Rituximab Phase III - Negative result

[Marky90]

Disappointing results obviously but I have a question.

If the placebo effect can be as high as 30%, could this be why the results didn't show a significant difference between Rituxan and placebo?

Yep! I read on a fb-group that someone asked Mella what the response rate in this study was, and he supposedly said 30 %. But dont take my word for it (might have been fogged^^)

 

[Rossy191276]

Disappointing results obviously but I have a question.

I have read that the placebo effect in studies can be as high as 30% in some studies. I also heard (trying to remember the source, but think it was my ME/CFS doc who talked to the folks at Cell Trend) that about 25-30% of patients in the Fluge and Mella phase lll study were found to have autoantibodies to the various adrenergic and muscarinic receptors that they found.

Assuming that auto-antibodies play a role in these 25-30% of patients' disease, and even if every patient with the antibodies was a responder, which we seem to know was not the case, then only 25-30% of the actual study patients could have shown an improvement from Rituxan. If the placebo effect can be as high as 30%, could this be why the results didn't show a significant difference between Rituxan and placebo?

Could it be that Rituxan is effective in a percentage of people with this antibody profile but not for patients who don't have them? And since the total percentage of people who had this profile was small compared to the total number of subjects, might that be an explanation for the negative results? Might it mean that not everything about the study was negative?

Hoping this study can at least help to tease out one subgroup of patients under the big umbrella of ME/CFS.

I would be amazed if study participants didn't have the autoantibody tests done and Fluge and Mella don't already have these data but even if they don't with such a big group it will be a simple matter of getting participants to do the cell trend tests now that study is finished and see if the responders are the ones with the positive cell trend results...

 

[deleder2k]

That seems very strange to me as the symptoms described are different. Fukuda seems like your immune system never got over mono or a severe cold (flu-like symptoms, sore throat, swollen lymph nodes, headaches, joint pain, etc) and I have none of these but yet I meet many of the symptoms of CCC and ICC. I don't see how they are the same.



Then wouldn't this actually be a positive result?!! How could 10/15 respond to Rituximab but only 2/15 in the placebo group? Wouldn't this actually mean something significant?

The result was positive. We were discussing the phase 2 double-blinded study from 2011. The primary endpoint at 3 months was not met, but patients were kept blinded and there was a major effect at 6 months. We don't know the exact results for the latest multi-centre trial. We only know that it will be negative, and that they will seize plans for upcoming rituximab trials. They also said a minor subgroup may benefit from rituximab, but we're talking about a few people.

Criteria: I edited my post, but it seems that a majority that have ME according to the CCC also have it according to Fukuda. That is not very strange.

Results from two of the studies by Jason et al33,52 suggest that 40–70% of the Fukuda-positive patients are also Canada positives

There are major differences, but I don't understand how anyone with ME according to Canada criteria only can check off one symptom from the Fukuda list.

http://bmjopen.bmj.com/content/4/2/e003973

 

[Gingergrrl]

The way I read the criteria is that with the CCC I meet: Pain, orthostatic intolerance, palpitations, exertional dyspnea, loss of thermostatic stability, subnormal body temp, cold extremities, and sensitivities to food/meds/chemicals (8 things) vs. with Fukuda I only meet muscle pain (1 thing).

I find it strange that none of them list muscle or breathing weakness which was severe for me (pre-treatment w/IVIG & Ritux) but I guess it is not a major symptom of CFS?

 

[Diwi9]

The way I read the criteria is that with the CCC I meet: Pain, orthostatic intolerance, palpitations, exertional dyspnea, loss of thermostatic stability, subnormal body temp, cold extremities, and sensitivities to food/meds/chemicals (8 things) vs. with Fukuda I only meet muscle pain (1 thing).

Your symptoms seem to describe dysautonomia. I have many symptoms of dysautonomia, but classic ME symptoms too. It's really been a huge gift to have you on this forum explaining your experiences and treatment, because it helps us all educate ourselves on where we overlap and don't. Sometimes policy-makers just do not have a feel for what we experience. I don't even trust that when everyone is interviewed for a clinical trial, that they properly represent their own symptom experience. People can be primed, even when their intentions are good. PEM is so distinct...so utterly different from any other sickness symptom. Your lack of mobility and weakness makes you look closer to a severe ME/CFS patient, but to be that extremely sick and yet without PEM...just isn't ME/CFS.

