Rituximab Phase III - Negative result

[Cam Newton]

Any new CycloME rumours? It was supposed to be published late 2017.

 

[jaybee00]

Haven’t heard anything other than the Fluge presentation at OMF, in which he said results are “interesting”.

 

[Gingergrrl]

Haven’t heard anything other than the Fluge presentation at OMF, in which he said results are “interesting”.

I think we are still waiting for the Phase 3 trial results on Ritux as well (unless they have been published somewhere)? I am hoping that someone (or lots of people!) will tag me when this happens

 

[Stacey1121]

Yea firstly I think @deleder2k explained the outcome of the rituximab trial very well. Rituximab wipes out antibody producing cd20 b-cells. As deleder2k said a trial like this will fail unless a high percentage of participants have a b-cell autoantibody disease. I.e. you could have a low level of b-cell autoantibody disease and a failed rituximab trial. In fact the answer with rituximab is to find auto-antibodies which cause the disease and then treat only those people e.g. with rituximab. The current auto-antibody tests are very poor i.e. false positives/negatives Ron Davis has proposed a way to improve them [https://www.omf.ngo/2018/02/12/tweak-assay-bolster-disease-detection-stanford-medicine-news-center/].

The separate study I referred to is a small scale study which indicates that you can diagnose ME/CFS using blood cells i.e. you measure an amino acid (phenylalanine) in the blood cells. High phenylalanine in your blood cells means means that you are using amino acids (e.g. phenylalanine) to produce energy (ATP) rather than glucose. This appears to result in the low energy state i.e. you get less ATP when you switch to this mode.

In effect this study may be a way of separating people with chronic fatigue:

• who have this change in cellular energy production (to using amino acids). This study found that 98% had switched to using amino acids;
• from those who do not have this change in cellular energy production (still using glucose). This study found that 2% had not switched to using amino acids.

If you look at the 2% then they could have anything e.g. a known b-cell autoantibody disease which responds to rituximab. To repeat, deleder2k said the rituximab trial will fail if there are a very low percentage of people with a b-cell autoantibody disease. I assume that the 2% estimate is based on a well controlled patient group. If you roll the test out, e.g. to everyone who presents at the local doctors surgery with chonic fatigue, then the percentage will be much higher.

It's a big day e.g. Phair is speaking (I assume) and he's looking at this cellular energy stuff.

As well as talking to each other on this site; why don't we try to talk to those who can actually fund the development of diagnostic tests/treatments etc - i.e. make a difference?

The European Union [EU] Committee on the Environment, Public Health and Food Safety (ENVI) are currently lobbying for increased funding for Lyme disease. The EU has already funded the development of a diagnostic test for Lyme disease i.e. 2 million euros/dollars. ME/CFS has received no EU funding. I've asked the Committee to lobby for funding for the development of a blood based diagnostic test for ME/CFS. See above, there appears to be a viable test available but we need validation studies. Here's a blog/thread on this site that I've been using [https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1001161].

Try to influence those who can fund studies to develop diagnostic tests, treatments etc. E.g. European Union through elected members [members of the European Parliament] or the Senate/Representatives in USA.

I am so glad I read this post bc I have high phenylalanine in my blood and it makes perfect sense that I am using amino acids instead of ATP on so many levels. can you remember where you saw the study by chance? My phenylalanine was 91 on a scale of 26-71 on the nutra eval. I won't take any amino complexes - I have to take everything separately (total pain in the....). It would also explain why glycine makes me feel SO much better. Unfortunately when I take the glycine I get discoid lupus lesions. Of course something that makes me "feel" better makes me sick. Perhaps if I could read the study there might be even more clues as to what is happening. Thanks for posting re all of this.

 

[Learner1]

Any new CycloME rumours? It was supposed to be published late 2017.

Cyclophosphamide can seriously damage mitochondria.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507312/

https://www.intechopen.com/books/to...f-anticancer-agents-from-lab-bench-to-bedside

 

[Learner1]

I am so glad I read this post bc I have high phenylalanine in my blood and it makes perfect sense that I am using amino acids instead of ATP on so many levels. can you remember where you saw the study by chance? My phenylalanine was 91 on a scale of 26-71 on the nutra eval. I won't take any amino complexes - I have to take everything separately (total pain in the....). It would also explain why glycine makes me feel SO much better. Unfortunately when I take the glycine I get discoid lupus lesions. Of course something that makes me "feel" better makes me sick. Perhaps if I could read the study there might be even more clues as to what is happening. Thanks for posting re all of this.

