{"id":14959,"date":"2017-11-28T09:04:28","date_gmt":"2017-11-28T09:04:28","guid":{"rendered":"http:\/\/wames.org.uk\/cms-english\/?p=14959"},"modified":"2017-11-28T09:04:28","modified_gmt":"2017-11-28T09:04:28","slug":"norwegian-rituximab-trial-reports-negative-results","status":"publish","type":"post","link":"https:\/\/wames.org.uk\/cms-english\/norwegian-rituximab-trial-reports-negative-results\/","title":{"rendered":"Norwegian rituximab trial reports negative results"},"content":{"rendered":"

The Norwegian Rituximab trial reports negative results ahead of the publication of the full results. Attempts are now under way to\u00a0determine the best way forward\u00a0in understanding what has been learned and how to\u00a0find out which patients may still benefit from the drug.\u00a0<\/strong><\/h3>\n

Simmaron Research<\/strong> blog post, by Cort Johnson,\u00a026 November 2017: Norwegian Rituximab Chronic Fatigue Syndrome (ME\/CFS) Trial Fails<\/a><\/h3>\n

Over the past five years or so, Rituximab has been the great hope for the ME\/CFS community. The anecdotal stories of dramatic recoveries were beyond enticing. A successful trial could ultimately have led to the first FDA-approved drug for ME\/CFS and relief for many, a huge shift in how the disease is viewed, and surely more research funding.<\/p>\n

That unfortunately is not to be. At a talk in Norway on Nov 21st, Dr. Mella revealed that the Rituximab trial that many laid their hopes on has failed. We don\u2019t know and won\u2019t know the details of the failure until the paper is published next year, and Drs. Fluge and Mella talk more about the study.\u00a0 Dr. Mella said they provided the result so that ME\/CFS patients won\u2019t try the drug on their own.<\/p>\n

The Norwegian trial was never by itself going to lead to FDA approval for Rituximab\u2019s use in ME\/CFS. The trial was large and rigorous enough, though, to ensure that, if successful, another trial which could lead to FDA approval would follow. The trial\u2019s rigor had equally negative consequences; it\u2019s hard to imagine in this funding-hampered disease that anyone is going to fund a large Rituximab trial in the future.<\/p>\n

The main finding of the Norwegian Rituximab trial was negative but Rituximab\u2019s\u00a0role in ME\/CFS may not be at an end.<\/p>\n

Rituximab may never be an FDA-approved drug for the general ME\/CFS population, but its role with ME\/CFS may not be over, and smaller, targeted trials are still a possibility. From the beginning, Fluge and Mella recognized the possibility of a trial failure and had a backup plan in case it failed:<\/p>\n

‘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\u00a0immunological, rituximab-responsive disease.’<\/em><\/p>\n

Efforts to find biomarkers that identify the responders will be critical and are already underway. David Patrick of Canada reported on his use of microarrays to try and tease out which ME\/CFS patients might respond to Rituximab at the 2016 IACFS\/ME Conference. Nancy Klimas suggested that the Rituximab sera could very well hold the key to Rituximab\u2019s future with ME\/CFS. If autoantibodies are present in the Rituximab responders\u2019 sera, they could be used to screen patients for future trials.\u00a0 She questioned whether the\u00a0autoantibody patterns she\u2019s seen in her studies might be predictive.<\/p>\n

Jorgen Jelstad pointed out that antibodies are used to identify responders to Rituximab and other immune-suppressing drugs in osteoarthritis. Patients with positive antibody findings get the drugs and patients with negative findings do not.<\/p>\n

We know that some people with ME\/CFS do respond very well to Rituximab. We\u2019ll know more about them and the next steps Fluge and Mella will take with the drug and their other studies in early 2018.<\/p>\n

The Rituximab Saga<\/strong><\/h3>\n

The Rituximab saga began in 2004 when two oncologists noticed that Rituximab \u2013 a B-cell depleting drug often used in cancer \u2013 not only cured one of their patient\u2019s cancer but eliminated their chronic fatigue syndrome (ME\/CFS) as well. After two more ME\/CFS patients responded similarly, they began their work on ME\/CFS in earnest.<\/p>\n

Several small case studies or trials ensued, all of which produced excellent results. The first one \u2013 called a preliminary case series in 2009 \u2013 reported on the three ME\/CFS patients who\u2019d improved on Rituximab.\u00a0 The second \u2013 a 2011 double-blinded, placebo-controlled 12 month trial of 30 patients \u2013 found Rituximab produced \u201cmajor or moderate\u201d results in 2\/3rds of the participants.<\/p>\n

