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Fluge & Mella’s pre-trial study highlights life-changing potential of rituximab

Professor Olav Mella (left) and Dr Oystein Fluge

Professor Olav Mella (left) and Dr Oystein Fluge

Sasha gives the background and Simon gives the interpretation of the latest study from Haukeland, published today…

It’s out! Dr Øystein Fluge and Professor Olav Mella have published their new study in PLoS ONE. And though the study was not a blinded, placebo-controlled trial, the results are further evidence that rituximab is beneficial in some ME/CFS patients, and potentially life-changing for a substantial minority. The findings also give important new insights into the optimum dosing schedule to maintain those benefits in the long run.

We all know the story that led up to this study: cancer specialists Fluge and Mella treated an ME patient for cancer with the immune-system drug rituximab. The patient’s ME symptoms improved markedly. The effect was confirmed in two additional patients and so Fluge and Mella set up a 30-patient, double-blind, randomised, placebo-controlled trial of rituximab in ME/CFS.

The results, when published in October 2011, were striking: although there were no differences between the two groups at the pre-defined endpoint of three months, 67% of patients receiving rituximab had moderate to major improvement during follow-up, compared to only 13% of placebo patients (p=0.003).

And not only that: there was a tell-tale delay of several months in the improvement. This time-lag suggested that it was rituximab’s B-cell destroying capabilities that were responsible. That, in turn suggested that rituximab was switching off an autoimmune process (some B-cells produce antibodies that attack the body’s own tissues).

The findings took the ME/CFS world by storm and started a sea-change in attitudes to the disease. The Norwegian Health Directorate apologised for how ME patients had been treated. Researchers and clinicians outside the ME/CFS community began to focus on autoimmunity as a hypothesis rather than psychology. Fundraising efforts for more rituximab trials started up all over the world, including MEandYou’s successful crowdfund in Norway and the ongoing fundraising for Invest in ME’s UK rituximab trial and B-cell studies.

Meanwhile, Fluge and Mella set up a small study – this newly published study – to inform the design of a larger trial. In their original placebo-controlled study, most of the patients who benefited from rituximab had a transient response and then relapsed. Fluge and Mella needed to investigate the best dosing schedule, and other aspects of rituximab’s use.

The large multi-centre rituximab trial is now underway in Norway, led by Fluge and Mella and funded by MEandYou, the Norwegian government, and others. It’s another double-blind, placebo-controlled, randomised study and has 152 patients, who will be followed up for 24 months post-treatment: results won’t be available until 2017 or 2018.

Meanwhile, this new study has much to tell us. Over to Simon, to take a look at it.

Haukeland University Hospital, the site of the initial pilot and ongoing rituximab studies

Haukeland University Hospital, the site of the initial pilot and ongoing rituximab studies

The science

Thanks, Sasha…

In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses.

Dr Fluge, Professor Mella and colleagues

The study findings are very encouraging.  64% of patients showed a clinical response, similar to the 67% seen in the original trial. Half were classed as major responders. And at the end of the study a quarter of patients were doing exceptionally well: in my opinion the data suggests they were close to recovery.

Some limitations

This was an ‘open label’ trial, in which all patients and medical staff knew the patients were on rituximab, and there was no control group. Some of the improvements recorded might have been down to placebo response, and/or ‘response bias’, in which patients subconsciously overstate their improvements (all outcomes were self-reported). Some patients may have simply improved naturally, regardless of the rituximab treatment.

Most of these patients had featured in the earlier trials: nine from the trial placebo group, nine from the rituximab group and one pilot patient.

Only ten patients were new, so response rates for this and the previous trial are largely based on a small and highly overlapping group of patients. The response rates seen here might not be replicated in a wider group of patients (leaving aside that this and the earlier trial are small studies).

The only way to remove such problems is to conduct a randomised, double-blind, placebo-controlled trial – which is exactly what Fluge and Mella have organised, with a large multi-centre trial under way in Norway. This latest study was set up to help plan that large trial.

A word of caution

I want to point out the limitations of this study – limitations the authors note in their paper – before I enthuse about how good some of these results seem to me.

The goal was to help establish the therapeutic effect of repeated maintenance doses of rituximab on long-term response, and to help guide the design of the large clinical trial now under way in Norway. However, it wasn’t a gold-standard placebo-controlled randomised trial, and wasn’t meant to be, and that means we have to be careful about interpreting the results.

First, the study was unblinded – patients and clinicians knew they were dealing with a drug with great potential. That can artificially boost results, to a modest degree.

Second, there was no control group (ideally a placebo group to see how patients would have responded to a dummy treatment), and some of the observed gains might have occurred even if no drug had been given.

And finally, 20 out of the 29 patients had been in previous rituximab studies.

More details are in the box.

