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Norwegian Rituximab Chronic Fatigue Syndrome (ME/CFS) Trial Fails

November 26, 2017

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.

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’t know and won’t know the details of the failure until the paper is published next year, and Drs. Fluge and Mella talk more about the study.  Dr. Mella said they provided the result so that ME/CFS patients won’t try the drug on their own.

The Norwegian trial was never by itself going to lead to FDA approval for Rituximab’s 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’s rigor had equally negative consequences; it’s hard to imagine in this funding-hampered disease that anyone is going to fund a large Rituximab trial in the future.

Ritxuimab's future in ME/CFS

The main finding of the Norwegian Rituximab trial was negative but Rituximab’s ,may role in ME/CFS may not be at an end.

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:

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.

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’s future with ME/CFS. If autoantibodies are present in the Rituximab responders’ sera, they could be used to screen patients for future trials.  She questioned whether the autoantibody patterns she’s seen in her studies might be predictive.

Norwegian journalist 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.

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

The Rituximab Saga

The Rituximab saga began in 2004 when two oncologists noticed that Rituximab – a B-cell depleting drug often used in cancer – not only cured one of their patient’s 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.

Several small case studies or trials ensued, all of which produced excellent results. The first one – called a preliminary case series in 2009 – reported on the three ME/CFS patients who’d improved on Rituximab.  The second – a 2011 double-blinded, placebo-controlled 12 month trial of 30 patients – found Rituximab produced “major or moderate” results in 2/3rds of the participants.

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.  The SF-36 scores of the major responders – about 50% of the study participants – 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.

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.

Why the Trial Failed

We won’t 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.

Was “Failure”Always the Most Likely Outcome (?) –  My probably minority opinion is that “failure” 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.

It’s important to note that Rituximab may still have a role to play in ME/CFS – just not as a drug for everyone. The key question now is how many people actually did respond to it.  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.

Patient Bias? – Inadvertent patient bias – a possibility Fluge and Mella considered as the trial started – 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:

“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).” Fluge and Mella

Placebo Effect? – 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 – possibly due to patients’ excitement about the treatment – 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’s possible that a similar situation has prevailed.

Endpoint – Not Disease? – It’s 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.

If different pathways exist to the same symptomatic or even cellular endpoints, then different treatment pathways will be needed. Alzheimer’s is possibly an excellent example of a complex endpoint – not a single disease – 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’s because the disease has been misidentified. Dale Bredesen’s studies suggest that an approach which assesses and treats a wide range of factors may actually work quite well in Alzheimer’s.

See Reversing Alzheimer’s: What Could it Mean for Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia

Drug Trial Failures Not Uncommon in Medicine

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.  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.

Rituximab subsets

The next step will be determining who did respond to Rituximab and why

Jelstad’s interesting blog “The ME Rituximab Trial is Negative” (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 – which subsequently bombed as well.  (Despite all that, Rituximab can still work in lupus and is used in patients who haven’t responded to other treatments. )

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’s Clonidine trial seemed set up to reduce the “arousal” that seems manifest in this disease. Not only did the trial fail, but the drug actually made Wyller’s young ME/CFS patients worse.  Medicine is full of surprises. It’s unrealistic to assume that ME/CFS won’t fall prey to some of them.

The Big Hurt: Second Major Drug Trial for Fibromyalgia Fails

Cautionary Findings?

The result is disappointing but it’s perhaps not entirely surprising.  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’m reading them right, the immune B-cell studies in ME/CFS which sought to identify the issue Rituximab has addressed haven’t exactly been sterling successes.

Fluge and Mella proposed that long-lived autoantibodies or some other “slow alteration in the immune function governed by B-cells” could be causing ME/CFS.  That idea was buttressed by a study finding increased rates of B-cell lymphoma in elderly ME/CFS patients.

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

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

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

Finally, researchers have had trouble figuring out what Rituximab was doing when it did work. Lunde’s 2016 study of ME/CFS patients receiving Rituximab found no difference in several immune measures (serum BAFF, T-Lymphocytes, T-cell activation) and just slight (but significant) reductions in immunoglobulin levels.

