowly and increased according to a specific pre-planned and timed schedule. One infusion session took approx 5-6 hours from start to finish.

That is a decent infusion rate for 500 mg of Ritux (assuming it was a 1:1 ratio of Ritux and saline). My Ritux infusions are 8-10 hours but I require a very slow rate beyond the average person.
 

Gingergrrl

Senior Member
Messages
16,171
Well shit, that just brightens my day

We already knew the Phase 3 Study results were negative, we just didn't know any details until this summary was released. I am looking forward to the entire article b/c the summary leaves a lot of unanswered questions (for me).
 

ukxmrv

Senior Member
Messages
4,413
Location
London
I have had cancer treatment but not Rituximab. Did a course of FEC-T (which includes Cyclophosphamide ).

My problem with the regime would have started with the paracetamol and the Dexamethosone. Can't tolerate either of these. In Europe we don't seem to use Benedryal in the same way USA docs I've seen do.

Does anyone know if the placebo arm also got the pre-meds or just saline?
 

Gingergrrl

Senior Member
Messages
16,171
I dont think that its behind paywall, there is a small logo where it says PDF where you can see the whole paper. You can see it here.

Thank you so much @Tias for posting that link. I won’t be able to read it until tonight b/c leaving soon for an appt but am looking forward to reading it.

Can't tolerate either of these. In Europe we don't seem to use Benedryal in the same way USA docs I've seen do.

I also find it strange that they would only use oral Zyrtec as their H1 blocker for their pre-med for Ritux (b/c it is not nearly as strong as IV Benadryl) and not expect adverse infusion reactions but that is a separate issue!

Does anyone know if the placebo arm also got the pre-meds or just saline?

If it was double blinded, I would have to assume that both groups received the same pre-meds (or else the nurses and patients would automatically know who was just getting the saline).

Some of the adverse reactions have to be from the Dexamethasone and many people do not tolerate it.
 

pibee

Senior Member
Messages
304
So they almost managed to prove placebo is superior to Ritux, then we'd have a problem with all those placebo prescriptions!
Wow

One thing i DONT understand about the conclusion Ritximab doesnt work so ME cant be autoimmune:

Rituximab doesnt work in MANY studies for Sjogrens (i think approx in half studies did, half didnt work from what i read), same with MS where they didnt manage to approve it even.. etc. And those are accepted autoimmune diseases. Sjogrens even tied to specific IgG antibodies.

For Sjogrens i read it might be because of BAFF increase after Rituximab so now they trial Rituximab+Belimumab, like for lupus/SLE.

Although this results that are so bad, do totally stir away the possibilty of B cells autoimmunity, there could be other explanations.
Especially if we consider cases like Whitney who got much worse after Rituximab (allegedly?)... cant this happen from BAFF increase?!
 
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Gingergrrl

Senior Member
Messages
16,171
One thing i DONT understand about the conclusion Ritximab doesnt work so ME cant be autoimmune: Rituximab doesnt work in MANY studies for Sjogrens (i think approx in half studies did, half didnt work from what i read), same with MS where they didnt manage to approve it even.. etc. And those are accepted autoimmune diseases.

I totally agree with you @pibee and think this is another excellent point. I have not read the study yet (I thought I would have time today but didn't) so I don't want to comment too much further before I have read the full study.

BUT, I had the exact same thought as you and there are many proven autoimmune conditions that do not respond to Rituximab. One of my best friends tried Rituximab for lupus and it did not help her whatsoever (but she ultimately went into remission from other treatments). I have known people with Rheumatoid Arthritis (which is one of the few autoimmune conditions in which Ritux is actually FDA approved) who were not responders to Ritux and got no benefit. And same with Sjogrens, Myasthenia Gravis, LEMS, and even MS.

So the fact that someone was not a responder to Ritux, does not inherently mean that their condition was not autoimmune. I am still not convinced that the 26% who were responders did not have an undiagnosed autoimmune condition. I want to know WHY those people were responders. They were diagnosed with ME/CFS which either means they are an autoimmune subset, or they had a co-morbid autoimmune condition, or they were misdiagnosed and did not have ME/CFS.

I really hope to read the entire study tomorrow. I want to understand why I was (and continue to be) a responder to Ritux beyond that I have B-cell driven autoimmunity b/c there are people with B-cell autoimmunity who are not responders. There has to be something more and I am wondering if it is people in which the EBV virus caused their autoimmunity vs. another cause?
 

pibee

Senior Member
Messages
304
I want to understand why I was (and continue to be) a responder to Ritux beyond that I have B-cell driven autoimmunity b/c there are people with B-cell autoimmunity who are not responders. There has to be something more and I am wondering if it is people in which the EBV virus caused their autoimmunity vs. another cause?

But you had no PEM right? no CNS problems? Maybe you just had other autoimmune disease, not ME.
 

Gingergrrl

Senior Member
Messages
16,171
But you had no PEM right? no CNS problems? Maybe you just had other autoimmune disease, not ME.

I had no PEM but am not totally sure what is included in "CNS problems" b/c I had severe dysautonomia and POTS. I spent 2+ years with a "CFS" diagnosis from every doctor I saw but I am actually not analyzing the Ritux study in relation to myself (and I no longer believe that ME/CFS was my correct diagnosis vs. multiple autoimmune disorders).

I am trying to understand the study in and of itself (separate from me) b/c it seems to have a major issue with the change in Rituximab dosing between Phase 2 (which had many responders) and Phase 3 (which did not). In addition to the potential adverse reactions to the pre-medications and the other questions that I posed above.

Everyone in the study was determined to have ME/CFS, and there were significant responders to Ritux in the Phase 2 trial (in which the 1000 mg dose was given), and there were still 26% responders in the Phase 3 trial (in which the 500 mg dose was given) and I want to know why. It very well may turn out that none of the subjects who were responders to Ritux had ME/CFS and if this is the case, it means that the rate of misdiagnosis (even in a highly regarded study with strict research criteria) is very high.