How the study worked

All patients met both Fukuda and Canadian consensus criteria. The average age of patients was 40, and 69% were women. They’d been ill for an average of nine years, and 20 (two-thirds) were at least housebound, including three who were mainly bedbound.

The main measure of success was change in fatigue from baseline (see box below). For clinical response, patients needed six consecutive weeks of improvement, and to average at least a slight-to-moderate improvement, including at least one week better than moderate (so at least one of the fatigue symptoms had to be rated as a major improvement). This could be at any time during the 36 months of the study.

Patients received an initial two doses of rituximab two weeks apart and then maintenance infusions at 3, 6, 10 and 15 months. They were followed up for a total 36 months.

How fatigue was measured

Patients scored four different aspects of fatigue (fatigue, malaise after exertion, need for rest, and lack of daily functioning) on a scale of 0 to 6. The overall fatigue score was the average of the scores for the four different aspects.

On the 0-6 scale, 3 was the midpoint, meaning there was no difference from baseline. 4, 5 and 6 corresponded to slight, moderate and major improvement from baseline, respectively. 2, 1 and 0 meant slight, moderate and major worsening, respectively.

This was the same scale as used in the small placebo-controlled trial. Although this scale hasn’t been formally validated, the authors also used the validated and widely used SF-36 health scale, and the SF-36 results told the same story as the fatigue scale.

Results

“Eleven of the 18 responders were still in remission three years after beginning the treatment, and some have now had no symptoms for five years,” says Fluge. “Suddenly, their limbs started to work again and their hands were no longer cold or sweaty.” (From an interview in the New Scientist)

Of the 28 patients who received any maintenance doses, 18 (64%) showed a clinical response, similar to the 67% seen in the initial trial. 14 were classed as major responders and four as ‘moderate responders’.

Thus, half of the patients showed a ‘major’ response, with an average response period of 105 weeks (out of 156 weeks in the study). Typically, patients didn’t start improving until 23 weeks after the first dose of rituximab.

Peak response, and relapse for some

The results for patients overall peaked at 20 to 24 months, which was 5 to 9 months after most patients had had their final dose. (Some patients who were responding slowly received more, but these additional doses didn’t seem to make much difference.)

During this peak response time, the average SF-36 scores for major responders matched average population scores (though some were well below average, at levels typically seen in people who have long-term illness). That’s a big improvement from baseline when the scores showed they were all well and truly sick.

However, some patients declined after this peak period, including four major responders who, after doing extremely well, relapsed severely – almost back to baseline levels.

Even so, nine out of 14 major responders (32% of patients) were still showing a clinical response, of various levels, at the end of the study. Including moderate responders, eleven were still in response at the end of the study, showing that repeated rituximab dosing had given a sustained response, right to the end of the study for some.

Rituximab in action: binds to CD20 protein on the B-cell surface, triggering cell death. Credit: NIAID

Rituximab in action: binds to CD20 protein on the B-cell surface, triggering cell death. Credit: NIAID

Mega-responders?

However, for me, the big story of this study is the substantial group who did exceptionally well, though I should stress this is my interpretation of the data in the paper rather than anything the authors have claimed. There is a wealth of data in the paper, down to the level of individual patients. Seven patients – a quarter of those who had maintenance rituximab doses – showed a response that looks close to recovery at the end of the trial, that is, at 32 to 36 months, which is the final data point on the graph of outcomes. Fatigue, SF-36 Physical Function and self-rated daily functioning scores all look very impressive:

  • Seven patients reported the maximum possible fatigue improvement from baseline, that is, major improvement in all four fatigue symptoms. One patient was actually just shy of the maximum, scoring approximately 5.9 out of 6.0 (Fig 2A).
  • Seven had an SF-36 Physical Function score of 85 or more, which is equal to or better than the population average (Fig 5A).
  • Seven had function levels of 80% or higher (someone at 80%-90% is defined as having “slight restrictions in physical or social functioning, who may perform all activities almost as a completely healthy person, but at a reduced pace or duration”), with two scoring 100% (Fig 6B).

All of the patients in the study started with low scores in each of these three areas, so those highs represent huge progress. There is no guarantee that the same seven patients have top scores in each of those three areas, but it seems very plausible.

While the placebo effect and response-bias may occur, they are relatively modest effects. And with ME/CFS, natural recovery rates are low. So these ‘mega-responder’ results strike me as very impressive, and important. Such life-changing improvements are not a common feature of ME/CFS clinical trials.

In the paper, the authors say:

“One pilot patient is still in complete response with no ME/CFS symptoms even after vigorous exercise, five years after the first, and 3 ½ years after the last rituximab infusion”.

“Some have now had no symptoms for five years,” added Fluge, talking to the New Scientist, which also quoted Nancy Klimas:

“I am very intrigued by the rituximab story,” says Nancy Klimas, an authority on CFS at Nova Southeastern University in Fort Lauderdale, Florida. “It’s particularly exciting when people seem to have experienced very long periods of remission, and even speak of recovery,” she says.