The third, a 2015 open-label (the patients knew they were getting Rituximab) study, which involved giving the participants doses over a longer period of time, achieved similar results.\u00a0 The SF-36 scores of the major responders \u2013 about 50% of the study participants \u2013 suggested that they might be back to near normal. Not only did the trial succeed, but the trial suggested that the relapses dogging the patients from the first study could be prevented by continuing to take the drug.<\/p>\n

The 152 person, double-blinded, placebo controlled trial that eventually resulted was spread across five hospitals in Norway. The trial had a rocky start with the Norwegian government pulling its support, but ultimately patient advocacy and patient support prevailed. The trial began in 2015 and wrapped up on time in September of this year.<\/p>\n

Why the Trial Failed<\/strong><\/h3>\n

We won\u2019t know why the trial failed or how many people the drug worked for until the paper is published in the first half of next year but speculation is rampant.<\/p>\n

Was \u201cFailure\u201dAlways the Most Likely Outcome (?)<\/strong>\u00a0\u2013\u00a0 My probably minority opinion is that \u201cfailure\u201d may have always been the most likely outcome of the study given the heterogeneity this community displays every day on Forums, Facebook and elsewhere on the internet. It may be too much to ask for many drug trials aimed at the entire ME\/CFS community to succeed.<\/p>\n

It\u2019s important to note that Rituximab may still have a role to play in ME\/CFS \u2013 just not as a drug for everyone. The key question now is how many people actually did respond to it.\u00a0 If a substantial number did, and a biomarker to identify them can be identified, the Rituximab trial will not go down as a failure at all.<\/p>\n

Patient Bias?<\/strong> \u2013 Inadvertent patient bias \u2013 a possibility Fluge and Mella considered as the trial started \u2013 is probably the best candidate at this point. It could be that the smaller early studies inadvertently plucked out a more receptive set of patients. Once more patients were added to the mix, the effect disappeared. This is not an uncommon result in large Phase III drug trials:<\/p>\n

\u201cHowever, 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).\u201d<\/em> Fluge and Mella<\/p>\n

Placebo Effect?<\/strong> \u2013 Jorgen Jelstad put forth the intriguing idea that a high placebo effect could have doomed the drug. A similar situation appears to have doomed the Synergy trial. The Synergy compound actually did quite well but the placebo effect \u2013 possibly due to patients\u2019 excitement about the treatment \u2013 was so strong that it was impossible to show clear separation between the effects of the drug and the placebo. Given the excitement around Rituximab, it\u2019s possible that a similar situation has prevailed.<\/p>\n

Endpoint \u2013 Not Disease?<\/strong> \u2013 It\u2019s also possible that ME\/CFS is not a single disease, but represents an endpoint or condition that can be reached in any number of different ways. Both Gulf War Illness and Lyme disease, after all, symptomatically appear to be the same as chronic fatigue syndrome but studies suggest that the three diseases are probably quite different biologically.<\/p>\n

If different pathways exist to the same symptomatic or even cellular endpoints, then different treatment pathways will be needed. Alzheimer\u2019s is possibly an excellent example of a complex endpoint \u2013 not a single disease \u2013 which will need a variety of approaches to resolve. Dale Bredesen MD believes that hundreds of millions of dollars and hundreds of prospective drugs have failed to make a significant dent in Alzheimer\u2019s because the disease has been misidentified. Dale Bredesen\u2019s studies suggest that an approach which assesses and treats a wide range of factors may actually work quite well in Alzheimer\u2019s.<\/p>\n

See<\/strong> Reversing Alzheimer\u2019s: What Could it Mean for Chronic Fatigue Syndrome (ME\/CFS) and Fibromyalgia<\/a><\/p>\n

Drug Trial Failures Not Uncommon in Medicine<\/strong><\/h3>\n

The ME\/CFS and FM communities have recently, unfortunately, been getting acquainted with the fact that disappointments in drug trials are more common than successes.\u00a0 Rituximab had two small, but good, Phase II trials and seemed likely to succeed, but surprises in medical research, as Ron Davis has pointed out so many times, are common.<\/p>\n

The next step will be determining who did respond to Rituximab and why
\nSwedish journalist Jorgen Jelstad\u2019s <\/a>interesting blog \u201cThe ME Rituximab Trial is Negative\u201d<\/a> (translated by Google into English) noted that Rituximab also failed in lupus despite the fact that it seemed hand-made for a B-cell associated disease. In fact, researchers were so shocked at the failure of the first large Rituximab lupus study that they immediately started another one \u2013 which subsequently bombed as well.\u00a0 (Despite all that, Rituximab can still work in lupus and is used in patients who haven\u2019t responded to other treatments. )<\/p>\n

