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The Biggest Chronic Fatigue Syndrome Treatment Trial Begins: Fluge/Mella On Rituximab

Doctor’s Fluge and Mella shocked the ME/CFS world with their 2009  case series and the 29-person 2011 study which found that about 2/3rds  of ME/CFS patients had a significant and positive response to the chemotherapy  and autoimmune drug Rituximab. With some patients achieving near miraculous recoveries, the results from Norway had the ME/CFS world buzzing.

rituximab-chronic-fatigue

The big question is – what percentage of ME/CFS patients will respond?

As encouraging as the results were, however, they were but a prelude to the big study ahead – the one that will definitively tell us how effective Rituximab is in this disorder.

As they begin the study, the doctors appear to be both cautious and optimistic. There’s no doubt now that Rituximab doesn’t significantly help some people with ME/CFS – the question is how many and how much – and that’s what this 152 person, multi-center study will tell us

Multi-dimensional in scope, it’s actually four studies in one – some of which are almost as exciting as the trial itself – that  could tell us much about ME/CFS. This very long study started up in the last quarter of last year – a bit later than expected. As  it did I asked the doctors some questions.

(Check  out the study on the ClinicalTrials.gov database).

How is the Rituximab (RituxME) study going? 

The RituxME study has just started recruiting patients. We plan to include 152 patients, in five centers in Norway. There will be 1:1 randomization between rituximab and placebo.

We will give the first two infusions two weeks apart (500 mg/m2, max 1000 mg, or placebo) followed by maintenance infusions 500 mg fixed dose (or placebo), at 3, 6, 9 and 12 months. The placebo solution with saline and some added albumin will look identical to the Rituximab solution. The study will be double-blinded and placebo-controlled.

The follow-up will be for 24 months, and the code for intervention will be revealed after the last included patient has been to 24 months visit and the database is locked.

measuring activity levels - me/cfs

Many measurements will be done – including activity levels.

Patients from 18-65 who have ME/CFS according to Canadian criteria (2003), age 18-65 ME/CFS for at least 2 years up to 15 years can be included.  People with severe, moderate/severe, moderate, mild/moderate and mild ME/CFS may be included.  If they have “mild” ME/CFS they need to have had the disease for at least 5 years. People with very severe ME/CFS (completely bedridden with need for help for all tasks) will not be included.

Self-reported symptom scores will be recorded every second week, and SF-36 questionnaires every third months. Activity levels will be assessed for seven consecutive days using the Sensewear armband at baseline, and repeated at the17-21 month follow-up.

Do you plan to publish the results of the open-phase trial? If not can you say anything about the results? (This was an open label (patients knew what they were taking) study with 29 patients using rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished). This trial continued patients on Rituximab (a maintenance dose) for much longer, in a effort to reduce the relapses seen in some patients after they went off Rituximab.)

We have used the experience from our open-label phase-II study using rituximab maintenance. This study ended in February 2014, but due to all the work with the new study we have not had time to complete the manuscript. However, we are now completing the manuscript, and hope to submit soon.

We included 29 patients in the open-label phase-II study (KTS-2-2010). In this study there was no placebo group, and that will of course be the main criticism of the study. The reason for doing an open-label study was to gain experience on dose-response relationships in order to better design the randomized phase-III study. We also wanted to give patients who had taken the placebo in our first randomized study (Plos One 2011, KTS-1-2008) an opportunity to take part in a study without being randomized again (that was in agreement with the ethical committee approving the KTS-1-2008 study).

One patient had an allergic reaction at the first infusion and did not get further intervention, leaving 28 patients to receive rituximab maintenance treatment. The patients received two infusion with rituximab two weeks apart,  followed by maintenance rituximab infusions after 3, 6, 10 and 15 months (7 patients received further infusions according to an approved amendment in the study).

We will not give details on the results here, even though the study has been presented at some meetings the last year. For now we can state the response rate was quite similar to the first KTS-1-2008 study, and that the response durations seem to be much prolonged (as compared to the Plos One study) when giving rituximab maintenance treatment.

Rituximab-chronic-fatigue

Fluge and Mella’s data indicated that maintenance doses of Rituximab worked: i.e. they largely kept patients from relapsing

To us, the most important issue now is to do a proper phase-III study which will determine if the results of the first trial can be trusted. It is important to understand that our first phase-II study (Plos One, 2011) – the first to evaluate the treatment principle of B-cell depletion in ME/CFS – had several limitations.