Safety

“There was no unexpected toxicity.”

Dr Fluge, Professor Mella and colleagues

Side-effects were as follows. One patient had an allergic reaction to the initial rituximab dose and took no further part in the trial, leaving 28 patients who passed the ‘induction’ phase. A second had an allergic reaction at the three-month infusion and received no further rituximab doses.

Two patients had an episode of uncomplicated late-onset neutropenia, with recovery after five days. (‘Neutropenia’ means low levels of neutrophils, which are first-response immune cells that are in the front line of the body’s immune response. Late-onset neutropenia is a known side-effect of rituximab treatment: 9% of patients on rituximab got it in one study, but neutrophil levels normally recover.)

Eight patients experienced one or more transient ME/CFS symptom flares after rituximab infusions. One patient developed breast cancer but this was not judged to be related to rituximab.

As Fluge and Mella state:

“Rituximab maintenance treatment is generally considered safe [the authors cite several studies where rituximab has been judged safe]. However, even if severe adverse effects are rare, they may occur and include defects in immune reconstitution, and reactivation of chronic viral infections such as hepatitis.”

Safety for ME/CFS will be assessed further in the ongoing large clinical trial. Monitoring of rituximab in other illnesses indicate it is generally safe, but not without some risk.

How does this compare with the PACE Trial?

Just to put them in some sort of context, it’s worth making a rough comparison (given available data) with the PACE Trial, whose cognitive behavioural therapy (CBT) and graded exercise therapy (GET) are often presented as the best treatments currently available to ME/CFS patients.

Obviously, PACE was a randomised trial, was very large, and had a control group – but there was no placebo group and the study was ‘unblinded’ like this one: that is, patients knew if they were in an active therapy group.

The PACE Trial authors claimed a 22% ‘recovery’ rate for both CBT and GET (compared with 8% for controls), but the recovery rate was built on the primary outcomes of fatigue and function, including an SF-36 Physical Function score of just 60, compared with the 85 I used above. These recovery criteria have been criticised as too weak, both by patients and at least one proponent of CBT.

On this basis, the new rituximab results look very good compared with PACE. We will, of course, have to wait until the full randomised controlled rituximab trial that is under way in Norway is complete before a proper comparison is possible. But in the meantime I think these results are very promising indeed.

Do not try this at home!

These results are promising but please bear in mind the authors’ caution: “We do not encourage the use of rituximab for ME/CFS outside of approved clinical trials, and this is especially important for the group with very severe disease.”

They also reported trying rituximab on four very severely affected patients, with disappointing results.

Evidence of Autoimmunithy

The authors finish up by pointing out that their new results are further evidence that a subgroup of ME/CFS patients have an autoimmune disease. Rituximab is a proven treatment for several autoimmune diseases. It destroys B-cells, wiping out the supply of autoantibodies. Antibodies are produced in bulk by plasma cells (created from B-cells). These are not affected by rituximab and so continue to produce antibodies for several months before dying off. That could explain the pronounced time-lag seen in the clinical responses: it’s not until plasma cells die off and are not replaced (because B-cells have been wiped out) that autoantibodies decline and symptoms improve.

However, say the authors, other mechanisms than autoimmunity may explain the observed clinical effects of B-cell depletion on ME/CFS symptom maintenance. Rituximab influences other types of immune function, including T-cell functioning.

Winning over sceptics?

These impressive new results for rituximab are already having an impact. Professor Sir Simon Wessely, a critic of the original rituximab trial, is impressed by the latest findings: “There is now a strong case to be made for a larger trial”, he told the New Scientist. Happily, just such a trial is in progress.

Disclaimer: my section of the blog was put together in a hurry. The paper is huge and while I think I’ve given a fair (though by no means comprehensive) report of the study there may be errors. If so, please let me know.

And back to Sasha…

An opportunity!

This story may well hit the news and if it does, we should hijack the media with our own messages: that ME/CFS is a serious, organic disease and that people should donate to the biomedical research charities (and in this instance, it would be particularly appropriate to mention Invest in ME’s UK rituximab trial fund). This is a great opportunity to educate, win hearts and minds, and grow our donor base. This recent article explains how.

And of course, we too can donate, including via JustGiving. Let’s get to it!

Further resources

Compilation of Phoenix Rising tweets on Dr Fluge and Professor Mella’s rituximab presentation at the 2015 Invest in ME conference

Dr Ros Vallings’s summary of the 2015 Invest in ME conference, including an account of Dr Fluge and Professor Mella’s rituximab presentation

Simon McGrath blogs about ME/CFS research
[appeal]?

{ 131 comments… add one }

  • Sasha August 7, 2015, 10:43 pm

    This is from November 2011 on the MEA website – I don't know if there's more recent guidance.

    MEA

    Will my doctor be able to prescribe rituximab?