I am so thankful that you are improving and I know PR picks up lots of people who suspect ME/CFS. Differential diagnosis is critical. Imagine someone in your position diagnosed with this ghastly disease who is denied rituximab when they might in fact be a responder? Your contributions are so valuable...as is this clinical trial.

 

[Rossy191276]

The result was positive. We were discussing the phase 2 double-blinded study from 2011. The primary endpoint at 3 months was not met, but patients were kept blinded and there was a major effect at 6 months. We don't know the exact results for the latest multi-centre trial. We only know that it will be negative, and that they will seize plans for upcoming rituximab trials. They also said a minor subgroup may benefit from rituximab, but we're talking about a few people.

Criteria: I edited my post, but it seems that a majority that have ME according to the CCC also have it according to Fukuda. That is not very strange.

There are major differences, but I don't understand how anyone with ME according to Canada criteria only can check off one symptom from the Fukuda list.

http://bmjopen.bmj.com/content/4/2/e003973

Hi Deleder2k... I am an example of someone who doesn't meet Fukuda (Since onset over 2 years ago I haven't had a sore throat, tender lymph nodes, new types of headaches, joint pain, specific muscle pain, and I wouldn't say I have had unrefreshing sleep or fatigue like they mean it), and I have had severe brain fog but only as a result of PEM...

But looking at ICC I meet Sections A and D all the time very severely and B when I have overexerted but not C...But from communicating on forums and groups there seems to be a large % (maybe 50% of ME sufferers who actually stop getting flu like illnesses when they get ME) so I think a lot of people don't meet Criteria C...

 

[Rossy191276]

The way I read the criteria is that with the CCC I meet: Pain, orthostatic intolerance, palpitations, exertional dyspnea, loss of thermostatic stability, subnormal body temp, cold extremities, and sensitivities to food/meds/chemicals (8 things) vs. with Fukuda I only meet muscle pain (1 thing).

I find it strange that none of them list muscle or breathing weakness which was severe for me (pre-treatment w/IVIG & Ritux) but I guess it is not a major symptom of CFS?

Gingergrrl ICC categorizes muscle weakness under motor disturbances in Section B and under Section D respiratory they mention air hunger and chest wall weakness which I guess is the breathing difficulties...

Extreme muscle weakness (and tremors especially upon waking) in upper legs, core, and chest resulting in breathing weakness, inability to talk more than a few words quietly, and being completely bed bound along with dysautonomia are my major symptoms.

 

[Murph]

Is there a subgroup? I'm getting the sense we think not. But that may all hinge on how Google translate has rendered Maria's blogpost, which reads as follows:

"If they find a way to separate the patients in the group Through biological markers, they will consider testing Rituximab on a smaller subgroup."

https://translate.google.com/transl...tudien-ikke-mulig-a-pavise-effekt/&edit-text=

That language ("if") suggests no subgroup has been found yet. But between delays in data analysis, scientific reticence, blogger interpretation or automated translation the impression we're getting might be wrong.

I can see Mella trying to put the whole population off trying it while they await publication of a paper that defines a responsive subgroup. That would be responsible.

Altho I guess it had to be a subgroup small enough not to lift the difference between groups to the level of significance.

I'd like to know precisely what Mella said.

 

[Jesse2233]

Some treatments to feel hopeful about:

• 20-pass ozone
• Immunoadsorption
• Photopheresis
• Rapamycin
• Everolimus
  
• Rega Compound 17
• Rega Compound A
  
• Suramin
• Actemra
• Filgotinib
  
• Cyclophosphamide

Rituximab is not the only game in town

 

[Ruthie24]

I would be amazed if study participants didn't have the autoantibody tests done and Fluge and Mella don't already have these data..."

My understanding from my ME/CFS doctor who talked to the CellTrends doctors was that participants did have the antibody tests done as part of the Mella/Fluge study. I am curious to see what the actual study papers say when they get them in print.

Ruthie, we are very similar re: the Cell Trend Abs and the GAD65. I also have POTS and MCAS (but do not have EDS or Sjogrens). Can you remind me if you test positive for any of the calcium channelopathies?
.