We do not know how much selection bias was present in our first two studies. If the putative immunological disease that we have seen is commonly found in the broad groups of ME/CFS patients that fulfill the Canadian criteria, we have a chance to get a significant result in favor of rituximab in the ongoing study.

However, if our selection bias in the first studies is large (i.e. if we selected out patients that are not representative of ME/CFS patients as a whole) the new study might very well turn out negative (i.e. no difference to placebo). Should that happen we would then focus our efforts on figuring out how to select the subgroup that has an   immunological, rituximab-responsive disease.

The Substudies

Blood vessel, exercise and gastrointestinal substudies occurring alongside the major study could tell us much about ME/CFS as well. Some of the substudies are, to my mind, almost as interesting as the Rituximab study itself. I asked Dr. Fluge about them. 

For the RituxME study, we will perform three substudies. (We originally planned to use these in the main study, with some parameters as secondary endpoints, but because all centers could not perform the analyses they were designed as substudies.)

All three substudies will be performed at baseline and repeated at the 17-21 months follow-up, which is the time interval our previous experience suggests that the therapeutic effect of rituximab maintenance to be most evident.

Endothelial Functioning Substudy

Our substudy of endothelial function (Bergen Notodden) in 72 patients will use flow-mediated dilation to test large blood vessel endothelial functioning.  We will also test microvascular endothelial function in Bergin using skin laser-doppler measurements.

blood vessels chronic fatigue

Is a problem in the blood vessels triggering the sympathetic nervous system activation found in ME/CFS?

We believe that endothelial function is important in ME/CFS. Even though many symptoms can be ascribed to the central nervous system we are not convinced that ME/CFS is primarily a central nervous system disorder. We believe the sympathetic nervous activation seen in ME/CFS may be (partly) secondary to an underlying (peripheral) pathology.

It is important to get an understanding of which symptoms that are caused by the primary pathology, and those which may be ascribed to secondary (compensatory) mechanisms.  We are working to elucidate whether endothelial dysfunction, and subsequent inadequate fine-tuned autoregulation of blood flow to meet the demands of tissues, may be an important feature of ME/CFS.

A study from Dundee in 2011 showed endothelial dysfunction to be present in ME/CFS. Our pilot studies in a group of ME/CFS patients suggest it is as well.

In the substudy to RituxME, we ask if we can reproduce the endothelial dysfunction in a larger cohort of ME/CFS patients? Is there a relation between endothelial dysfunction and disease severity? Is there a relation between endothelial function and a later clinical response (in the rituximab group)? In patients that improve after B-cell depletion therapy (Rituximab) is there a relation between improvement in self-reported symptoms or in physical activity levels, and changes in endothelial function?

We have written a manuscript on our thoughts and hypotheses including the relation between immune response, endothelial function, and the possible effector system for symptom maintenance in ME/CFS. However, we still believe that we need more data to underpin out thoughts and have therefore not submitted the paper yet.

[Dysfunction of the endothelial cells lining the blood vessels in the circulatory system has been a subject of interest in ME/CFS since MERUK’s pioneering efforts in the early 2,000’s. These cells  – present everywhere from largest arteries to the small capillaries – control how dilated or narrowed the blood vessels are, affect inflammation, control blood clotting and more.  Each of these factors have been implicated in ME/CFS at one time or the other. In 2012 Newton et al.  reported both small and large blood vessel dysfunction was present in ME/CFS.

The finding last year that  autoantibodies to the adrenergic receptors found on endothelial cells are present in postural orthostatic tachycardia syndrome (POTS) suggested an autoimmune process was knocking out one group of POTS patients. Now Fluge/Mella appear to be proposing that a similar autoimmune process is messing up the blood vessels and producing the sympathetic nervous system activation in ME/CFS. If that’s so Rituximab’s efficacy could lie in its ability to restore proper blood flows (and presumably blood volume) to ME/CFS patients allowing them to exercise, think, digest, etc. as healthy people do.  This is a hypothesis that is pregnant with possibilities.

Fibromyalgia patients should note that Rice has found evidence of small blood vessel dysfunction in the hands that may also be impeding normal blood flows throughout the body. – Cort. ]

 Exercise Substudy

The cardiopulmonary exercise tests for two following days will be performed at baseline and repeated in the 17-21 months follow-up. We will do this substudy in Bergen, Notodden and Oslo, but only for patients with mild and moderate disease (not severe), The total number may be 50, perhaps more.

exercise chronic fatigue syndrome

The ultimate test of Rituximab’s effectiveness – an aerobic exercise test.

