Rituximab study in norway. An application to The Research Council of Norway

[deleder2k]

You have a remarkable way of explaining things. I think I got the most of it, even though I don't know much about medicine. Thank you so much!

I'll try to post updates from the Norwegian study as news become available.

 

[DanME]

Thank you so much, Dr. Edwards, your expertise in the field is always very informative. So we are able to hope for a response rate around 67% (maybe 50%, if we account the placebo effect). I like that, and I still believe Fluge and Mella's work will be a real game changer!

 

[deleder2k]

In the first study the two who experienced a placebo effect had ME for a short period of under 2 years. One of them had a history with psychiatry. New requirements for the new upcoming study is that the patient has had ME for 2-15 years. 5-15 years if the patient is suffering from a mild degree of M.E

 

[DanME]

They didn't publish anything on the 7-8 severe patients, right?

 

[deleder2k]

Nope.. nothing on the severe patients, and nothing on the Enbrel study.

 

[NK17]

As much as @Jonathan Edwards is our pillar here on PR on all matters regarding the use of Rituximab in autoimmune conditions as well as being an educator in the classic sense of the word, meaning that he wants to bring out the best from us and raise the level of the discussion/s.
I have to say that both @deleder2k's and @DanielBR's interventions and informations are absolutely exceptional and invaluable!
Thank you, takk, danke .

 

[Jonathan Edwards]

As much as @Jonathan Edwards is our pillar here on PR on all matters regarding the use of Rituximab in autoimmune conditions as well as being an educator in the classic sense of the word, meaning that he wants to bring out the best from us and raise the level of the discussion/s.
I have to say that both @deleder2k's and @DanielBR's interventions and informations are absolutely exceptional and invaluable!
Thank you, takk, danke .

I will second that. I am learning a huge amount here in this discussion. The others are doing all the real hard work on the literature and the tricky questions.

Oystein Fluge has said to me that he thinks very severe patients may respond less well to the current protocol. I am not sure if we should read anything more in to that.

As Deleder2k points out the entry criteria are a bit different this time. There is no doubt that there is a risk of a 'dilution' effect with a big multicentre trial but I think they have done as much as they can to offset that by powering the study adequately. There is a sort of catch22 here - the bigger the study the bigger it needs to be. I actually think we need a completely different way of getting hard statistical endpoints out of trials in ME. The hope is that one can do that using pharmacodynamic analysis but it is hideously complicated and we do not yet have a reliable yardstick. People are working on it, but I will not say more until things have become a bit clearer.

 

[Sasha]

I remember reading somewhere that for their first RCT, Drs Fluge & Mella recruited patients with some sort of focus on neurological symptoms. I vaguely remember that they might have been referred patients via a neurology unit (which would naturally get PWME with more predominant symptoms, or maybe that's just where PWME end up in Norway). Not sure if that would make the patients unrepresentative, given that neurological symptoms feature heavily on the serious diagnostic criteria (the CCC). My memory is all a bit vague on this, though.

 

[Jonathan Edwards]

Yes, the patients were recruited from a neurologist for the first trial. I don't know what services are getting involved in the new study, however.

 

[A.B.]

In the first study the two who experienced a placebo effect had ME for a short period of under 2 years. One of them had a history with psychiatry. New requirements for the new upcoming study is that the patient has had ME for 2-15 years. 5-15 years if the patient is suffering from a mild degree of M.E

Thanks, I was just looking at the study and was wondering about that.

I'm guessing the placebo responder who had ME for fewer than two years is patient B in figure 4. The symptom scores steadily improve over time. Isn't this what you would see in a case of post-viral fatigue (or something similar) being misdiagnosed as ME?

 

[Sasha]

Thanks, I was just looking at the study and was wondering about that.

I'm guessing the placebo responder who had ME for fewer than two years is patient B in figure 4. The symptom scores steadily improve over time. Isn't this what you would see in a case of post-viral fatigue being misdiagnosed as ME?

I've just checked my vague memory (all so vague!) an issue about the placebo-responders not being CCC and this below suggests that one of them wasn't:

http://www.mecfsforums.com/index.php?topic=10036.150

As far as diagnosis, the patients were diagnosed by a neurologist at a "tertiary referral clinic" at a hospital by Fukuda criteria. I do not believe that Fluge and Mella don't understand what CFS is...it is clear that they have researched the topic thoroughly and are studying real ME for the most part. They did go back and checked the patients with the CCC, and 28 of the 30 met CCC. Of the two who did not, both were in the placebo arm, and one of them had a remission and was counted as one of the two placebo responders.​

If that placebo responder wasn't CCC then possibly they weren't a PWME and their "placebo response" was a natural remission from whatever they had (being in a placebo group is also controlling for simply not being treated, in most study designs: I think we don't know that PWME have any placebo response of any magnitude). That being so, the true response rate is going to be closer to the 67% (not that arguing the toss over one or two patients in a sample this small is going to tell us too much).