    No. The whole process of drug discovery and clinical trial assessment is a long and costly process – especially when it involves a drug such as rituximab which has the potential to cause very serious short term and longer term side effects.

    In simple terms the UK drug regulator – the Medicines and Healthcare Products Regulatory Authority (MHRA) – will want to see the results of phase 2 and phase 3 clinical trials, and then be sure that the drug is both effective and safe to use in ME/CFS, before it can be granted a product license.

    Phase 2 trials test a treatment in patients to find out how well it works as well as its safety.

    Phase 3 trials compare the treatment in much larger numbers, gather more information on how it works, and examine safety in more detail.
    This a process that takes years rather than months.

    Once this data is ready the MHRA in the UK, or the European Medicines Agency for the whole of the EU, can consider whether it can be given a product license for use in a specific condition.

    This whole thing of off-label use confuses me. My GP has for years prescribed me, on the NHS, a drug for sleep which I now find is an off-label use for it: and yet I can't get rtx on the NHS for my ME.

    Is that because the risks are higher, and/or the costs?

  • Sallyagerharris August 7, 2015, 10:47 pm

    Having read and I appreciate it is early days that so far rituxamib seems to work better with younger patients with ME it is helpful and hopeful to know that there may be possibilities to potentially be able to get proper access to treatment.

    The hope of course is via the NHS for everyone but time and money are huge factors in getting any newly approved drug let alone with the challenging history ME has and continues to have.

    One of the many sad things about ME for me is not having capability to raise awareness more, raise funding … I do a tiny bit with the energy I have but do "envy" people who can run marathons or who have normal energy to campaign. This illness seems particularly harsh with the physical, mental and emotional restrictions for so many of us.

    I would rather have a shorter but more quality of life but with some capability "to do" (i.e. To be well enough to give rather than taking and particularly do stuff with ME) but do realise that we need to see what happens as the Norweigan trials continue.

    Sorry bit of a vent

  • Scarecrow August 7, 2015, 10:58 pm
    Sasha

    I know that the follow-up period in the Phase III trial that's now ongoing is 24 months but if benefit is clear earlier, would there be a possibility of the trial being stopped early and rtx being rolled out faster?

    Don't quote me on this and I'm not sure if I'm going to be able to find the source but I think F&M have ruled out an early unblinding. They're going to see it out to the bitter end.

  • Scarecrow August 7, 2015, 11:02 pm
    Sallyagerharris

    Having read and I appreciate it is early days that so far rituxamib seems to work better with younger patients with ME

    Yes, this was true in the Phase II but the number of participants was too small to have any significance. As you stated later in your post, we just need to wait and see what happens in the larger trial. :)

  • MeSci August 8, 2015, 9:43 am
    Violeta

    Warnings and Precautions
    TUMOR LYSIS SYNDROME

    • Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12−24 hours after the first infusion of RITUXAN in patients with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden, confers a greater risk of TLS. Administer aggressive intravenous hydration and anti hyperuricemic therapy in patients at high risk for TLS

    That label is for Non-Hodgkin's Lymphoma and Chronic Myeloid Leukaemia. You won't get Tumour Lysis Syndrome unless you have a tumour. I think we have discussed the differences between warnings/risks for ME (and doses?) and cancer elsewhere.

    EDIT – sorry – Chronic Lymphocytic Leukaemia – getting my words wrong at the moment – I knew it was Lymphocytic as it is what my friend has and she is taking a drug that can cause TLS.

  • Jonathan Edwards August 8, 2015, 10:14 am
    Sasha

    This is a massive surprise to me – in all these years on PR that people have been discussing rtx, I hadn't been aware that this was even a theoretical possibility in the UK. I don't think I've ever seen anyone mention it.

    That's promising.

    In some trials, data are so clear about the benefit of an intervention that they stop the trial before completion because it would be unethical to continue the study.

    I know that the follow-up period in the Phase III trial that's now ongoing is 24 months but if benefit is clear earlier, would there be a possibility of the trial being stopped early and rtx being rolled out faster?

    I think that is unlikely, partly because Drs Fluge and Mella are very keen to play things exactly by the book to avoid any compromise of the results. However, things may change in other ways. The publication of the follow on data is an important extra piece of confidence building.

  • Izola August 10, 2015, 11:52 pm
    Violeta

    I don't know, but the "off-label" would probably have to carry the same warning.