We want to see (in a double-blind fashion) if the performance (VO2max, VO2 at anaerobic threshold, workload at max and at anaerobic threshold) of patients who respond to Rituximab will improve on day two of the exercise test.

It may be a disadvantage that we exclude patients with a high symptom burden from this substudy, but we did not want to put patients with moderate/severe or severe ME/CFS through such physical exertion because they may worsen for many following weeks. They will also start the intervention (Rituximab or placebo) three weeks after these tests  – maybe too soon for some moderate/severe or severely ill patients to fully recover.

Gastrointestinal Functioning Substudy

The substudy on gastrointestinal function will only performed in Bergen, and only for patients with GI symptoms resembling functional dyspepsia or irritable bowel disease. Approximately 15-20 patients will be included.

Gastroenterologists in Bergen will evaluate the patients using several self-reported forms, and with a soup meal followed by ultrasound assessment, and also with endoscopy and biopsies from those willing to participate in this (in fact, most of those we have evaluated are willing to do the endoscopy!). The GI studies will be performed at baseline and repeated after 17-21 months.

Genetics Study

Dr’s Fluge and Mella will  also be looking at the genetics of ME/CFS patients and their families. Dr. Fluge wrote

genetics-chronic-fatigue

The list goes on…Fluge and Mella are also looking at genetics

To further elucidate possible clues, we are also working on exom-sequencing of families with many affected individuals among first- and second-degree relatives, sequencing all coding parts of the genome (with flanking introns) both from affected and healthy family members. We test candidate genes with targeted sequencing in all patients included in our studies. We hope to be able to link the genetic and clinical data, to underpin the hypotheses.

An Autoimmune Disorder?

I asked Dr. Fluge why they thought the patients responding to Rituximab may have an autoimmune  disorder?

Why we think this is a variant of an autoimmune disease? First, we have not shown that ME/CFS is an autoimmune disease. However, we believe that in a subgroup of patients an autoimmune pathogenesis involving B-lymphocytes and possible immunoglobulins (autoantibodies) makes sense.

The arguments are as follows:

  • The observed pattern of responses and relapses after rituximab treatment, with a lag time of several/many months from initial and rapid B-cell depletion until start of clinical responses. Such patterns are also seen in established autoimmune diseases after rituximab treatment, such as Wegener’s granulomatosis and rheumatoid arthritis.
  • A high proportion of women with ME/CFS
  • Our studies suggest a high occurrence of autoimmune diseases exists among relatives of ME/CFS patients (could also be a marker for a selected population in our studies?)
  • A moderate, but highly significant risk of B-cell lymphomas in elderly ME/CFS patients, shown in a large case-control study from National Cancer Institute in 2012. To me, this is an important study, showing that patients may have a chronically activated B-cell system.
  • Emerging data from a few other poorly understood diseases (POTS, Chronic Regional Pain Syndrome, CRPS) which have some common characteristics and possibly to some extent may overlap with ME/CFS, in which research groups have detected (functional) autoantibodies.

Long Lag Time Also Suggests Autoimmunity

Epstein-barr chronic fatigue

The different responses Fluge/Mella’s ME/CFS patients and their chronically activated EBV patients have had to Rituximab suggest to them autommunity, not EBV reactivation, is ocurring.

The long lag time from rapid initial B-cell depletion to start of the clinical response (2-8 months) is why we do not think elimination of EBV or CMV is the principle mechanism for symptom relief in our patients. In my work as a lymphoma oncologist, I have treated a few patients with chronic EBV infection, with moderate lymphadenopathy, night sweats and general symptoms for several years, and with no clear clinical benefit from valganciclovir.

In one patient, the B-cells in bone marrow and in lymph nodes were packed with EBV and she had a high EBV titer in her peripheral blood. When given rituximab, her symptoms waned in a few days after start of treatment – very different from what we see when treating ME/CFS patients.

Two Cautionary Notes

Dr. Fluge wanted to make two cautionary notes: 

caution rituximab chronic fatigue

Caution! Rituximab use in severely ill patients is not recommended…

Very severely ill ME/CFS patients – We are also conducting a study (KTS-3-2010), which includes very severely ME/CFS patients. Only four very severely ill ME/CFS patients have been at our hospital, and it is very difficult to give them the care they need in a very busy oncology ward. For these for patients, although rituximab has influenced their disease in a slightly positive manner for two, none of the four could be characterized as responders. We do not encourage treatment of patients with very severe ME/CFS with rituximab outside clinical trials!

In fact, until further scientific data and evidence are available, all patients receiving rituximab for ME/CFS should be treated within clinical trials.

