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

geraldt52

Senior Member
Messages
602
I don't think the trial says anything whatsoever about autoimmunity, or Rituxan. You can't say that the 26% who "improved" responded to Rituxan any more than you can say the other 19% who "improved" responded to saline. It all ends up being just another bunch of nonsense. Not the fault of the researchers or the participants, just the way it is when you lack a biomarker or any marker that can be tracked and recorded.
 

msf

Senior Member
Messages
3,650
They acknowledge the point about the maintenance dose being reduced, but claim that this is not a plausible explanation for the lack of efficacy as it doesn't explain the lack of initial response to Rituximab.
 

Gingergrrl

Senior Member
Messages
16,171
I don't think the trial says anything whatsoever about autoimmunity, or Rituxan

Sadly, I fully agree with you.

They acknowledge the point about the maintenance dose being reduced, but claim that this is not a plausible explanation for the lack of efficacy as it doesn't explain the lack of initial response to Rituximab.

I respectfully don't agree with this b/c it makes no sense to me. The autoimmune dosing of Rituximab is based on a formula using the patient's BSA (body surface area). I am not speaking about the cancer dosing of Ritux which may be different. But in autoimmunity, the ideal dose is based on this formula which for me was 600 mg per infusion. Therefore someone taller and/or weighs more than me, would receive a higher dose.

In the original Fluge & Mella study (Phase 2) which had responders to Ritux, every patient received one gram (1000 mg) of Ritux instead of using the BSA formula. However, one gram is a very high dose which would have captured all of the subjects (and was most likely higher than some of the subjects would have needed but it was definitely NOT lower than what they needed).

Therefore, for consistency of results, all subjects in the Phase 3 trial should have also received one gram (1000 mg) of Rituximab for all of their infusions. But they did not and they received individual dosing based on the BSA formula for their first two infusions and then everyone received 500 mg for the remainder of the infusions. This is literally HALF the dose of the Phase 2 study, and is even smaller than my own dose of 600 mg per infusion.

It took me a full nine months of Rituximab to go into remission where I could walk without a wheelchair, drive my car, and have my independence back. So for the subjects to only have two weeks of the BSA dose, and then months 3, 6, 9, 12, etc at the 500 mg dose, does not make sense to me (and cannot be compared to Phase 2 in which everyone received the 1000 mg dose). To me this makes the Phase 2 and Phase 3 trials completely different studies.

If Phase 3 had used the SAME dosing as Phase 2, then we would be comparing apples to apples but we are not. If they reduced the dose in an individual patient for a clinical reason (outside of a trial), than this makes sense. But to cut the dose in half for ALL subjects, appears to be for financial reasons b/c I can't think why else they would do it?
 

andyguitar

Moderator
Messages
6,595
Location
South east England
My view of the final report is different from what has been expressed so far on this thread. I am pleased to see that the researchers have, by chance, stumbled on a treatment that was effective for so many of those who took part in the clinical trial. It's not the Rituximab. It's the pre-meds I am refering to. Allergy and auto-immune disorders are very often mentioned by sufferers. There has been research posted on this website recently about auto-immune and cfs/me. The premeds cetirizine and dexamethasone are both used to treat allergy. Unfortunatly both can have side effects. But that does not mean they are not having a benefit. Dex is also used to treat 'Brain inflammation caused by head injury'- reports from sufferers that they have suffered head injury in the past do crop up here now and again. By all means shoot me down about this, but give it some thought first. The final repor,t when considered with other findings over the years, indicate that for many cfs/me IS an autoimmune/allergic type disorder which can be treated using 10mg Cetirizine Hydrochloride and 8mg of Dexamethasone.
 

Gingergrrl

Senior Member
Messages
16,171
By all means shoot me down about this, but give it some thought first. The final repor,t when considered with other findings over the years, indicate that for many cfs/me IS an autoimmune/allergic type disorder which can be treated using 10mg Cetirizine Hydrochloride and 8mg of Dexamethasone.