I do a NutrEval every 9-12 months. My aminos were consistently at the bottom of the range, wirh glutamate, phenylalanine, and taurine being normal. The pattern matched well with Fluge and Mella's study.

This was on a diet of 95g a day of protein. It took getting my protein intake up to 135-140g a day to get them to low normal. Commercial protein powders have the wrong ratios of aminos for my needs (too much arginine which can support herpes family) so my doctor ordered me a custom blend of aminos from Personalized Nutrients in Sisters, Oregon, which has helped a lot. I also take BCAAs on top of this to avoid/reverse PEM.

 

[FMMM1]

I am so glad I read this post bc I have high phenylalanine in my blood and it makes perfect sense that I am using amino acids instead of ATP on so many levels. can you remember where you saw the study by chance? My phenylalanine was 91 on a scale of 26-71 on the nutra eval. I won't take any amino complexes - I have to take everything separately (total pain in the....). It would also explain why glycine makes me feel SO much better. Unfortunately when I take the glycine I get discoid lupus lesions. Of course something that makes me "feel" better makes me sick. Perhaps if I could read the study there might be even more clues as to what is happening. Thanks for posting re all of this.

I'm trying to do some lobbying for ME in the European Union (EU). Lyme disease got 33.9 million euros from the EU Commission; ME got zero. I haven't been keeping up with this site; hence the late reply.

First if you Google then you'll find this "A new approach to find biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) by single-cell Raman micro-spectroscopy" [https://www.ncbi.nlm.nih.gov/pubmed/30207334].
Note that the researchers found high intracellular levels of phenylalanine i.e. not blood plasma/serum levels. This might remind you of Phair who found high intracellular levels of tryptophan (metabolic trap).

Second if you look at Chris Armstrong's 2015 paper on phenylalanine and tryptophan (+ other amino acids) then you'll notice that he found the levels low in blood plasma/serum [https://www.researchgate.net/public...pathways_in_chronic_fatigue_syndrome_patients]. Chris reckoned these amino acids were being used as cellular fuel rather than the normal glucose. In 2016 Fluge and Mella published a similar study [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].

So I've garbled my post from these studies (from memory).

I've just read that Chris Armstrong has joined OMF as their Science Liason and has moved to the US. I hope this works out well for Chris and us!

Good luck.

 

[Stacey1121]

Thank you very much for your response. I will check out the links and yes, hopefully this works out well for everyone!

 

[Jani]

Two studies from Norway showed the efficacy of the B-cell-depleting antibody Rituximab in more than half of the patients [11] . The results of the recently published multi-center study are unfortunately negative, but the dose was halved compared to the first studies.

If they halved the dose, I'm not surprised that the result of the study was negative.

Does anyone know what blood values (CD20 etc.) you need to have in order for rituximab to help?

 

[Hip]

If they halved the dose, I'm not surprised that the result of the study was negative.

They did not halve the dose. They actually increased the dose.


There were only two double-blinded placebo-controlled rituximab studies performed by Fluge and Mella:

• 2011 phase II study — response rate: 67% in the rituximab group, and 13% in the placebo group.
Here two initial rituximab infusions at 500 mg/m2 were given two weeks apart. No further follow-up infusions.

• 2019 phase III study — response rate: 26% in the rituximab group, and 35% in the placebo group.
Here two initial rituximab infusions at 500 mg/m2 were given two weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9 and 12 months.


So in the negative 2019 study, a lot more rituximab was used, compared to the positive 2011 study. See this post for more info.


There was also an open label 2015 study which used the most rituximab of all, and this was also positive (but there was no placebo arm).

 

[Gingergrrl]

They did not half the dose.

They did not half the dose for the final 2019 Study but they greatly reduced it. In the prior versions of the F & M Rituximab Studies, they used the BSA (body surface area) dosing for each subject but in the 2019 Study, they only used the BSA formula for the first two infusions (often called the loading dose) and then they gave every single subject 500 mg of Rituximab for the next FOUR infusions (#3 to #6) regardless of their BSA.

A dose of 500 mg would be too low for many patients, including for myself in which my dose for ALL infusions of Rituximab is 600 mg based on the BSA formula. Therefore a dose of 500 mg would be too low for many of the subjects (especially if they were men or women who are taller and/or weigh more than I do).