Etanercept - We started a clinical open-label phase-II study on weekly subcutaneous etanercept (a TNF-alpha inhibitor). Only four patients were included, and we decided to stop the trial because two patients had a clear worsening of ME/CFS symptoms, while two were unchanged (no response). Ideally, we should have included additional patients to gain experience for a more solid conclusion; we however decided to stop the trial.

New Open Phase-II Trial

After observing a few pilot patients for one year, we have decided to begin another open-label phase-II study in Spring 2015 on another immunomodulatory drug, in three sets of ME/CFS patients:  ME/CFS patients who have not treated before with rituximab, in nonresponders to rituximab treatment, and in patients with a clear response to rituximab but with evidence of gradual relapse the last year. This study has been approved by the Ethical Committee, and will occur at a single center study in Bergen (Haukeland University Hospital)

Conclusion

In conclusion, we hope our efforts will help to increase our knowledge of ME/CFS, and that the results of the new randomized study will provide some important answers to aid further research, either by us or others in the research community. We need a better understanding of the disease with regards the genetic predisposition, the immune disturbances and the endothelial dysfunction present and the effector systems for symptom maintenance in order to develop rational treatments for this devastating and misunderstood disease.

 

 

 

 

 

 

 

 

 

 

 

 

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65 Comments

  • Nadja Kiiskinen

    January 20, 2015 at 8:59 pm - Reply

    Thank you for the comprehensive explanation on the Rituximab study. There’s just one thing I don’t really understand. How can saline infusions be used as placebo in the study? As we all know, many ME/CFS patients tend to suffer from dehydration and when this condition gets worse receiving IV saline helps a great deal. Wouldn’t this real physiological effect not mess up the placebo controls, who should have no effect from the infusion, other than an actual placebo effect?

    • Cort Johnson

      January 20, 2015 at 9:58 pm - Reply

      Good question! The big difference between saline and Rituximab is that salines effects last only a short time while Rituximab’s effects can take a long time to work. By the time they assess symptoms the effects of the saline will be long gone..

      • Nadja Kiiskinen

        January 21, 2015 at 8:24 am - Reply

        Thanks Cort, of course. I should have thought about that!

      • Olav Jensen

        January 22, 2015 at 10:02 am - Reply

        Remember that there is just as much saline in RTX as there is in the placebo saline mix. Even though someone would feel better for a day or two it will not matter as it would lead to the same improvement for both groups.

        • Cort Johnson

          January 22, 2015 at 4:44 pm - Reply

          Thanks

    • Lauren Stiles

      January 26, 2015 at 8:52 pm - Reply

      Hi Cort,

      Great article!

      I had the same question, but not just about saline. Have they determined how long the albumin blood volume boost will last? It likely lasts longer than saline. Since it’s a large protein, it attracts water into the vascular space. The blood volume benefit could lead to symptom benefits in patients who have orthostatic intolerance as part of their CFS. I doubt it would be a 3 month benefit, but it’s something they should account for in their manuscript because someone will point it out. Hopefully they are measuring some other blood markers of inflammation and autoimmunity.

      In response to the person who raised concerns about their intent to identify a subpopulation that Rituxan may work in if the overall study doesn’t show statistical significance, this is not uncommon in pharmaceutical research. CFS is a very heterogeneous condition. If it works for a subset of patients in the study, but not enough to show overall statistical significance, it’s natural to ask, why did it help these patients? Do they have anything in common or anything that distinguishes them from the patients it didn’t work for? Or was this person misdiagnosed with CFS when they had an autoimmune disease known to be responsive to Rituxan? In my case, as you know, that would be a resounding yes.

      Looking forward to seeing the results from this study. Good luck to all involved!

      Sincerely,
      Lauren

  • John Buettner

    January 20, 2015 at 10:25 pm - Reply

    Did you intend to write this statement this way (doesn’t vs. does) and “how much”. I apologize, my ME brain is having a difficult time with it.

    “There’s no doubt now that Rituximab doesn’t significantly help some people with ME/CFS – the question is how many and how much – and that’s what this 152 person, multi-center study will tell us – See more at: http://simmaronresearch.com/2015/01/chronic-fatigue-syndrome-rituximab-fluge-mella/#sthash.yH9Ta9Fs.dpufhttp://simmaronresearch.com/2015/01/chronic-fatigue-syndrome-rituximab-fluge-mella/

    • Cort Johnson

      January 21, 2015 at 4:47 pm - Reply

      Yes – I think we know that Rituximab helps some people with ME/CFS – the question what percentage of the population does it help and how much. Only a big study like this can tell us that.