Interesting theory and these are my thoughts about it... Zyrtec (Cetirizine) is actually a pretty benign H1 Blocker and much less stronger than the first generation antihistamines like Benadryl. I have taken Zyrtec for a good portion of my life (and was taking it 2x a day for MCAS for several years). I cannot see the effects of Zyrtec lasting more than about 24 hours for anyone.

Dexamethasone (Decadron) however is hardcore and 8 mg is a very high dose. I was given IV Decadron for intracranial hypertension/ excruciating headache in the ER after my very first dose of IVIG was infused at too high of a rate in 2016. I was then given a second dose at home (in pill form) and I had a HORRIFIC reaction to it including very high tachycardia that would not stop and had to go back to the ER. In my case, it would be crystal clear that I had received Decadron (vs. placebo) b/c of the intensity of the negative reaction.

However, there are other patients who have had very positive reactions (including normal energy levels and functioning) from Decadron which led them to feel much better. So I can definitely see patients (in both groups) having either a negative or a positive reaction to the Decadron which could last for weeks (as it did in my case) and then getting more Decadron with each infusion. They could therefore believe that their reaction was from the Rituximab but it was indeed from the Decadron.

For me, this factor alone does not prove anything, but at the same time, it is a major issue which cannot be discounted IMO. I'm still sort of surprised that the study did not use Benadryl and avoid all of the potential reactions (both negative and positive) from Decadron. I have never had a steroid with Rituximab so it definitely is not required.
 

andyguitar

Moderator
Messages
6,595
Location
South east England
Page 13 of the report, Appendix Table 1. Lists the medical history of particpants in the trial. Allergy is listed for 40.3% of those who got Ritux, 41.9% of those who got placebo. Page 14, Appendix Table 3. Lists the type of medication participants recieved during the 24 month follow up period. Allergy/Asthma meds for 58.4% of the Ritux group and 51.4% of the Placebo group. So they were an allergic bunch of subjects. Is it suprising that the results are what they are when they were all given 2 powerful anti-allergy drugs as a pre-med? Anyone got $3,000,000 to fund a re-run?
 

andyguitar

Moderator
Messages
6,595
Location
South east England
Appendix Table 3 also reveals that about 40% of subject were taking ABX during the 24 month follow up. Does'nt say what for. I would say that a clinical trial of Dexamethasone and Cetirazine should be undertaken. I absolutly do not believe the positive results in the 'Placebo' group are due to a placebo effect.
 

Gingergrrl

Senior Member
Messages
16,171
I would say that a clinical trial of Dexamethasone and Cetirazine should be undertaken. I absolutly do not believe the positive results in the 'Placebo' group are due to a placebo effect.

I agree that both very positive or very negative results can occur from Dexamethasone (depending on the individual person) and this factor cannot be dismissed.

But I still feel the bigger issue is the change in Rituximab dosing from Phase 2 (1000 mg per person) to Phase 3 (BSA dosing for first two infusions and then 500 mg per person for the remaining four infusions). 500 mg is not high enough for many people to keep B cells at zero (vs. 1000 mg would cover everyone). I cannot understand how such a huge issue is not being addressed and feel like there must be an explanation!
 

Gemini

Senior Member
Messages
1,176
Location
East Coast USA
Dr. Fluge presented a detailed review of the RituxME trial at the IIME Research Conference on May 31, 2019:

RituxME Study review Dr. Fluge.JPG


A video of his entire 30-minute presentation including his observations about the results is here:
www.investinme.org/IIMEC14.shtml

@Gingergrrl @Murph @andyguitar @geraldt52
 

Gingergrrl

Senior Member
Messages
16,171
Thx for tagging me @Gemini and I bookmarked this to watch next week. I don’t want to comment before actually watching it!
 

Gemini

Senior Member
Messages
1,176
Location
East Coast USA
Thx for tagging me @Gemini and I bookmarked this to watch next week. I don’t want to comment before actually watching it!
@Gingergrrl I'm still watching all of the IIME Conference videos, one by one!