    "
    IMPORTANT SAFETY INFORMATION
    BOXED WARNINGS

    WARNING: FATAL INFUSION REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

    • Infusion Reactions: RITUXAN administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of RITUXAN infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Monitor patients closely. Discontinue RITUXAN infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion reactions
    • Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving RITUXAN
    • Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with RITUXAN, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with RITUXAN. Discontinue RITUXAN and concomitant medications in the event of HBV reactivation
    • Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving RITUXAN

    Warnings and Precautions
    TUMOR LYSIS SYNDROME

    • Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12−24 hours after the first infusion of RITUXAN in patients with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden, confers a greater risk of TLS. Administer aggressive intravenous hydration and anti hyperuricemic therapy in patients at high risk for TLS

    INFECTIONS

    • Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of RITUXAN-based therapy. Discontinue RITUXAN for serious infections and institute appropriate anti infective therapy

    CARDIOVASCULAR

    • Discontinue infusions for serious or life threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RITUXAN for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina

    RENAL

    • Severe, including fatal, renal toxicity can occur after RITUXAN administration in patients with NHL. Monitor closely for signs of renal failure and discontinue RITUXAN in patients with a rising serum creatinine or oliguria

    BOWEL OBSTRUCTION AND PERFORATION

    • Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving RITUXAN in combination with chemotherapy. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur

    IMMUNIZATION

    • The safety of immunization with live viral vaccines following RITUXAN therapy has not been studied and vaccination with live virus vaccines is not recommended

    LABORATORY MONITORING

    • Obtain complete blood counts (CBC) prior to each RITUXAN course

    Additional Important Safety Information

    • The most common Grade 3 or 4 adverse reactions in clinical trials of NHL and CLL were infusion reactions, neutropenia, leukopenia, anemia, thrombocytopenia, and infections. Additionally, lymphopenia and lung disorder were seen in NHL trials; and febrile neutropenia, pancytopenia, hypotension, and hepatitis B were seen in CLL trials
    • The most common adverse reactions (incidence ≥25%) in clinical trials of NHL and CLL were infusion reactions. Additionally, fever, lymphopenia, chills, infection, and asthenia were seen in NHL trials; and neutropenia was seen in CLL trials
    • Pregnancy: Category C. There are no adequate and well-controlled studies of rituximab in pregnant women

    For additional safety information, please see the full prescribing information, including BOXED WARNINGS and Medication Guide.

    Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

    You may report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch.

    You may also report side effects to Genentech at (888) 835-2555.

    © 2015 Genentech USA, Inc. and Biogen Idec Inc. All rights reserved. This site is intended for U.S. residents only.
    Jointly Marketed by: Biogen Idec Inc. and Genentech USA, Inc. Rituxan® is a registered trademark of Biogen Idec Inc.

    • [​IMG]
    • [​IMG]"

    Oh dear, Violetta. I can't possibly read all that misery. It's good I spent my money on mine and other's kids! iz 😀

  • Izola August 10, 2015, 11:54 pm
    MeSci

    That label is for Non-Hodgkin's Lymphoma and Chronic Myeloid Leukaemia. You won't get Tumour Lysis Syndrome unless you have a tumour. I think we have discussed the differences between warnings/risks for ME (and doses?) and cancer elsewhere.

    EDIT – sorry – Chronic Lymphocytic Leukaemia – getting my words wrong at the moment – I knew it was Lymphocytic as it is what my friend has and she is taking a drug that can cause TLS.

    I'm so sorry about your friend. iz

  • panckage August 11, 2015, 5:56 am

    Is there an easy way to give myself cancer so I can try this? Maybe eat mcdonalds every day or something? 😀

  • Jo Best December 7, 2016, 12:41 pm

    Just cross-referencing to this thread – http://forums.phoenixrising.me/index.php?threads/dr-%C3%98ystein-fluge-to-give-public-talk-in-norwich-uk-26th-jan-2017.47946/#post-791642
    Invest in ME Research have arranged for Dr Øystein Fluge from Haukeland University Hospital in Bergen, Norway, to give a public lecture in Norwich in January 2017. http://www.investinme.org/ce-news-1611-04.shtml
    This is connected with the IiMER UK rituximab trial planned to take place in Norwich (hub of the IiMER Centre of Excellence for ME) – http://www.investinme.org/ce-news-1611-03.shtml

  • Jo Best December 8, 2016, 1:32 pm

    News of inaugural awards from the Solve ME/CFS Ramsay Award Program includes the UCL and Charite teams working on rituximab research and autoimmunity – http://solvecfs.org/2016-ramsay-award-program-results/

  • joshualevy December 9, 2016, 4:35 pm
    Sasha

    I know that the follow-up period in the Phase III trial that's now ongoing is 24 months but if benefit is clear earlier, would there be a possibility of the trial being stopped early and rtx being rolled out faster?

    I don't know how things work in other countries, but in the US, that would be very unlikely for at least three reasons:

    First, phase-III trials for drugs are usually double blind. If a trial is double blind, and properly done, and there is no intermediate check by independent researchers, then there is no way to even know the trial has been successful until the data is unblinded. That happens at the end of the trial. Before that, no one even knows if it has been wildly successful or not. Does anyone know if the RTX has an intermediate analysis as part of the protocol? I did not think so.