  • Thomas

    January 21, 2015 at 3:01 am - Reply

    Excellent write-up Cort. This is very exciting and hopefully will lead to something in the way of a standardized treatment for an identifiable subset group. Question: How are they defining or categorizing “mild”, “mild/moderate”, “moderate”, “moderate/severe” etc patients? Is it based on physical or cognitive (or both) functionality? One person’s “severe” is another person’s good day…

    • Cort Johnson

      January 21, 2015 at 4:47 pm - Reply

      Good question – I don’t know the answer to that. It may be in the Clinical trials website.

      • Olav Jensen

        January 22, 2015 at 10:06 am - Reply

        Each person gets a level of functioning in per cent before the study. I think that score is based on questionnaires and discussion between a doctor and the patient. I think the score is based on the average of the last 3 months.

        I think theres more info here: https://clinicaltrials.gov/ct2/show/NCT02229942

  • Preben Aavitsland

    January 21, 2015 at 8:58 am - Reply

    I took note of the following statement by Dr Fluge and Mella:

    “…the new study might very well turn out negative (i.e. no difference to placebo). Should that happen we would then focus our efforts on figuring out how to select the subgroup that has an immunological, rituximab-responsive disease.”

    I interpret this to mean the if the treatment response is the same in the placebo group (which has received saline) as in the rituximab group, the two doctors will in the future try to identify a subgroup of ME/CFS patients which is more likely to respond to rituximab. It seems that with that outcome of the study, they will still be convinced that rituximab works, but probably only in a subgroup.

    Excuse me if I have misunderstood, but this seems strange. If the treatment response turns out to be the same in the two groups, this is good evidence for the lack of efficacy of rituximab. It is then hard to understand why they would want to proceed with studies of rituximab, and not saline which is just as efficacious, much less expensive and without major side effects. Following their thinking, it would be equally justified to state:

    “…the new study might very well turn out negative (i.e. no difference to placebo). Should that happen we would then focus our efforts on figuring out how to select the subgroup that has an immunological, SALINE-responsive disease.”

    This leads me to the obvious question: What will it really take for the two doctors to reject their hypothesis that rituximab is efficacious against ME/CFS if the results of a randomised double-blind placebo-controlled study does not?

    • Cort Johnson

      January 21, 2015 at 4:46 pm - Reply

      To me this is a not unlikely possibility given the many different types of ME/CFS that may be present and I would guess that statement could apply to any large treatment trial. It may be that the group of ME/CFS patients that respond to Rituximab won’t be numerous enough for the entire trial to have a significant result. That group, however, could have a very positive result. They would then focus in on that group. I think it’s pretty clear that some people with ME/CFS do respond to Rituximab very well – the question are – how many of them do – and is it a big enough group to recommend Rituximab be tried by the entire ME/CFS population or should it be recommended for a part of it..

      • Preben Aavitsland

        January 23, 2015 at 9:45 am - Reply

        This study is to designed to measure how much fatigue can be reduced in CSF/ME patients with rituximab compared to placebo (saline). 76 patients will be randomised to receive rituximab and 76 to placebo. If there is no difference in outcome, then the conclusion is that rituximab does not reduce fatigue in CSF/ME. That is the logic of the randomised controlled trial.

        The size of the study has presumably been decided with the intention of comparing the whole groups, so probably there will be enough statistical power only for this comparison. However, one could imagine that rituximab works only in a subset of patients, such as women, patients aged between 20 and 44, patients with a certain pre-trial finding in the blood or any other group. This can be tested by dividing the patients in such groups and comparing rituximab versus placebo in each of those groups. Such subset analysis, however, needs to be pre-specified in the protocol so that one avoids bias when groups are decided after the results are in. The protocol for Fluge & Mella’s study has not specified any subset analyses. Thus, results from such analyses will hardly be valid and needs to be confirmed in one or more new randomised trials.

        To illustrate with an example: Let’s say that 30 patients on rituximab and 30 patients on saline have a good response. Then the study is negative, rituximab does not work against CSF/ME. However, the researchers then find that if they compare only patients that had «severe CSF/ME», they find that 8 of 10 patients on rituximab and 2 of 9 patients on placebo had a response. Given that this comparison was decided after the study results were in, it is only an indication of efficacy. Then a new randomised trial among only «severe CSF/ME» patients needs to be performed to find out whether rituximab really works against «severe CSF/ME».

        I think it is very important that both the researchers, who think they are on track of something big, and the hopeful patients and observers, still entertain the idea that this study may simply turn out to show that rituximab does not work against CSF/ME.