 

[deleder2k]

This is a letter from the doctor in charge for the study at The University Hospital of North Norway in Tromsø. This hospital required a diagnosis from a hospital, but i underline that this is not a requirement given by Haukeland University Hospital who manages the study. This translate was done mainly by Google, so I am not to blame

We are looking for participants to a study.

Physical and rehabilitation medical department of the University Hospital in North Norway is seeking participants for a study that examines whether Rituximab may be an effective treatment for CFS / ME. The study is conducted by five collaborating hospitals (Haukeland University Hospital, Oslo University Hospital, Telemark Central Hospital Department Notodden, St. Olav's Hospital in Trondheim and the University Hospital of North Norway).

To participate in the study, you must be between 18 and 65, be diagnosed with a mild, moderate or severe ME, and have had symptoms of ME in 2-15 years (5-15 years if you have a mild degree ME). Patients who are bedridden can not participate in the study.

You have to have a diagnosis from a University Hospital or another hospital department that diagnoses patients with CFS / ME. The patient has to fulfill the Canada criteria. Other diseases that can cause symptoms must be excluded, and you may not have had a history of cancer or systemic treatment with immunosuppressive medicines.

Pregnancy preclude participation in the study and it must use effective contraception prior to initiation of treatment and the first 12 months after the last treatment, i.e the first 2 1/2 years after the start of treatment. Women who are breastfeeding can not participate in the study.

The study conducted with a double-blinded design, meaning that neither the patient nor the investigator knows whether the patient has received the active drug or placebo (an inactive substance believed). This will prevent the patient or the investigator's belief or lack of belief in the active drug affect the outcome of the study. This means that the chances are equally good that you get the inactive (placebo) as the active substance (rituximab) in the study. The treatment can cause side effects.

The study implies that you must keep a record of symptoms, your progress every other week throughout the study period (24 months.) With respect to disease symptoms and possible side effects of treatment. It shall also be conducted activity monitoring using a small bracelet (SenseWear) on the arm of the patient, in 7 consecutive days prior to the first infusion to monitor physical activity. The use of SenseWear will be repeated after 17 to 21 months.

It is desirable that patients do not use other medications (including herbal remedies) or treatments that can affect the symptoms of ME during the observation period (ie at least 2 years from start of treatment), without it being clarified with the responsible study physician. Medicines for other illness onset may be used when necessary, after review by a doctor. All medications you use at the start of treatment and changes in medications will be monitored.

At Universtiy Hospital of North Norway a total of 24 patients will participate in the study. If you are interested to attend, we ask you to consider whether you meet the above conditions. In addition, you must carry out regular filling of questionnaires and meet about 12 times over two years in Tromsø.

If this applies to you please contact the department's head Christoph Schäfer in 08.15.2014 by sending an e-mail christoph.schaefer@unn.no or letter to

Physical and Rehabilitation Medical Branch v / Christoph Schäfer University Hospital of North Norway mailbox 1

9038 Tromsø

The email / letter should include how long you have been ill, when you were examined and contact with telephone number. We ask that in the first place is not attached to hospital records, or other confidential information. If there are more applicants than places in the study, a drawing between applicable patients will be held. Those who have previously approached our department or Department of Oncology at Haukeland hospital to participate in the study do not need to apply again.

 

[deleder2k]

Thanks, I was just looking at the study and was wondering about that.

I'm guessing the placebo responder who had ME for fewer than two years is patient B in figure 4. The symptom scores steadily improve over time. Isn't this what you would see in a case of post-viral fatigue (or something similar) being misdiagnosed as ME?

That could be. One of the patients had M.E for 0.9 years...

 

[Sasha]

Good to see that they want to use a form of actimeter - I think this ought to be mandatory in trials of therapies for ME.

 

[greeneagledown]

@Jonathan Edwards -- I don't know what treatment schedule Fluge and Mella are using for the big trial, but let's say hypothetically that it's the same regimen they used in their most recent open-label study: 2 doses at the beginning, then one follow-up dose at 3, 6, 10 and 15 months. Let's also say hypothetically that the study is very successful, but that for a lot of responders, the response only lasts about 2 years (which I believe is what they saw in the open-label study). Leaving aside issues of cost, would it be reasonably safe for patients to go through that regimen -- 6 doses in 15 months -- every two or three years? With that dosing frequency, wouldn't you essentially be without B cells -- and without any antibodies -- a majority of the time? Is that a major problem?

Obviously, the hope is that some people will have long-term remission, but F&M's experience thus far seems to suggest that a significant portion of responders wouldn't go into long-term remission and would need some sort of continuous regimen like the one outlined above.

I know this is an issue that you've discussed in general terms, but I was hoping to get your take on this particular treatment schedule.

Thanks.