No, I do not have the calcium channelopathies, as far as I am aware. I do have thyroid, and antimitochondrial antibodies in addition to the others listed previously. And, of course, the chronically elevated EBV/viral component.

 

[Jesse2233]

@Ruthie24 glad to hear you're doing better!

 

[Ruthie24]

Thanks! Me too.

It has been slower than @Gingergrrl 's response to Rituxan but has definitely been a big improvement.

I was able to dance at my sister's wedding last month. My daughter said she hadn't seen me move like that in years. And, best of all, I didn't end up in bed for days after that.

My step count on my Fitbit has gone up significantly and my exercise tolerance has improved as well. I still have days where I just need to take it easy because I am afraid of causing a crash or feel like I may have overdone it, but so far even with some very stressful family situations, travel and long hours at a time out of the house, I have not crashed or even felt close to having one.

I think my family and I are all afraid that it won't last, but so far it has been really good. I have had a lot of side effects from IVIg which have made it hard to sort out my progress since starting the Rituxan in May.

Still not back to my old normal, but I am also almost a decade older than I was when I last felt "normal" so who knows what normal will be for me now.

 

[Jesse2233]

@Ruthie24

That's great to hear and for other patients to hear as well.

Do you have data on number of average number of daily steps before and after Ritux?

 

[nandixon]

The way I read the criteria is that with the CCC I meet: Pain, orthostatic intolerance, palpitations, exertional dyspnea, loss of thermostatic stability, subnormal body temp, cold extremities, and sensitivities to food/meds/chemicals (8 things) vs. with Fukuda I only meet muscle pain (1 thing).

@Gingergrrl, Look at the top left of the table @deleder2k posted under “Symptoms” where it says the word “Fatigue.” Fatigue, i.e., energy impairment, is a basic requirement of all three diagnostic systems. I thought you've mentioned before that you don't suffer from that(?), so that could explain why Fukuda and the CCC seem so far apart for you.

Note also that the CCC (and effectively the ICC) makes PEM (or post-exertional fatigue) an absolute requirement as well. I thought you've also mentioned before that you don't suffer from that either.(?) (Fukuda doesn't make PEM an absolute requirement, which is its biggest shortcoming under current thinking, I believe.)

Having neither “fatigue” nor PEM would seemingly make it difficult to entertain a diagnosis of ME/CFS. But perhaps with needing a wheelchair you’re never able to exert yourself enough to experience those... (And certainly regardless of any diagnosis I hope you stay here.)

 

[Gingergrrl]

Gingergrrl ICC categorizes muscle weakness under motor disturbances in Section B and under Section D respiratory they mention air hunger and chest wall weakness which I guess is the breathing difficulties...

Thanks and I was only comparing the CCC and Fukuda criteria when I typed that post. If I use ICC then I also had the muscle weakness (and I had pretty bad weakness to the diaphragm before treatment).

That language ("if") suggests no subgroup has been found yet. But between delays in data analysis, scientific reticence, blogger interpretation or automated translation the impression we're getting might be wrong.

I am very curious, too, re: the subgroups and hoping they will explain more in the future.

It has been slower than @Gingergrrl 's response to Rituxan but has definitely been a big improvement.

I think my progress has been faster but that I started at a lower point. For me to get out of wheelchair and walk around a store for 5-10 min at a time is a true miracle to me. I am not even close to dancing or exercising and they are not even on my list of goals (yet)!

My main goals are to be able to walk for 20-30 min, to climb more than one stair, and to drive a car again. Dancing and exercising surpasses my wildest dreams although I do believe it is possible (just not yet). I am so happy for you, Ruthie, and it's great to hear your progress. And our doctor is definitely in touch w/the head of Cell Trend b/c I told them about each other in 2016.

 

[Gingergrrl]

so that could explain why Fukuda and the CCC seem so far apart for you.

I wasn't comparing them to mean that I meet the criteria, vs. that Fukuda seemed like it described someone who was chronically sick with flu-like symptoms, sore throats, swollen lymph nodes, etc, and CCC or ICC seemed to have many more categories of symptoms and really include dysautonomia, cardiac/neuro symptoms, allergic reactions, and orthostatic intolerance.

Having neither “fatigue” nor PEM would seemingly make it difficult to entertain a diagnosis of ME/CFS.