Came across Dr. Fluge answering "interesting" audience questions [end of the Tronstad video about 20:20]

He indicates interest in a possible Rituxan ME/CFS subgroup; David Andersson's Fibromyalgia IgG autoantibody findings [separate video]; and Ron Davis' something in the blood "serum factor" wondering if it might possibly be an antibody.

Dr. Fluge IIME Conference 2019.JPG


The full Tronstad and Andersson presentation videos are here:
www.investinme.org/IIMEC14.shtml
 

Gingergrrl

Senior Member
Messages
16,171
@Gingergrrl I'm still watching all of the IIME Conference videos, one by one!

Wow, that is impressive! I am only going to watch the Rituximab link that you gave me above :)

Came across Dr. Fluge answering "interesting" audience questions [end of the Tronstad video about 20:20]

Did anyone ask him re: the change in dosing from Phase 2 to Phase 3 of the Ritux trials (and how this is not a confounding variable)? The only reason I can think of for the lower doses in Phase 3 was the cost of the medication and I cannot think of a clinical reason.

He indicates interest in a possible Rituxan ME/CFS subgroup; David Andersson's Fibromyalgia IgG autoantibody findings [separate video]; and Ron Davis' something in the blood "serum factor" wondering if it might possibly be an antibody.

That is really interesting and I am looking forward to watching the video later so I can properly discuss with you and anyone else who is following. Thx again!
 

Inara

Senior Member
Messages
455
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...
From the paper:

One hour before infusions, all patients received premedication with 1 g of oral acetaminophen, 10 mg of cetirizine, and 8 mg of dexamethasone...
To me, this explains improvements and severe side effects, also in the placebo group.
I reacted with severe side effects to 2mg dexamethasone, and at the same time, it is responsible for the substantial improvements I experience since taking it (in a "pulsed" fashion). I think about starting a poll here about others's experiences with dexamethasone - might be interesting.
I could also imagine that albumine infusions might help some if there are issues (but I don't know).
 

Gingergrrl

Senior Member
Messages
16,171
8 mg of Dexamethasone is an incredibly high dose that would send me to the ER with uncontrollable tachycardia (and actually did in 2016). This was one full year prior to me starting Rituximab and had no relation in my case.

Edit: @Inara I think you should start that poll
 
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Gingergrrl

Senior Member
Messages
16,171
Dr. Fluge presented a detailed review of the RituxME trial at the IIME Research Conference on May 31, 2019:
Came across Dr. Fluge answering "interesting" audience questions [end of the Tronstad video about 20:20]

@Gemini I just watched the full presentation of Dr. Fluge's review of the RituxME trial and also his audience questions at the end of the Tronstad video. Thank you again for tagging me. These are my thoughts and I would LOVE it if some day, someone can explain to me where I am wrong b/c I see several flaws in the trial.

He explicitly said that the Rituximab doses for the final Phase 3 trial were NOT the same doses as the Open Label trial which had many long-term responders. If you change the BSA (body surface area) formula dosing, which is specialized for each patient, to a standard dose of 500 mg per patient, it is NOT the same thing. My own Ritux dose (using the BSA formula) is 600 mg per infusion which means that 500 mg would not be a strong enough dose for me. The only reason I can think of for the change in dosing is the cost of the medication. I cannot think of a single clinical reason for the change.

Dr. Fluge replied to an audience question that the positive results of the Phase 2 open label trial will be something that he wonders about for the rest of his life. I wish I could ask him WHY the change in dosing between those two trials is not considered a major factor? There is no question in my mind that in the final Phase 3 trial (for doses 3, 4, 5, and 6) that 500 mg per infusion simply was not a high enough dose for many of the subjects. In addition, it was a change in protocol which makes it an inconsistent or confounding variable in my opinion.

I also saw many other problems. When he said that some of the reactions (both positive and adverse) were short-lived, there is no question in my mind that some of the subjects were responding to the incredibly high dose of Dexamethasone. 8 mg is an extremely high dose that literally sent me to the ER with uncontrollable tachycardia and other adverse events (in my case this was a full year before I ever started Rituximab).