    • Olav Jensen

      January 22, 2015 at 10:10 am - Reply

      No patient treated with RTX have had effect before weeks after the infusion. After a few weeks there is no saline left in the body. It is no way saline could produce the same results that RTX do.

      • Preben Aavitsland

        January 23, 2015 at 9:46 am - Reply

        I guess this is what the study is designed to find out.

        • Olav Jensen

          January 23, 2015 at 2:57 pm - Reply

          No, the study has nothing to do with saline. Did you know that the amount of saline in a infusion equals a bag of chips? (quote Jonathan Edwards).

          No one believes saline has anything to do with. Saline could help the poorest patients maybe for a day or two. Thats it. Remember that infusions are given every 3 months.

          • Preben Aavitsland

            January 26, 2015 at 10:30 am -

            As of now, we do not know whether rituximab is an efficacious treatment of ME/CFS. That is why this study is being done. In the interview, Fluge & Mella mentions one possible (or even likely) outcome of the trial; that there is no difference between the rituximab and the placebo (saline) group. My point is that in that situation, rituximab and saline have produced the same results: neither of them works, or they both work just as well. Then it’s time to forget about rituximab and move on. In that situation it does not make sense to focus more on rituximab than saline.

  • Darach Conneely

    January 21, 2015 at 10:34 am - Reply

    Wouldn’t side effects (or the lack of them) give the game away for people on a placebo? Of course there are probably ethical issues deliberately causing side effect symptoms…

    • Preben Aavitsland

      January 23, 2015 at 9:50 am - Reply

      This is clearly an important. issue. The blinding of patients, and thus the validity of the whole study, is threatened if patients can guess which group they are in, for instance because they experience side effects. This may be especially important with such a powerful drug as rituximab. I think it would be prudent if the researchers at every assessment point with patients ask them which group they BELIEVE they are in. Then one could get an indication, when the allocation code is broken at the end of the study, whether patients have guessed correctly what group they were in, and whether this influenced their response to treatment. I do not know whether this is planned.

  • Tory

    January 21, 2015 at 12:40 pm - Reply

    Thanks Cort as always. Is there any way I can find out why the patients used in the Phase 3 trial have to have had the illness less than 15 years? I am worried that even if it gets approved, long term suffers may not get treatment. thanks

    • Cort Johnson

      January 21, 2015 at 4:40 pm - Reply

      I don’t know. My guess is that they’re worried that either the disorder has changed a bit over time or they’re simply trying to exclude people who have developed other conditions over the years….I would be surprised, though, if a drug approval would focus on disease duration – hopefully not!

    • Olav Jensen

      January 22, 2015 at 10:11 am - Reply

      Hey, Tory. From Clinical Trials:

      “Duration of CFS/ME disease 2-15 years. For patients with mild CFS/ME duration of disease must be 5-15 years”.

      https://clinicaltrials.gov/ct2/show/NCT02229942

  • The Walking Dead

    January 21, 2015 at 3:20 pm - Reply

    I think that most iv medications are like 50-250 ml, so it probably will be minimal amounts anyway. I so wish that these studies went faster, but am excited that there is actually a drug being tested. Did I read that they are doing another trial with an Immunity drug? Ampligen?

    • Cort Johnson

      January 21, 2015 at 4:36 pm - Reply

      They are soon beginning another trial of an immune drug (not stated) and they trialed Etanercept, I think it was, in some people who did not respond to Rituximab – if memory serves.

  • L

    January 21, 2015 at 6:28 pm - Reply

    “There’s no doubt now that Rituximab doesn’t significantly help some people with ME/CFS ”

    Is’nt this a typo? It does siginficantly help some people with ME/CFS?

  • Victoria

    January 22, 2015 at 1:22 am - Reply

    Why do these researchers say, “First, we have not shown that ME/CFS is an autoimmune disease. However, we believe that in a subgroup of patients an autoimmune pathogenesis involving B-lymphocytes and possible immunoglobulins (autoantibodies) makes sense”? Don’t they understand that this is an autoimmune disease and the work was fully replicated upon publication by Dr. Hokama years ago when he was funded by the National CFIDS Foundation? Shouldn’t they already know of the science of this illness that already exists?

    • Cort Johnson

      January 22, 2015 at 4:54 pm - Reply

      Hokama’s results are certainly interesting – http://www.ncbi.nlm.nih.gov/pubmed/19623655 but they need to be replicated and validated. Unfortunately nobody other than Hokama has done that yet. Several groups have been looking for autoantibodies – thus far not successfully. Hopefully someone will replicate Hokama’s results. It may be necessary to remove the autoantibodies and show that the illness goes away or lessens significantly as well.