 

[Jonathan Edwards]

@Jonathan Edwards -- I don't know what treatment schedule Fluge and Mella are using for the big trial, but let's say hypothetically that it's the same regimen they used in their most recent open-label study: 2 doses at the beginning, then one follow-up dose at 3, 6, 10 and 15 months. Let's also say hypothetically that the study is very successful, but that for a lot of responders, the response only lasts about 2 years (which I believe is what they saw in the open-label study). Leaving aside issues of cost, would it be reasonably safe for patients to go through that regimen -- 6 doses in 15 months -- every two or three years? With that dosing frequency, wouldn't you essentially be without B cells -- and without any antibodies -- a majority of the time? Is that a major problem?

Obviously, the hope is that some people will have long-term remission, but F&M's experience thus far seems to suggest that a significant portion of responders wouldn't go into long-term remission and would need some sort of continuous regimen like the one outlined above.

I know this is an issue that you've discussed in general terms, but I was hoping to get your take on this particular treatment schedule.

Thanks.

The main safety issues with rituximab relate to infusion reactions following the first dose. Reaction rates are very low in units with nurses who know exactly how to titrate the infusion rate - as you will get in an oncology unit or a unit like ours at UCL where we use a lot of rituximab. Reaction rates are higher with inexperienced staff. There are also a small number of cases of pneumonia/pneumonitis a few days after the first infusion which is probably an immune reaction rather than an infection. Mostly this resolves rapidly. It is only a serious issue in my experince in people who already have major lung problems like emphysema or as part of their illness (e.g. lupus). These problems are independent of the follow up regime.

More directly related to your question, it does not seem to matter much if you have no B cells. This surprised all of us at first but it makes sense. Antibodies are made by plasma cells and the plasma cells that make antibodies to infections last for years. For some reason quite a lot of autoantibody producing plasma cells seem only to last a few months so by good luck rituximab takes away the disease antibodies but not the protective ones. For some autoimmune conditions the autoantibodies hang on as well and that may be a reason for slow or poor response.

B cells themselves are really only there to meet new infections and generate new sorts of plasma cells. Most adults probably have a good range of plasma cells so can manage without B cells for ages. We know of people with no B cells for five years with no problems.

So to be specific, I think it is entirely reasonable to keep people with no B cells for 20 months - which is about what this protocol will do. We have thought of doing that for RA and in some cases we end up keeping people without B cells for even longer, but we do not do this as standard. (Note that the license for RA allows giving rituximab every 6 months for ever - which means no B cells for ever - which was not my idea.) The other thing is that you can measure antibody levels as you go along and change the schedule accordingly. I am quite sure that if in Norway a patient on the trial was starting to show low total antibody levels that rituximab would be held off until things improved. We do that all the time at UCL and it is very rare for antibody levels to drop seriously without warning.

Even having no antibodies at all (agammaglobulinaemia) is not as disastrous as one might think. People with genetic agammaglobulinaemia get infections but once the problem is identified they manage pretty normally with replacement therapy. In our experience with rituximab I think we only needed to give antibody replacement temporarily to 3 out of about 250 patients.

To put it another way, the Norwegian team know exactly what they are doing with this schedule and if it turns out to work I do not think safety will be a major issue.

 

[deleder2k]

If the plan is to keep people with no B cell for 20 months - what is the plan after that period has passed? Do one wait until b-cell production is back before maintenance therapy with Rituximab? Wouldn't that lead to a relapse every 20 months?

 

[Jonathan Edwards]

If the plan is to keep people with no B cell for 20 months - what is the plan that period has passed? Do one wait until b-cell production is back before maintenance therapy with Rituximab? Wouldn't that lead to a relapse every 20 months?

Yes, that is the simple reality of it. And it does not seem like a long term answer, I agree. But it is where we are in RA and so far it seems to be practical in the medium term. Both Oystein Fluge and I feel that rituximab alone as used now can only be an interim solution, but it has the great advantage that it tells us what we are trying to achieve. And we have patients with RA who have been very happy on rituximab for up to fifteen years - and we do not even get any permanent remissions in RA - they all need retreatments. I guess I would say that if ME is as bad as it looks to me it is for many people then a holding operation that is good for ten years is probably pretty encouraging!

 

[deleder2k]

But could one go without b cells for 10 years? Do we know if it is safe? If not the question is whether one can do a Rituximab infusion in time before the disease gets really bad again. I hope you'll learn more about that at UCL.
What about plasma exchange when a patient is facing relapse?

I recall that you said every individual produces b cells in a different cycle. The issue is then to find out each patients cycle.

I also think of all the patients treated by Øystein Fluge at Haukeland who still havent relapsed. Will they relapse or not? That's the million dollar question.

Sometimes I wish I could fast forward 5 years and see where we would be. I hope we will see a lot of big news in the coming years. Rituximab is not the answer to M.E, but it looks like it could be beneficial for a majority of patients as you say, @Jonathan Edwards.

 

[A.B.]

If Rituximab is confirmed to be effective in a significant portion of ME/CFS patients, it will be hard to continue labelling this illness as psychosomatic.