Dr. Fluge also said that 40% of the subjects had "allergies". I realize this does not mean "MCAS", but I suspect it is highly likely that many of them did have MCAS and that the Dex temporarily brought relief (and in others it triggered very adverse effects like agitation, tachycardia, insomnia, steroid induced psychosis, etc).

In addition, he did not state the infusion speed (unless I missed it which is possible). When I get Rituximab, in addition to having ZERO steroids, I get an unbelievably slow infusion speed to reduce the chance of any allergic reactions or any infusion related reactions (and I have never had any). I also get no extra fluids and my pre-meds are IV Benadryl, (oral) Tylenol (Acetaminophen), and (oral) Pepcid (Famotadine).

These are the pre-meds that happen to work the best in my own personal case but every person is unique and different so it is possible that some subjects reacted to the pre-meds that they were given (especially to the Dexamethasone). I also believe that some subjects reacted to the Albumin (and I have never heard of giving Albumin with Rituximab but maybe this is more common in Europe vs. in the US)?

I also have thoughts re: the selection criteria and outcome measures but those are less concerning to me b/c none of that even matters with the discrepancy in dosing between the Phase 2 Open Label Study and the Phase 3 RituxME Trial. I truly wish that there was someone who could explain this to me re: the dosing issue!
 
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Gemini

Senior Member
Messages
1,176
Location
East Coast USA
@Gemini I just watched the full presentation of Dr. Fluge's review of the RituxME trial and also his audience questions at the end of the Tronstad video... These are my thoughts and I would LOVE it if some day, someone can explain to me where I am wrong b/c I see several flaws in the trial.
@Gingergrrl, excellent RituxME questions! Wish we could roll back time and put you in the IIMEC14 audience to ask them of Dr. Fluge! He seems quite confounded and perplexed by the trial results and keen to explore them further.

I see he's speaking again on Sept 7th at the upcoming OMF Symposium. Wonder if you could submit them thru OMF beforehand [he's on their Board I think] such that he might address them during his talk? @Ben H ?

https://www.omf.ngo/2019/07/16/3rd-annual-community-symposium-speakers/
 

Gingergrrl

Senior Member
Messages
16,171
How can one have a serious adverse event under Placebo? (18%).

Because in this case the placebo involved IV saline, albumin, 8 mg of Dexamthasone, Tylenol & Zyrtec.

There could be allergic reactions to anything from the IV materials to the meds. Plus there could be infusion reactions to the infusion speed, the amount of fluid, or even to traveling to the infusion center/hospital repeatedly.

I had a horrific reaction to Dexamethasone in 2016 that sent me to the ER and in 2014 I got pulmonary edema from IV saline that was infused too quickly (due to third spacing).

@Gemini I am going to reply later re: your idea of getting my questions to Dr. Fluge via OMF and think it is a great idea.
 
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Gingergrrl

Senior Member
Messages
16,171
@Gingergrrl, excellent RituxME questions! Wish we could roll back time and put you in the IIMEC14 audience to ask them of Dr. Fluge!

That would have been amazing and I would love the opportunity to ask Dr. Fluge my questions!

He seems quite confounded and perplexed by the trial results and keen to explore them further.

That was my sense as well, that he seemed perplexed as if something was still niggling at him that there was more to investigate with Rituximab. He explicitly stated that there were responders but he did not know how to identify these individuals for the future. He talked about it from many different angles but never was the issue of the change in dosages (between the Open Label Study and the Phase 3 trial) or the pre-meds (especially the super high dose of Dexamethasone) brought up.

I see he's speaking again on Sept 7th at the upcoming OMF Symposium. Wonder if you could submit them thru OMF beforehand [he's on their Board I think] such that he might address them during his talk? @Ben H ?

Gemini, thank you for tagging @Ben H and if there is a way to get my questions to Dr. Fluge that would be amazing! I will not be attending the symposium (in person or on-line) but I remain very interested in Rituximab. Even if this trial had been with subjects with Rheumatoid Arthritis (for which Rituximab is FDA approved in the US) instead of ME/CFS, I still would have the identical concerns and questions re: the changes in dosing and the pre-meds.