      Even a successful Rituximab trial might not mean ME/CFS is an autoimmmune disease – although I imagine that it would point strongly towards that – because Rituximab, a chemotherapy and autoimmune treatment, can affect the body in several ways.

  • mark kent

    January 22, 2015 at 6:40 am - Reply

    having a lot lot trouble getting your newsletter by e.mail. can you help

    i have m.e,

    mark

    • Cort Johnson

      February 3, 2015 at 7:01 pm - Reply

      I signed you up Mark – Be sure to look in your spam folder first.

  • Victoria

    January 22, 2015 at 5:14 pm - Reply

    Dr. Hokama never published without first having the work replicated. That’s a requirement of the journal he would consistantly publish in, Cort. And the includes all his work on this illlness including the anesthesia protocol.

    • Cort Johnson

      January 22, 2015 at 5:33 pm - Reply

      I was referring replication of his work by an outside researcher – that’s the critical next step. I like what he did – I hope others will try to validate it. :)

  • Victoria

    January 22, 2015 at 9:05 pm - Reply

    I really don’t think you can find an “outside” researcher any better than the Journal of Clinical Laboratory Analysis who does the replication from each article submitted in their own laboratory, Cort. Dr. Hokama was also an expert consultant to every agency of our government.

  • Dawn

    February 2, 2015 at 2:04 am - Reply

    I wish they would work on trialling LDN to the extent it could be licensed and tried by all CFS/ME sufferers everywhere and get it known but those who have no idea it exists.

  • joe bonavita

    February 25, 2015 at 2:19 pm - Reply

    thank you

  • Lindsey

    February 26, 2015 at 10:33 pm - Reply

    Can I volunteer for this trial? I live in the USA.

  • Allen

    February 27, 2015 at 12:32 am - Reply

    I am a 73 year old male (2015). What about those of us who are older than 65? I have had CFS since 1997. It has gotten a bit more moderate since I retired. Moderate CFS is an everyday condition for me. It is very limiting. I wonder if I will ever get better before the end of my life span. I can easily go into fatigue for hours. Some days are better than others. I keep hoping for some kind of healing like the rest of us suffers. I hope for good results from Rituximab but I know that it is expensive.
    Allen

  • denise

    March 1, 2015 at 1:32 pm - Reply

    Hi I have fibromyalgea an looking into polymyalgea. Iv suffered with this for years but doctors seem confused about me. Iv got terminal cancer an iv just finished rituxamab a for 2.5 years an iv felt worse an worse. Can’t wait for my body to recover from cancer treatment. I’m getting worse with pain an fatigue an I’m wondering whether iv got cos or me.

  • denise

    March 1, 2015 at 1:33 pm - Reply

    Cfs or me meet to say

  • Joolz

    May 7, 2015 at 8:31 am - Reply

    Cort,
    AFAIK Rituximab is not a chemotherapy drug. Would you be able to verify this and maybe correct your text? It might scare people unnecessarily.

    • Cort Johnson

      May 10, 2015 at 11:35 pm - Reply

      Actually Rituximab is a lot of things – among them a chemotherapy drug. It was first used for chemotherapy and it was during its use as a chemotherapeutic agent that Fluge and Mella first discovered its efficacy in ME/CFS. (They had ME/CFS patients with cancer whose ME/CFS symptoms lifted as a result of Rituximab).

      Many drugs now are used for multiple (and sometimes surprising!) purposes.

      http://chemocare.com/chemotherapy/drug-info/Rituximab.aspx

      • Joolz

        May 16, 2015 at 10:16 am - Reply

        Has there actually ever a been a lymphoma & CFS patient who has received Rituximab? I’m not so sure about that, at least no such patient has been mentioned in the research papers if I remember correctly? The patient who made Fluge & Mella think that B cell depletion could have an effect on CFS received treatment with the MIME protocol (including Methotrexate) and even Cyclophosphamide later on (as part of the BEACOPP protocol) – as described in the 2009 PLoS ONE paper. But she never received Rituximab, as far as I know. Nevertheless, the discovery led to the first Rituximab trial for CFS. Luckily!