There’s certainly more to know about B-cells in ME/CFS – the Solve ME/CFS Initiative’s (SMCI) is funding a small study of B-cell energetics – but if B-cells are causing ME/CFS, they haven’t been giving up their secrets easily.

Enormous Impact

While the Rituximab trial failed in its main objective – to provide a drug for ME/CFS patients – there’s 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.

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.  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.

fluge_mella_research_team

Fluge and Mella and their supporters did the seemingly impossible: put on a large and expensive ME/CFS drug trial in a small country

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 – 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.

Plus, Fluge and Mella are continuing with their cyclophosphamide trial. 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.  The drug is being tested in several hospitals across Norway.

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’s multi-center Norwegian study is examining lactic acid production in ME/CFS.  RItuximab’s early success prompted researchers to examine B-cells and autoantibodies more closely.  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.

The Rituximab saga showed that there’s no need to look to the U.S. for potential breakthroughs in this disease.  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.

We’ll know more about the next steps with Rituximab and Fluge and Mella’s work in 2018.

The Clinical Trials Picture

The loss of Rituximab puts renewed focus on Hemispherx Biopharma’s Ampligen – the other major drug possibility for ME/CFS.

Nancy Klimas at the Institute for Neuro-immune studies feels she has treatments to test now.  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.

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

Other Reports on the Rituximab Finding

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.

 

More is Better: Rituximab Trial Boosts Hopes for Chronic Fatigue Syndrome

The Rituximab  Story

“I was completely revitalized. Suddenly, I could be sociable again. I would go to work, go home, eat dinner and feel restless.” An ME/CFS patient in the study

The Rituximab story started in 2004 when Fluge and Mella two Norwegian oncologists noticed that some of their cancer patients with chronic fatigue syndrome were doing very well on a drug called Rituximab. In fact, they were doing too well. Not only had their cancer gone into remission but so had their chronic fatigue syndrome symptoms.

tweaking treatment protocol RItuximab

In this study Fluge and Mella tweaked their original treatment plan to produce more powerful and lasting results

Fast forward 11 years, one case series and another study later and we find Fluge and Mella not just treating ME/CFS patients with Rituximab but aggressively tweaking their formula to achieve a lasting remission in the responders and to provoke a remission in treatment resistant patients.

In the initial Rituximab trial published in 2011 Fluge and Mella gave 30 chronic fatigue syndrome patients two Rituximab infusions  two weeks apart and then followed them for 12 months. Three months into the trial there was no evidence the drug was working but 6-12 months later two-thirds of the participants had responded and some had responded in truly dramatic fashion. Years of disability and pain dropped away as some patients almost miraculously achieved normal lives.

Many of the responders, however relapsed later. In this study Fluge and Mella tried to do something about that. They gave Rituximab to 29 ME/CFS patients more often and for longer and they followed them for longer.

Rituximab

Rituximab induces B-cells to kill themselves by attaching to the CD20 receptor on them. It also enhances the ability of natural killer cells to kill them.

Originally developed and FDA approved to treat cancer (lymphoma) Rituximab is also FDA approved to treat rheumatoid arthritis and is used off-label to treat multiple sclerosis, lupus, chronic inflammatory demyelinating polyneuropathy, autoimmune anemia, Sjogren’s Syndrome and many others.  Chronic fatigue syndrome may be the first disease outside of known autoimmune disorders, that Rituximab has been tested in.

The Study

B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O, Mella O. PLoS One. 2015 Jul 1;10(7):

After the two infusions in the first two weeks (500 mg/m2 (maximum 1000 mg) Rituxmab was given four more times at 3, 6, 10 and 15 months (500 mg/m2 (maximum 1000 mg) and the patients were followed for no less than three years. The participants assessed their symptom levels every two weeks and health related quality of life using the SF-36 form.

Lymphocyte subpopulations, including CD19 positive B-cells were assessed before the infusions and at 3, 6, 10, 15, 20, 24, 30 and 36 months.

In an attempt to boost their response seven of the patients who showed slow and gradual improvement after twelve months received up to six additional infusions at two month intervals.