Closer to home, two major Phase III fibromyalgia trials, one involving 10,000 patients, failed over the past year. As with ME\/CFS and Rituximab, their Phase II trials had produced stellar results. Likewise, Wyller\u2019s Clonidine trial seemed set up to reduce the \u201carousal\u201d that seems manifest in this disease. Not only did the trial fail, but the drug actually made Wyller\u2019s young ME\/CFS patients worse.\u00a0 Medicine is full of surprises. It\u2019s unrealistic to assume that ME\/CFS won\u2019t fall prey to some of them.<\/p>\n

The Big Hurt: Second Major Drug Trial for Fibromyalgia Fails<\/a><\/p>\n

Cautionary Findings?<\/strong><\/h3>\n

The result is disappointing but it\u2019s perhaps not entirely surprising.\u00a0 Rumors from doctors using the drug in the U.S. on ME\/CFS suggested the success rates might be lower than hoped for. If I\u2019m reading them right, the immune B-cell studies in ME\/CFS which sought to identify the issue Rituximab has addressed haven\u2019t exactly been sterling successes.<\/p>\n

Fluge and Mella proposed that long-lived autoantibodies or some other \u201cslow alteration in the immune function governed by B-cells\u201d could be causing ME\/CFS.\u00a0 That idea was buttressed by a study finding increased rates of B-cell lymphoma in elderly ME\/CFS patients.<\/p>\n

When a German study found significantly reduced levels of muscarinic and B-adrenergic antibodies in Rituximab responders<\/a>, the way forward seemed clear. Rituximab\u2019s B-cell depleting properties were preventing B-cells from producing autoantibodies that were affecting blood flows and other processes.<\/p>\n

The study possibly provided a cautionary note, however, when only 30% of the ME\/CFS patients not given Rituximab (n=268) displayed the antibodies \u2013 a far smaller percentage than had responded in the early Rituximab trials. If those antibodies were what Rituximab was affecting \u2013 which was certainly not clear \u2013 many patients simply didn\u2019t have them.<\/p>\n

Meanwhile, studies that had focused on the B-cells in ME\/CFS didn\u2019t seem encouraging. Several studies prior to the Rituximab finding had not shown consistent B-cell differences between ME\/CFS patients and healthy controls.\u00a0 A more recent found mostly modest alterations in B-cells<\/a> in ME\/CFS patients. Bradley\u2019s conclusion that ME\/CFS patients exhibited a \u201csubtle tendency to autoimmunity\u201d didn\u2019t seem to jive with the idea that ME\/CFS is a B-cell mediated autoimmune disorder\u201d. Another study which found some B-cell abnormalities<\/a> was unclear what their functional impact might be.\u00a0 A 2013 study simply found no differences<\/a> in the B-cells of ME\/CFS patients and controls.<\/p>\n

Finally, researchers have had trouble figuring out what Rituximab was doing when it did work. Lunde\u2019s 2016 study of ME\/CFS patients receiving Rituximab <\/a>found no difference in several immune measures (serum BAFF, T-Lymphocytes, T-cell activation) and just slight (but significant) reductions in immunoglobulin levels.<\/p>\n

There\u2019s certainly more to know about B-cells in ME\/CFS \u2013 the Solve ME\/CFS Initiative\u2019s (SMCI) is funding a small study of B-cell energetics \u2013 but if B-cells are causing ME\/CFS, they haven\u2019t been giving up their secrets easily.<\/p>\n

Enormous Impact<\/strong><\/h3>\n

While the Rituximab trial failed in its main objective \u2013 to provide a drug for ME\/CFS patients \u2013 there\u2019s no denying that its impact has been enormous. Two highly creative researchers, Oystein Fluge and Olav Mella, have entered the field and say they intend to remain. Their wide-ranging efforts have and are touching on everything from autoantibodies to blood vessel functioning to metabolomics to exercise.<\/p>\n

They and the Norwegian ME\/CFS community put together the largest non-CBT\/GET trial ever in ME\/CFS, produced one of the largest biobanks, and created collaborations with researchers in Europe and the U.S.\u00a0 It proved that ME\/CFS patients and their supporters from across the world will respond (Dr. Maria Gerpe reported that over 90 days, 5000 donors from more than 49 different countries contributed to the study). The Rituximab saga has provided a jolt of energy across the entire ME\/CFS community.<\/p>\n

Plus, the trial was not just about Rituximab. Several other studies baked into the study will add to our understanding of ME\/CFS. A study examining endothelial function and skin microcirculation should tell us about blood flow issues \u2013 very possibly a key issue in ME\/CFS. Their two- day exercise test should validate the highly unusual decline seen in the ability of ME\/CFS patients to produce energy after exercise. Their gastrointestinal functioning test should, likewise, tell us about gut functioning in this disease.<\/p>\n