        Of course Rituximab is a cancer drug, but that doesn’t make it chemotherapy. Both the Norwegian health authorities and the American Cancer Society don’t list Rituximab under chemotherapeutic drugs, but under “monoclonal antibodies for cancer treatment” and “immunotherapy” respectively (see http://www.cancer.org/cancer/non-hodgkinlymphoma/detailedguide/non-hodgkin-lymphoma-treating-immunotherapy). There is a lot of contradictory information on the web, some (few) websites even state that treatment with Rituximab will lead to serious fertility issues while many experts say it’s unproblematic.

        This being said – otherwise your article is absolutely brilliant, I’ve sent the link to many people over the past few months. It is currently the most comprehensive article about the ongoing trial that is out there on the internet. Thanks so much!! :-)

      • Joolz

        May 16, 2015 at 10:22 am - Reply

        P.S. Shouldn’t the Roche guys know best?
        http://www.roche.com/media/store/releases/med-cor-2011-01-31.htm
        “Rituxan PLUS chemotherapy”. All the way.

        • Diana Saba

          May 16, 2015 at 1:57 pm - Reply

          Polycythemia in remission using hemp oil cbd rsho with no side affects!

        • Diana Saba

          May 16, 2015 at 5:54 pm - Reply

          No mention that Rituximab wipes out the entire immune system!

          • Dawn

            December 3, 2015 at 9:52 am -

            It does?

  • Allen Fugelseth

    May 11, 2015 at 3:56 am - Reply

    I wish the study great success. I believe Rituximab is also very expensive. Keep us posted.

  • Aidan Walsh

    May 24, 2015 at 7:39 am - Reply

    95% of ‘labels’ CFS, Fibro, Lyme have ‘undiagnosed’ Ehlers Danlos Syndrome a genetic born mutation of Collagen deficiency…Hypermobility Unit EDS team London, United Kingdome high Salt diets fully reccomended in these patients…Stop being labeled fatigue is also a symptom of EDS as many as 675,000 patients misdiagnosed every year with EDS ‘label’ illnesses…Rituximab has no merit at all in EDS whatsoever…

  • Brahms

    June 13, 2015 at 10:26 pm - Reply

    Its pity that the researchers doesn’t even categorize the CFS patients based on the initial onset cause; virus, mold exposure. The onset of CFS caused by chronic infection in maxillofacial region and malaria clearly shows that there are multiple pathophysiology of this illness.

    My guess is Rituximab would probably help on CFS patients with onset of mold exposure, but of course will make others worse.

  • AllMov

    June 26, 2015 at 4:56 pm - Reply

    Does anyone know if people can still apply for this program?

  • Peterson Oleg

    July 4, 2015 at 11:21 am - Reply

    “It’s been hard fighting Cancer…. sometimes tears roll down my face knowing how terrifying it was i fought cancer for horrible years until i came across the Phoenix Tears cannabis oil curing cancer in November 12 2012. I was able to obtain some medical marijuana oil through Dr Palmer (Rick Simpson Oil) from it and applies regularly the recommended dosage by mid March 2013. I had a cancer reassessment which consisted of an MRI with the art Tesla 3 MRI machine. Results States – NO SIGN OF CANCER! CANCER FREE I was Marveled,it was a Miracle oil. I kept on believing on God and with the solemn advise and care from Dr Palmer help me fight through. My warm gratitud to Dr Palmer and RSO. Letting every one know that till date i’m cancer free. You can contact him directly on email:drjacquelinepalmerhealthcare@live.com were i purchase from.Thank you;

    • Dawn

      December 3, 2015 at 9:55 am - Reply

      So happy for you, and God bless x

  • San

    July 13, 2015 at 2:14 am - Reply

    My amazing Sister wasa Bio Chemist, taught at Oxford UK. Went from Australia to do this. Her IQ was unmeasurable. She discovered numerous things about diseases. I have no qualifications in medicine to even assume anything. I just hope it works because I am scared and tired.

    San

  • Sandra Schneider

    July 22, 2015 at 12:55 pm - Reply

    I have had both progressive chronic fatigue and diagnosis of IBS since I was 12. At the age of 20, I was diagnosed with MS, which turned progressive at 41 Diagnosed with ulcerative colitis at 35. Am now 50 and am a paraplegic. Neurologist wants me on Rituxan, but it can cause ulcerative colitis or worsen existing ulcerative colitis, so I am resisting, MS patients have endothelial dysfunction, reduced brain perfusion and Chronic Cerebro-Spinal venus insufficiency- I believe CFS patients have all these as well. There is a relationship between the two.

  • Robin Celius

    December 7, 2015 at 3:23 am - Reply

    You just have to excuse Preben Aavitsland, he know for his strange attitude in Norway, with few friends. So just excuse him. I hink his childhood was not very good.

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