The Participants

This was Norway but the study population looked like that found anywhere else. Sixty-nine percent of the participants were women and 31% were men. The average age was forty and the average duration of illness was nine years. The severity of their illness ranged from mild (n=5), mild/moderate (n=4); moderate (mainly housebound) (n-13), moderate/severe (n=4), severe (bedridden) (n=3). Almost 60% associated an infection with their illness, 34% did not and 7% were not sure.

Seven patients had had Rituximab before but relapsed later and three had tried it and received no or a minimal response. Nine participants had been in the placebo arm of the former study.  All met both the Fukuda and Canadian Concensus Criteria for ME/CFS.

The Results

The Responders

As in the first trial over 60% of the participants reported significant clinical improvement; i.e. they achieved an improvement in their Fatigue score ≥ 4.5 for at least six consecutive weeks. Fourteen or 78% of those  who did were described as “major responders” and four (22%) were described as moderate responders.

more is better Rituximab

More was indeed better as many of the responders maintained their response a year and a half after receiving their last treatment

Some evidence suggested that the major responders were close to functioning normally or in some cases were fully recovered.  With their average SF-36 scores showing remarkable increases it appeared that many of the responders really responded. (More is better with the SF-36).

The average social functioning score – which denotes how much a person is inhibited from functioning socially – increased from 18.4 to 70.8, the average vitality score tripled from  17.7 to 61.3, the average physical functioning score – probably a really difficult one to improve on in ME/CFS – almost doubled (42.9 – 83.3), and bodily pain scores more than doubled (32.2 to 72.3).

At the end of the trial the responders average SF-36 score meet population norms; i.e. you wouldn’t be able, using this test, to tell them from healthy people. It didn’t mean they were all healthy- the test is not precise enough for that – but they were much, much improved.

Some limited Sensiware armband data validated the findings: the number of steps the responders took at the end of the trial indicated they were about as active as normal people.

The Non-Responders

The ten people who did not respond – really didn’t respond; no significant increases in any of the SF-36 scores were seen. It appears that most of the responders do pretty well while nothing much happens for the non-responders.

Maintaining Health – the Maintenance Strategy Mostly Works

The maintenance strategy of providing Rituximab more often to produce a longer-last effect was mostly successful.  Again, those who responded to it responded well. Those did not respond – really did not respond.

The duration of the response zoomed in the responders from 25 weeks (half a year) in the first study to almost 100 weeks (two years) when taking maintenance infusions in the second study.  The responders stayed healthier longer once they were off the drug as well. Three years after beginning the treatment and a year and a half after their last infusion  the treatment was sticking for about 60% of the responders. Some former patients were clearly well.

“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,” Fluge.

B-cell tests indicating the B-cell numbers of all the responders were back to normal suggested their systems may have been reset. If they’d had an autoimmune problem it had disappeared during their long period of immune suppression.

The maintenance dose did not enhance the duration of the response in everyone, however; about forty percent had relapsed a year after receiving their last dose.

The More Is Not Better (Except When it Is) …..Group

Giving Rituximab more often (at the end of one year) to patients who’d had a moderate initial response to it failed to turn them into major responders.  One person, however, who didn’t respond to the two-dose first trial, did respond to five dose second trail.

More doses of Rituximab early on, then, might help but if a year of increased dosage is not helping then it’s time to try something else. Why some people respond and others don’t isn’t clear. Sophisticated immune analyses, however, are underway to attempt to figure that out.

Concerns

Placebo Response

There’s concern about the lack of a placebo group. No treatment will ever get approval without having a placebo controlled study but I wonder how serious the placebo concern is. The long time to the response seen (several months) and the long duration of the response argue (a year and a half in some) argues against a placebo response making a difference for many.

Study Size

A bigger concern is probably the small study size.  Thus far we have  response data on a small slice of the ME/CFS population in an ethnically homogeneous region.  (The upside to doing the study in Norway is that they can apparently get things done pretty quickly; the downside is that the country simply doesn’t have the ethnic diversity the U.S. has.)

subset

The biggest questions facing the two studies done so far is how closely the study participants resemble the ME/CFS population as a whole.