So for me the results remain inconclusive b/c of the change in dosing (which is a big factor). We can agree that the results are a failure but because the dosing is so different from the prior study (which was a success) that for me, this makes the results of the 2019 null and void.

We discussed it a lot more in the thread that you linked in #410 (above) as well as some other threads if I did a search of PR. I am still hoping that some day, Dr. Fluge or Mella, can explain why they changed the dosing for the final 2019 trial and how this factor does not nullify the results?

 

[Hip]

They did not half the dose for the final 2019 Study but they greatly reduced it.

No, in fact they greatly increased the dose in the 2019 study, compared to the 2011 study.

In the 2011 study, they only gave two initial rituximab infusions, and then no further infusions at all. But in the 2019 study, they gave the same two initial rituximab infusions, plus 4 further infusions over the following year. So a total of 6 infusions in the 2019 study.

 

[Gingergrrl]

@Hip I meant the 2015 and 2019 studies like we discussed in the other thread (using the BSA formula for all infusions compared to only using it for the first two infusions).

ETA: To clarify, I am not saying the Ritux is an effective treatment for ME/CFS (like it is for proven autoimmunity), only that it cannot be ruled out based on the change in dosing between the 2015 and 2019 studies.

 

[Hip]

@Hip I meant the 2015 and 2019 studies like we discussed in the other thread (using the BSA formula for all infusions compared to only using it for the first two infusions).

Sure, the 2015 study used the most rituximab of all, but the 2015 was not a double-blinded placebo-controlled study; there is no control group in this 2015 study.

The only two F&M studies which were double-blinded and placebo-controlled were the 2011 and 2019 studies.

The 2011 used the least amount rituximab out of all three studies, yet had the best result, with a 67% response rate. The 2019 study used much more rituximab than the 2011 study, yet only had a 26% response rate (which was actually lower than its control group response rate).

 

[Hip]

@Gingergrrl, just posted this new thread which may be of interest:

Can the Giardia lamblia ME/CFS outbreak in Bergen explain why the phase II rituximab trials were positive, but the phase III trial negative?

(I originally posted the above thread on S4ME, but there was not much in the way of good discussion there, so I've reposted it here).

 

[Gingergrrl]

Thanks @Hip and I will read your new thread and reply later to both posts.

 

[Learner1]

A double blind placebo study is not appropriate for ME/CFS patients for any treatment.

We are a heterogeneous group of patients, with different genes, different disease etiologies, different immune systems, vurak histories, mycoticmxin and heavy metal levels, different autoimmune antibodies, different hormone levels, different comorbidities, etc.

I say this as I am acutely aware that there is no patient exactly like me, and therefore, I read any ME/CFS study with a jaded eye, looking to see what similarities or differences there are from my situation, to decide if it's useful to me.

Much as it is inconvenient, personalized medicine is the way to go, picking and choisung treatments based on the patient's unique characteristics.

Rituximab has been shown to work for patients with autoimmunity. It is apprived for certain "name brand" autoimmune diseases, but has worked fir patients with other sorts of autoimmune antibodies, like @Gingergrrl.

The ME/CFS Ritucimab trials were done in patients who were likely a mixed bag of varying or NO autoimmunity. We don't know what they had. So, it shouldn't be a surprise. that the results are a mixed bag.

In my case, I have 4 types of autoimmunity that were identified by my doctors. I spoke to multiple doctors about my options and got independent second opinions from experts. Based on my autoimmunity, which us quite different than Gingergrrl's or that of the patients with "name brand" autoimmunity, the consensus was that it is low risk, and worth a try, as long as I didnt have active infections.. Based on my info gathering, I put my odds at about a 30% chance it would work. But, as its a path to getting rid of my worst symptoms, it seemed worth trying

I am 4 1/2 months into Rituximab treatment, and my symptoms are somewhat better. Not sure where this will lead, but glad I didnt just read the studies and conclude it doesn't work for ME/CFS and let it dissuade me.

 

[Hip]

In my case, I have 4 types of autoimmunity that were identified by my doctors. I spoke to multiple doctors about my options and got independent second opinions from experts. Based on my autoimmunity, which us quite different than Gingergrrl's or that of the patients with "name brand" autoimmunity, the consensus was that it is low risk, and worth a try, as long as I didnt have active infections..