I absolutely agree which is why I now believe I was misdiagnosed in 2013 and 2014.

But perhaps with needing a wheelchair you’re never able to exert yourself enough to experience those...

A few people from this board have tried to convince me of this in the past, and even told me that I was in denial and that I have ME/CFS, but don't get fatigued or have PEM b/c I use a wheelchair. This seemed strange to me b/c in 2013 and 2014, I did not yet own a wheelchair and when I got the wheelchair in Oct 2014, I initially only used it for long distances. I worked an entire year with severe POTS and I became debilitated where I could not walk from my car to my office. And yet I still did not feel fatigue or PEM, I just literally could not breathe when I stood up and was gasping for air and getting angina.

But sitting (at desk, table, wheelchair, etc,) I had no limitations. I had no reactions to mental, social, or cognitive exertion yet my muscles lost the ability to open a water bottle or my front door. With each new decline (like no longer being able to open my front door), once I lost it, it never returned. I could rest for days straight, as I believed I was supposed to from reading this board, but it did not return my muscle strength.

The first thing to improve my muscle strength, POTS, allergic reactions, breathing weakness, and ability to stand and walk without wheelchair was IVIG and then additional improvements from Rituximab. And (so far) once a new skill has come back (like being able to turn on faucets in shower or squeeze the shampoo bottle) it is now back permanently! My condition does not vary from day to day. I have something different yet with a lot of overlap.

(And certainly regardless of any diagnosis I hope you stay here.)

Thanks, Nan, and I am planning to stay as long as you guys will have me LOL

 

[Gingergrrl]

@Diwi9 I've had an incredibly difficult week due to personal issues and your post brought tears to my eyes, thank you so much for the kind words.

It's really been a huge gift to have you on this forum explaining your experiences and treatment, because it helps us all educate ourselves on where we overlap and don't.

This means a lot to me and I have decided to stay here, in addition to all of the amazing information and support, b/c I want to believe that somehow my case will be useful to someone reading the board either now or in the future.

Your symptoms seem to describe dysautonomia.

Absolutely 100% and one of the only things that every single doctor I have ever seen agrees on is that I have POTS and dysautonomia. My HR and BP were so abnormal in 2013, it was scary. On the average day, before I started the beta blocker, my HR was going into the 160's and 170's and nothing was stopping it.

Your lack of mobility and weakness makes you look closer to a severe ME/CFS patient, but to be that extremely sick and yet without PEM...just isn't ME/CFS.

This is what made it so confusing. I did a one-off consult w/a cardio in 2015 and although he confirmed I had POTS and MCAS, he said that none of his other patients had the level of muscle and breathing problems and he was so struck by the fact that I literally could not stand and walk about 5-10 steps across the room (at that time) that he thought I might have muscular dystrophy. I of course did not have MD, but he was the first doctor to pick up on that and said that none of his "regular" POTS patients had this. I believe this was due to the auto-antibodies but no one had ever tested me for them at that time.

Imagine someone in your position diagnosed with this ghastly disease who is denied rituximab when they might in fact be a responder? Your contributions are so valuable...as is this clinical trial.

This is part of why I keep posting b/c I believe there must be others out there like me who actually could benefit from IVIG or Ritux and just don't know it. Even in my case, my doctor said there was no guarantee that I would be a responder but I literally felt as if I had nothing left to lose at that point and whatever I had was going to kill me. One of my docs (my Endo) said if we do not stop the progression, I could end up on a ventilator and we would not even know why (and no one knew I had these auto-antibodies yet). Now I am 100% certain (unless something drastically changes) that I will never end up on a ventilator and I walked around a store tonight w/o wheelchair while carrying things and can inhale a full, normal breath unlike before.

 

[bspg]

Is it weird that I meet Fukuda, CCC, and ICC? Am I an outlier?

 

[Gingergrrl]

Is it weird that I meet Fukuda, CCC, and ICC? Am I an outlier?

Not at all and I think you are an inlier (is that even a word LOL) and I am the outlier.

 

[Sasha]

Some good news though...
A slide showed

Marky, are you sure it's OK to publish that slide on the internet? The data are marked as 'unpublished' and we don't want to do anything to make it harder for them to publish a paper.