    Second, except in unusual situations, the US requirement is two separate phase-III studies for marketing approval. Therefore, unless it is AIDS-in-1983, you need two phase-III studies for approval. So even if the first one really is wildly successful, you need the second one.

    Three, drug approvals are generally done by pharma companies. That is not a law or a rule, but in the last 10 years, I've never heard of a university research team doing the paperwork required for drug approval for a new indication (ie. public marketing approval). Obviously, they do IND (Investigative New Drug) approval paperwork, so they can start their trials, but they are not similar. Marketing approval requires a ton of specialized paperwork.

    (There is a separate issue, which is will the US FDA accept this trial at all? The primary end point is defined it such a way that the FDA may simply ignore it. The secondary end points look better (to me), but usually the FDA focuses on the primary end point, so I'm not sure what they would do in this situation.)

    Obviously, none of this impacts "off label" use.

  • viggster December 16, 2016, 3:49 am

    Clinical trials in the US can be stopped early if there is a clear benefit detected, although it is rare. The cases I know about are in cancer care. In big, government-sponsored cancer clinical trials, a group called a 'data safety & monitoring board' (DSMB) can review data as the trial is ongoing and if a clear benefit or a clear harm strongly emerges, end the trial early. I have no idea how things work in Norway but I doubt a smaller trial like this would have a DMSB looking at data early.

    Here's a piece that explores the pluses and minuses of stopping trials early. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC516093/

  • Snow Leopard December 16, 2016, 4:31 am
    viggster

    Clinical trials in the US can be stopped early if there is a clear benefit detected, although it is rare. The cases I know about are in cancer care. In big, government-sponsored cancer clinical trials, a group called a 'data safety & monitoring board' (DSMB) can review data as the trial is ongoing and if a clear benefit or a clear harm strongly emerges, end the trial early. I have no idea how things work in Norway but I doubt a smaller trial like this would have a DMSB looking at data early.

    Here's a piece that explores the pluses and minuses of stopping trials early. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC516093/

    To be frank, we have one major shot at this, best to let it go full term, since that is best practise. I think stopping early due to efficacy is suggested in cases where the people in the control group are dying! (or vice versa for harm)

  • Jo Best December 16, 2016, 6:36 pm

    The January 2017 Norwich talks posted by IFR today – http://www.ifr.ac.uk/news/events/2017/01/mecfs-biomedical-research/

  • deleder2k December 17, 2016, 4:48 am
    slayadragon

    I'm concerned about the use of this drug in this disease.

    Here is an interesting finding from the medical school of my own institution, for instance.

    http://www.northwestern.edu/newscenter/stories/2009/05/bennett.html

    The initial results of the mold avoidance survey that I am doing suggests that especially for severe ME patients (at the level of the ones in the Rituximab study), even basic mold avoidance is more successful than the what these authors are reporting about RItuximab.

    Mold avoidance also is less costly than taking this drug. It is true that many patients cannot afford to move to a better home because they have no money at all. But just an initial $10,000 or $20,000 could make all the difference in terms of giving a lot of people the option of getting to a better environment where they could improve.

    Compare that to the $100,000 or more per year, indefinitely, that somebody is paying for people to get Rituximab.

    And then there is the tiny little fact that any way you slice it, Rituximab is a dangerous drug.

    In terms of PR, having Ritiuximab be shown to have some effectiveness at addressing this disease seems possibly to be a good thing, if it is getting even Wessely to change course.

    But in terms of the treatments that patients actually pursue – I do not think it is a good option, compared to avoiding mold.

    Best,

    Lisa Petrison, Ph.D.

    You can receive two infusions 1grams infusions of Mabthera at Kolibri Medical in Norway for $9500 (+ consultation fee at your first appointment). Two infusions should be enough to see whether you respond or not. I am not sure if it is recommended though. Say you do two infusions at 1 gream each. After 10 months you start to recover. You feel extraordinary for 4-5 months. Then you deteriorate quickly. The B-cells has returned, and so has the autoantibodies. At this stage you will probably need a full start dose of two infusions for $9500 + maintenance infusions for say 3 times. That is $7000 more. If you have an enormous effect after say 9 months, I would do one more. That is what they are doing at the current Haukeland trial. Longer B-cell depletion leads to much longer remission. Some feel fine after several years. I think I remember that 50% or so had gradually increasing symptoms of a relapse after 2-3 years. If you read the open label phase 2 study you can see some data about this.

    It is a big risk, but that risk is mostly money wise. I don't know what to recommend. If cash was not an easy I would do it. If doing this treatment means that you have to stop paying your medical insurance, or that if is means that you have to get a quick personal loan with a 15% APR, you better reevaluate it. My guess that the results will be revealed in 1.5 years. Unless you have a lot of greenbacks lying around I would wait. But it all depends on what life you have.

    Tough decision for many of us to take, or not to take.