If you are taking rituximab to target your 4 autoimmune conditions, then you are not really taking it for ME/CFS, but for autoimmunity. In this case, it may be relevant to look at any clinical trials of rituximab for those autoimmune conditions, to see if rituximab is known to help those.

By treating the autoimmune conditions, hopefully there may be a knock-on beneficial effect on your ME/CFS too.

Out of around 22 people who tried rituximab on this forum, only 1 out of that 22 did really well on it, and that patient had several autoimmune conditions. But most of the 22 rituximab patients did not see benefit.

 

[Learner1]

Exactly. There are several of us ME/CFS patients who ALSO have one or more sets of autoimmune antibodies. Some don't, but many dont even know because they haven't been adequately tested.

So, randomly giving Rituximab to ME/CFS patients without a full picture of their autoimmunity (and the status of any infections) isn't going to give useful information to base decisions on. It's like putting a randim group of patients in a leg cast. If they don't have a broken leg, they wont be able to walk any better after 6 weeks un a cast. If they do have a broken leg, and tgat is figured out first, well then, that interventuin is more likely to be helpful.

My doctor is carefully selecting patoents based on autoimmunity, and had me talk to multiple patients independently before I went ahead. None were sorry they'd done it, no matter what the outcome. We all understand there are no guarantees, and no outsize promises were made.

Just like all of us ME/CFS patients won't benefit from spinal surgery, Valcyte, IVIG, or Mestinon, though some will.

 

[Gingergrrl]

@Gingergrrl, just posted this new thread which may be of interest:

Sorry I got delayed and am planning to read your link shortly @Hip (and thanks for tagging me). I am confused though, is there a known mechanism or connection between Giardia Lamblia and autoimmunity/ B-cells? (I'm not saying that there isn't and am not familiar with it). Also, if it was an active infection, then it would not be safe to do Rituximab.

Rituximab has been shown to work for patients with autoimmunity. It is apprived for certain "name brand" autoimmune diseases, but has worked fir patients with other sorts of autoimmune antibodies, like @Gingergrrl.

I never get to have the "name brands" (just kidding ...)

The ME/CFS Ritucimab trials were done in patients who were likely a mixed bag of varying or NO autoimmunity. We don't know what they had. So, it shouldn't be a surprise. that the results are a mixed bag.

I agree that the patients were a mixed bag re: autoimmunity. But in addition, I still cannot understand why changing the Rituximab dosing from the 2015 to the 2019 study is not a confounding variable re: the results? I think it is very possible that Ritux would not have proven to be effective in that study no matter what but I feel we will never know with the dosage change. I am literally on the edge of my seat waiting for someone to explain this to me some day (and this is not directed at Learner1)!

In my case, I have 4 types of autoimmunity that were identified by my doctors.

That is interesting and in my case, our doctor feels that all four of my diagnoses are now autoimmune mediated, too (Hashimoto's Disease, POTS, MCAS, and atypical LEMS/Calcium Channelopathy). I also have all kinds of other rogue autoantibodies like the seven Cell Trend Abs, anti GAD65, etc.

Based on my autoimmunity, which us quite different than Gingergrrl's or that of the patients with "name brand" autoimmunity, the consensus was that it is low risk, and worth a try, as long as I didnt have active infections..

I agree and in my case, I had such a good response from high dose IVIG, that it was an additional indicator that I might be a responder to Rituximab.

I am 4 1/2 months into Rituximab treatment, and my symptoms are somewhat better.

That is really good news.

If you are taking rituximab to target your 4 autoimmune conditions, then you are not really taking it for ME/CFS, but for autoimmunity. In this case, it may be relevant to look at any clinical trials of rituximab for those autoimmune conditions, to see if rituximab is known to help those.

I don't think most autoimmune conditions have clinical trials for Rituximab yet including POTS, MCAS, calcium channelopathies, etc.

Out of around 22 people who tried rituximab on this forum, only 1 out of that 22 did really well on it, and that patient had several autoimmune conditions. But most of the 22 rituximab patients did not see benefit.

I personally know several people from this forum (excluding myself and Rebecca2z who I think you are referring to) that have had positive responses to Rituximab. Every single one of us was initially given an ME/CFS diagnosis and some still have that diagnosis today (even though my diagnoses changed).