We can say that Rituximab works well  and sometimes very, very well in a subset of patients but we don’t know how big that subset is. I expect the response rates to drop as more types of ME/CFS patients sample the drug. Even a thirty or twenty percent response rate would be very exciting.

The results from the multicenter trial will not be available until 2017 or 18 – two or three years. If the 152 person trial goes well it’s hard to imagine – at least from this layman – that large trials will not quickly open up in the U.S. The infrastructure and the network of physicians needed to engage in a major trial is present. They will simply need access to the drug.  With all the federal reports citing the need for better treatments a way has to be found to get the” big lug” to mount a major trial.

The Severely Ill Study

Thus far in a separate study none of the four severely ill ME/CFS patients in a small open-label study have responded to Rituximab. Four more patients are being assessed. They do not encourage the use of this very strong drug in the severely ill at this time.

The Autoimmune Question – If it Looks Like A Duck…

Chronic fatigue syndrome with it’s female predominance, it’s often infectious trigger, it’s symptoms and the changes that sometimes occur in pregnancy has always looked like it might be, at least in part, an autoimmune disorder.

Fluge and Mella’s autoimmune hypothesis ties several aspects of ME/CFS together in a neat package. First an infection triggers the body to produce antibodies that target the blood vessels and stop them from delivering normal amounts of blood to the tissues. The drop in oxygen to the mitochondria resulting from explains the fatigue, lowered aerobic capacity and exercise problems. Given the brain’s enormous need for oxygen it also explain the brain fog. Several studies back up the muscle and brain issues – the question is whether antibodies are the result.

duck autoimmunity ME/CFS

If it looks like a duck and walks like a duck… is it a duck?

Thus far the Rituximab findings suggest autoantibodies play a role at least in a subset of patients. As before the responders took their sweet time – several months – to respond to the drug.  That several month time lag, though, is about how long it would take Rituximab to clear auto-antibodies from the body. That time-lag strongly suggests an autoimmune process is going on.

Increased rates of autoimmunity (41%) in the first-degree relatives of the patients buttressed the autoimmune hypothesis; a genetic predisposition is often present in autoimmune disorders.

If auto-antibodies are the key Fluge and Mella and others, however, have not found them yet.  They do have a hypothesis, though that ties several aspects of ME/CFS together in a neat package. They believe an infection triggers the body to produce antibodies that target the blood vessels and stop them from delivering normal amounts of blood to the tissues. The drop in oxygen to the mitochondria resulting from the reduced blood flows explains the fatigue, lowered aerobic capacity and exercise problems. Given the brain’s enormous need for oxygen it also explains the brain fog. it’s a theory with a nice foundation: several studies back up

We should see a paper explaining Fluge/Mella’s hypothesis soon and studies embedded in the 150 person trial will help assess whether their hypothesis is correct.

Norway!

It’s worth noting again what a remarkable role the small country of Norway has played in this unlikely scenario.  Size doesn’t always matter – and one suspects that it may be a hindrance in some cases. Two Norwegian physicians birthed the Rituximab findings, Norwegian advocates raised money and pressured the Norwegian government to do what nobody else has been able to do – fund and produce a very expensive and large treatment trial.  Not only did they do that but they did much more quickly than anyone else.

It’s a scary thing to have to depend on a small country with almost no history of ME/CFS research or on private donors in another country to follow up on the most exciting treatment finding in ME/CFS’s history.  If Rituximab works out – and it’s hard to imagine that it will not at least in part work out – the worldwide ME/CFS community will owe the two doctors, the Norwegian advocates and the Norwegian government a huge debt.

The UK is on board. It may be that UK advocates – driven by their awful circumstances – try harder when it comes to jumping on a hot treatment finding. Since June, 2013 Invest in ME has raised over $600,000 US dollars for its own Rituximab trial. According to Dr. Jonathan Edwards, who pioneered Rituximab’s use in autoimmune disorders, Invest in ME has enough money now for a small trial involving 30-40 patients.