  • Kati December 17, 2016, 4:57 am
    deleder2k

    You can receive two infusions 1grams infusions of Mabthera at Kolibri Medical in Norway for $9500 (+ consultation fee at your first appointment). Two infusions should be enough to see whether you respond or not. I am not sure if it is recommended though. Say you do two infusions at 1 gream each. After 10 months you start to recover. You fell extraordinary for 4-5 months. Then you deteriorate quickly. The B-cells has returned, and so has the autoantibodies. At this stage you will probably need a full start dose of two infusions for $9500 + maintenance infusions for say 3 times. That is $7000 more. If you have an enormous effect after say 9 months, I would do one more. That is what they are doing at the current Haukeland trial. Longer B-cell depletion leads to much longer remission. Some feel fine after several years. I think I remember that 50% or so had gradually increasing symptoms of a relapse after 2-3 years. If you read the open label phase 2 study you can see some data about this.

    It is a big risk, but that risk is mostly money wise. I don't know what to recommend. If cash was not an easy I would do it. If doing this treatment means that you have to stop paying your medical insurance, or that if is means that you have to get a quick personal loan with a 15% APR, you better reevaluate it. My guess that the results will be revealed in 1.5 years. Unless you have a lot of greenbacks lying around I would wait. But it all depends on what life you have.

    Tough decision for many of us to take, or not to take.

    If a drug is approved for a designated disease, in many countries, then this drug is covered by the country's insurance or the private insurances.

    Personally, access to mainstream medicine is better for patients communities who have been left behind for decades, because it makes mainstream medicine legitimate. We very much need access to treatments that work. It all starts with the approval of one drug. Then there will be more.

    Mold avoidance stuff is very much 'out there'.

  • deleder2k December 17, 2016, 5:23 am

    If RTX is approved for everyone with ME then every Norwegian citizen with ME can obtain it for free. Today one can claim up to 90% of costs of other kinds of drugs, even though they are not approved for the condition. With respect to Rituximab, it doesn't work like that in Norway. Rituximab is classified as a cancer medicine The Regional Health Authority (there's four of them in Norway) will be in charge. For patients that means they need to get treated with RTX at a hospital. If else they will have to cover the cost entirely. It is expensive. Very expensive – but still much cheaper than getting treatment in San Francisco. They charge around 2.5 times more or so if I am not mistaken.

  • Gingergrrl December 17, 2016, 6:54 am
    Kati

    Mold avoidance stuff is very much 'out there'.

    I think these are two different topics like apples and oranges (mold/mycotoxin illness and Rituximab). For me it is not one or the other. I had a viral trigger, and then exposure to severe toxic black mold as an additional trigger, and both contributed to the downfall of my health. Moving away from the mold, getting rid of our belongings, and doing mold testing/treatment was crucial as is now treating the autoantibodies with IVIG and hopefully later RTX. For me they are not mutually exclusive and not in competition with each other, they are just two different issues.

    deleder2k

    Very expensive – but still much cheaper than getting treatment in San Francisco. They charge around 2.5 times more or so if I am not mistaken.

    I think that is true if someone were purely a private pay patient at OMI but if someone got insurance to cover part of the cost, or got financial aide from Genentech, it would be cheaper. Am not saying either would actually occur, just that it would be worth trying.

  • Kati December 17, 2016, 7:31 am
    deleder2k

    If RTX is approved for everyone with ME then every Norwegian citizen with ME can obtain it for free.

    Yeah I said that. In Canada too, it would be free if there was a doctor willing to prescribe it and a hospital willing to administer it. All we need is approval, and for the doctor to unlearn everything they have learnt about ME. I think it is where reside te hurdle.

  • deleder2k December 18, 2016, 9:00 pm
    Gingergrrl

    I think that is true if someone were purely a private pay patient at OMI but if someone got insurance to cover part of the cost, or got financial aide from Genentech, it would be cheaper. Am not saying either would actually occur, just that it would be worth trying.

    Absolutely, I don't know whether some insurance plans will cover it or not. It is not my area of expertise. As a Norwegian I know nothing about health insurance. It is an unknown world for me. It goes both ways though. I remember when I was trying to convince University of Miami that the Kingdom of Norway would pay my medical bills if I got sick, and that pre-existing conditions were included. They refused to accept the letter from the Norwegian Department of Health three times because they didn't believe that the actual Norwegian government would pay anything since I hadn't paid a dime for it, and since pre-existing conditions were included. They claimed that if I was medically covered it must have been through a private company which then the government paid… After more letters they finally accepted my medical insurance certificate from the Department of Health in Norway.

    One odd thing though is if you pay for Rituximab in Norway you'll be charged 25% VAT (similar to sales tax). That means you pay thousands of dollars for a medicine because the public healthcare system has nothing to offer you – and top of that you'll be charged a 25% tax…

    Lets hope Rituximab will be approved for some of us shortly. I don't know whether it will be approved in the UK if the results are good, but then UK residents can fly over the North Sea to Norway to get private treatment if they can afford it.