Plus, Fluge and Mella are continuing with their cyclophosphamide trial.<\/a> Cyclophosphamide has some real advantages over Rituximab. While Rituximab selectively targets B-cells, a more broadly based immune drug like cyclophosphamide may be more effective than Rituximab and has the decided benefit of being much, much cheaper.\u00a0 The drug is being tested in several hospitals across Norway.. Cyclophosphamide has some real advantages over Rituximab. While Rituximab selectively targets B-cells, a more broadly based immune drug like cyclophosphamide may be more effective than Rituximab and has the decided benefit of being much, much cheaper.\u00a0 The drug is being tested in several hospitals across Norway.<\/p>\n

Fluge and Mella have also published studies indicating breakdowns in energy production and the effects of cytokines on ME\/CFS. Jorgen Jelstad pointed out that Katrina Lien\u2019s multi-center Norwegian study is examining lactic acid production in ME\/CFS.<\/p>\n

Rituximab\u2019s early success prompted researchers to examine B-cells and autoantibodies more closely.\u00a0 Maureen Hanson is working with Norwegian researchers to assess the effectiveness of fecal transplants. None of this work would have been possible if Rituximab had not come to the fore.<\/p>\n

The Rituximab saga showed that there\u2019s no need to look to the U.S. for potential breakthroughs in this disease.\u00a0 Activists in smaller countries should be encouraged. Norway put the U.S. to shame in its ability to put together and fund the largest non-behavioral ME\/CFS treatment trial ever. The Rituximab saga has shown that an active community and dedicated researchers in small countries can make a major impact on this disease.<\/p>\n

We\u2019ll know more about the next steps with Rituximab and Fluge and Mella\u2019s work in 2018.<\/p>\n

The Clinical Trials Picture<\/strong><\/h3>\n

The loss of Rituximab puts renewed focus on Hemispherx Biopharma\u2019s Ampligen \u2013 the other major drug possibility for ME\/CFS.<\/p>\n

Nancy Klimas at the Institute for Neuro-immune studies feels she has treatments to test now.\u00a0 Klimas has been chafing against federal restrictions that make it difficult to get ME\/CFS clinical trials funded for years now. Neither the Research Centers grant nor, advocates take note, the Program Announcements for the ME\/CFS SEP grant review panel, allow for the submission of clinical trial proposals. That means Dr. Klimas has go to rheumatology review panels to try and get her ME\/CFS clinical trials funded.<\/p>\n

Dr. Klimas reports that she\u2019s received private funding for a phase I exploratory trial for\u00a0women to start in Jan\/Feb of next year and has raised half the money needed for a men\u2019s study to hopefully begin shortly after that. (More on those later.)<\/p>\n

Other Reports on the Rituximab Finding<\/strong><\/h3>\n

Invest in ME\u2019s Statement on Rituximab<\/a>
\nJorgen Jelstad\u2019s blog<\/a>
\nMaria Gjerpe\u2019s blog<\/a><\/p>\n

Put simply, clinical trials of treatments for ME\/CFS are the missing link and the next mandate, and experience suggest we consider designing them around disease subsets.<\/p>\n

ME Association Statement: Negative phase III clinical trial result from Norway for Rituximab in ME\/CFS<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

The Norwegian Rituximab trial reports negative results ahead of the publication of the full results. Attempts are now under way to\u00a0determine the best way forward\u00a0in understanding what has been learned and how to\u00a0find out which patients may still benefit from … Continue reading →<\/span><\/a><\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[1],"tags":[499,618,1618,51,1102,50,2328],"class_list":["post-14959","post","type-post","status-publish","format-standard","hentry","category-news","tag-b-cell","tag-cort-johnson","tag-cyclophosphamide","tag-dr-oystein-fluge","tag-prof-olav-mella","tag-rituximab","tag-simmaron-research"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/p5qkYK-3Th","_links":{"self":[{"href":"https:\/\/wames.org.uk\/cms-english\/wp-json\/wp\/v2\/posts\/14959","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/wames.org.uk\/cms-english\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/wames.org.uk\/cms-english\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/wames.org.uk\/cms-english\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/wames.org.uk\/cms-english\/wp-json\/wp\/v2\/comments?post=14959"}],"version-history":[{"count":2,"href":"https:\/\/wames.org.uk\/cms-english\/wp-json\/wp\/v2\/posts\/14959\/revisions"}],"predecessor-version":[{"id":14962,"href":"https:\/\/wames.org.uk\/cms-english\/wp-json\/wp\/v2\/posts\/14959\/revisions\/14962"}],"wp:attachment":[{"href":"https:\/\/wames.org.uk\/cms-english\/wp-json\/wp\/v2\/media?parent=14959"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/wames.org.uk\/cms-english\/wp-json\/wp\/v2\/categories?post=14959"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/wames.org.uk\/cms-english\/wp-json\/wp\/v2\/tags?post=14959"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}