That’s great and Norway  has already produced a much larger study and is years ahead of everyone.  That quick start is important given how long these treatment trials take and how long it can take to get approval for a drug.

A Rituximab Timeline

Let’s look at a Rituximab timeline. Fluge and Mella identified their first Rituximab responsive ME/CFS patient in 2004. Their three person case study was published in 2009.  Their 30 person placebo-controlled study was published in Oct. 2011. They began the 152 person multicenter trial at the end, if I remember correctly, of 2014. That study should end in late 2016/early 2017. It will take some time to analyze the results and then get them published. Perhaps we’ll see a paper in early 2018.

You can argue that moving from a small case-study in 2009 to a large multi-center trial beginning in 2014 is good progress and it probably is, but it’s still five years in the life of an ME/CFS patient.

The Big Lug

Much of the innovative research, both inside and outside the public sphere, is occurring in the U.S. but the Rituximab trials might never have happened for all the work that’s been done here. That’s something that ought to give one pause.  A possible new treatment for a disorder with no FDA-approved drugs occurs and the biggest and richest country in the world does nothing.

head in sand

The country with the biggest medical system in the world hasn’t figured in the Rituximab story at all yet

How does that happen? Norway got funding from both advocates and the government. UK advocates have raised $600,000 by themselves. No group has mounted a serious effort in the U.S. and federal funding for clinical trials is difficult to achieve.

It’s pretty clear right now that nothing’s going to happen around Rituximab in the U.S. until the Norwegian trial ends up in mid 2017. Say the Norwegian results published in 2018 are impressive and the U.S. gets a major year-long trial started in early 2019.  The results are in by mid-2020, they’re submitted for publication in early 2021, are published in mid-2021. The FDA examines the data from the US, Norwegian and UK trials and in early 2022 seven years from now, approves Rituximab for use in a subset of ME/CFS patients.

When U.S. – because of bureaucratic or institutional barriers or whatever, is simply sitting on the its hands everything takes longer. In another disorder the Oct 2011 Fluge/Mella study might have sparked an extensive U.S. treatment trial in 2012.  The first results of that multi-year trial might have been published in say 2015.  In this scenario with the big Norwegian study underway we’d have enough data to apply for FDA approval in two years.

An Unlikely Ally

The two studies have created an unlikely ally. Simon Wessely – the foremost proponent of the idea that ME/CFS is caused by poor coping and deconditioning – has been impressed enough by the results to call for a large trial. “There is now a strong case” he said  “to be made for a larger trial”.  Whatever you think of Wessely that’s a very helpful statement coming from a man of his background.

The silver in the lining of the United Kingdom’s embrace of CBT/GET is the extent to which they’ve funded it. The UK, per capita, has been far more generous with ME/CFS funding than the U.S. and they’ve shown the willingness to put significant dollars (or pounds) behind a treatment trial. Drug trials in the U.S., on the other hand, appear to be almost solely funded by pharmaceutical companies. Wessely – recently knighted – has a lot of pull in the U.K.  Could Wessely prod the UK government to get behind an enlarged Invest in ME Rituximab study? That would a be flip of major proportions.

Wessely also said “The belief that [CFS] is all in the mind has been around since the beginning,” he says. “It’s tragic that it might take a study like this to take sufferers seriously.” That’s quite a statement given his history. Check out how that statement jives with Wessely’s past ones in Simon Wessely’s Big Shift? CBT Icon Calls For Big Rituximab Trial

Conclusions

It was a remarkable thing to see almost half the study population exhibiting normal or near normal SF-36 and activity scores after three years.  Even if this is a small study the almost identical response rates (a strong 60 plus percent) found in it and the first study  are encouraging.

This study also demonstrated that give doses more often eliminates many of the relapses that dogged the patients in the first study and it presented more evidence that this powerful drug  is generally safe for use in ME/CFS patients.

As promising as the results of the first two studies are it should be noted that they are small studies and surprises may show up in the larger study underway. It is using the same improved treatment protocol used in this study. It’s results will probably not be published for several years.

In the meantime, this study prompted a major CBT advocate to call for larger studies and a smaller UK trial is in the process of being produced. (You can support that study here.)