  • Kenny Banya April 26, 2017, 6:40 pm
    Scarecrow

    I can't remember exactly where this was discussed but @charles shepherd conservatively estimated not before 2022. He seemed to suggest that a UK Phase III trial would be required.

    I'd start saving for private treatment now if you're in a position to. We're likely to know the Norway results in 2018.

    2022??!!!
    Does that need to be adjusted for Brexit?

  • Kenny Banya April 26, 2017, 6:48 pm
    panckage

    Is there an easy way to give myself cancer so I can try this? Maybe eat mcdonalds every day or something? 😀

    You could fake Rheumatoid Arthritis.

  • deleder2k April 26, 2017, 7:17 pm

    If the Norwegian trial does show good results, and if we also get a biomarker that shows who's likely to benefit or not I would certainly decide getting treatment at a private hospital. I don't know the rules in U.K or Australia, but I would guess that great doctors at private hospitals would be able to treat patients off label with rituximab. Then you have two phase 2 studies, + a major study with 152 patients. Rituximab is not a new drug. I can't see why an experienced rheumatologist/oncologist at a private facility shouldn't be allowed to decide to go down this path if the results are as good as we hope.

  • Kenny Banya April 27, 2017, 3:00 am
    deleder2k

    If the Norwegian trial does show good results, and if we also get a biomarker that shows who's likely to benefit or not I would certainly decide getting treatment at a private hospital. I don't know the rules in U.K or Australia, but I would guess that great doctors at private hospitals would be able to treat patients off label with rituximab. Then you have two phase 2 studies, + a major study with 152 patients. Rituximab is not a new drug. I can't see why an experienced rheumatologist/oncologist at a private facility shouldn't be allowed to decide to go down this path if the results are as good as we hope.

    My understanding is that off label is not government subsidised so the cost would be huge
    Admittedly, it would at least save the $10,000 in accomodation & plane flights from Australia to Norway, 5 times over 12 months!!

  • deleder2k April 27, 2017, 7:18 pm
    Kenny Banya

    My understanding is that off label is not government subsidised so the cost would be huge
    Admittedly, it would at least save the $10,000 in accomodation & plane flights from Australia to Norway, 5 times over 12 months!!

    Lets hope some doctors in AU or NZ will act after the study is published. I guess flyin' to Sydney or Brisbane is somewhat cheaper than flying to Stavanger from the land of kangaroos and convicts! 😎

  • RogerBlack May 4, 2017, 4:56 pm

    I note that Rituximab has just in the last couple of years fallen out of patent protection.

    http://www.gabionline.net/Biosimilars/General/Biosimilars-of-rituximab

    There are approved biosimilars in several countries, Russia, India, … How safe these are is a not completely unreasonable question.

  • Gingergrrl May 4, 2017, 6:20 pm
    RogerBlack

    There are approved biosimilars in several countries, Russia, India, … How safe these are is a not completely unreasonable question.

    Thank you for that info and I bookmarked the link but I would be very hesitant to use a bio-similar version of Rituximab at his point b/c we don't know what additives or fillers are in it that could be toxic or cause an allergic reaction. If I truly get the opportunity to try it (still don't know), it would only be the true brand version of Rituximab even if it costs more.

  • deleder2k May 4, 2017, 6:34 pm
    RogerBlack

    I note that Rituximab has just in the last couple of years fallen out of patent protection.

    http://www.gabionline.net/Biosimilars/General/Biosimilars-of-rituximab

    There are approved biosimilars in several countries, Russia, India, … How safe these are is a not completely unreasonable question.

    http://forums.phoenixrising.me/inde…uxan-biosimilar-wins-european-approval.49439/

    Check this out if you're interested.

  • Snow Leopard May 5, 2017, 10:41 am

    Biosimilars are each completely different drugs and have to undergo their own safety and efficacy trials to be considered safe and viable treatments.

    Truxima being approved is interesting, however being approved for a cancer which is highly likely to kill you is different from being approved for an autoimmune condition. Cancer drugs can often be tentatively approved without very large phase three trials, even if there is risk of death from the drug, simply because the overall risk of death with the treatment is less than the alternatives.

    edit – it seems Truxima has been approved for RA… Interesting. If the current Rituximab trials demonstrate efficacy, there is scope for Truxima trials for ME.

  • Gingergrrl May 5, 2017, 11:04 pm
    Snow Leopard

    edit – it seems Truxima has been approved for RA… Interesting. If the current Rituximab trials demonstrate efficacy, there is scope for Truxima trials for ME.

    That is very interesting and I am going to confirm w/my doctor that if I am indeed approved for RTX that I am given the REAL RTX and my insurance does not try to give me Truxima or some generic version. Am so glad I saw this.