Cytokine inhibition - a randomized placebo-controlled, double-blind trial

[Jonathan Edwards]

James Coyne said this on Twitter: "This trial exploits #CFS patients, is unethical if consent does not inform no scientific basis for cytokine target."

But surely the patients would be informed that the use of the drug is highly speculative and it is uncertain if IL-1 is involved at all?

I can't tell from the article.

Yes, I am surprised by that comment. I can imagine that the patients might not get a very balanced account of the reasons for trying IL-1 inhibition. The evidence for IL-1 being a mediator of ME is weak. But if the trial is carried out properly it would actually tell us something important scientifically if it produced no benefit. And anakinra is a reasonably safe drug to give. If I had ME and knew what I know at present I would probably volunteer for the trial if I was happy with the methodology otherwise.

 

[Gijs]

I think that CBT and especially GET is unethical. There is no scientific basis for this therapy.

 

[Jonathan Edwards]

I think that CBT and especially GET is unethical. There is no scientific basis for this therapy.

There is at least as much scientific basis for this trial than there was for the rituximab trial. A number of ME symptoms are similar to symptoms suffered by people whose diseases are mediated by cytokines. And Dr Fluge has also run an anti-TNF trial on that basis.

 

[Gijs]

There is at least as much scientific basis for this trial than there was for the rituximab trial. A number of ME symptoms are similar to symptoms suffered by people whose diseases are mediated by cytokines. And Dr Fluge has also run an anti-TNF trial on that basis.

No, i don't mean the IL1 trial but CBT/GET I am very happy with the IL1 trial. I hope it will work.

 

[Jonathan Edwards]

No, i don't mean the IL1 trial but CBT/GET I am very happy with the IL1 trial. I hope it will work.

Sorry, I misattributed 'this therapy'.

 

[BurnA]

Sorry, I misattributed 'this therapy'.

Whew! I was getting worried there.

 

[FancyMyBlood]

I'm not as negative as most of you. Sure, the inclusion criteria (CDC) are a bit to broad and I know Radboud doesn't really have a good reputation re: ME/CFS, but I believe they genuinely want to give this drug a fair go and are open to change their opinion if it demonstrates benefit.

You know, they really didn't have to start this study. They have nothing to gain from it - in contrary- (although van der Meer has said he really wanted to find a biological cause) and there is no real evidence IL-1 is/isn't involved in ME/CFS, so I don't really have a negative opinion about this study.

 

[user9876]

I actually think that if this score system is used:


I feel tired.
Physically I feel exhausted.
I feel fit.
I feel powerless.
I am rested.
Physically I feel I am in bad form.
I tire easily.
Physically I feel I am in an excellent condition.

and a truly blinded study is done then if no difference at all is seen the drug is pretty useless and if a big difference is seen the drug is worth investigating further. I would have thought it would work for almost any disease that limits mobility. I am pretty sure if I used it for my RA rituximab trial it would have given the right result. As we have discussed in the thread on end points I am sure one could do much better but if the study is truly blinded this sort of endpoint is fine.

For me the key to improving the quality of research is to get the critique precisely on target. The problem with PACE is the combination of no blinding and this sort of end point. This study does not appear to suffer from that - although blinding is easily broken. That is an important issue but if blinding is broken then none of these assessments are likely to be much good - even functional ones that might be affected by beliefs about the treatment.

The issue comes when trying to treat such question sets as if they are linear scales and scoring each adding up the scores and quoting mean differences and effect sizes.

 

[Jonathan Edwards]

The issue comes when trying to treat such question sets as if they are linear scales and scoring each adding up the scores and quoting mean differences and effect sizes.

I agree that the mathematical treatment is probably horrible. And if effects are modest that is crucial. But I actually think we are interested in major benefits if using biologics. There was a piece in the paper yesterday about a press release from Roche on the effect of ocrelizumab (the updated version of rituximab) in MS. It reduces relapses by 50% in comparison to beta interferon - i.e. not just against no treatment but 50% better than the best available treatment. With rituximab in RA 50% of patients got a lot better - enough for it to be identifiable with a scoring system just based on 'are you a lot better?'. If the treatment is blinded then I suspect that something pretty simple will do. The medical profession went through a period in the 1970s and 1980s when new treatments had marginal effects so that huge trials had to be set up with complicated assessments. So if something like CBT seems to give a statistically significant, but to be honest pretty marginal, effect everyone shouts Eureka!! We have a treatment, problem solved. But for biologic drugs there are always worries about serious adverse events so we are only interested if the result is barn door obvious anyway. And for rituximab in RA and ocrelizumab in MS it is, so that should be what is being aimed at.

Not that, as said, I don't agree that these scores are often a dreadful muddle and that trying to refine them would be very worthwhile - since one wants to get the maximum value out of any study.

 

[Valentijn]

You know, they really didn't have to start this study. They have nothing to gain from it -

It's not uncommon for psychobabblers to be involved with these sorts of studies with the intent to disprove something. Usually they will ensure that with bad study design, such as using too small of a patient sample, or an inappropriate patient sample, or inappropriate timing of endpoints, or inappropriate outcome measurements.

Though it can be fun watching them freak out when they still somehow come up with a result which would support biological disease theories and/or contradict psychological theories. The spin they apply then can be very inventive and highly entertaining

 

[Bob]

There was a piece in the paper yesterday about a press release from Roche on the effect of ocrelizumab (the updated version of rituximab) in MS. It reduces relapses by 50% in comparison to beta interferon - i.e. not just against no treatment but 50% better than the best available treatment.

There's a thread about this if anyone is interested in reading more:
http://forums.phoenixrising.me/inde...sis-drug-can-cut-relapses-by-nearly-50.40409/

 

[A.B.]

James Coyne said this on Twitter: "This trial exploits #CFS patients, is unethical if consent does not inform no scientific basis for cytokine target."

But surely the patients would be informed that the use of the drug is highly speculative and it is uncertain if IL-1 is involved at all?

I can't tell from the article.

I'm not sure if I can express this right. CFS demonstrates that there are illnesses we don't understand. Reasoning about the disease based on current knowledge will result in stagnation. We do need speculative and hypothesis generating studies because they're the only ones that can actually advance our knowledge at this point!

Is it unethical? Perhaps, but so is doing nothing and leaving patients to rot and die. We don't die quickly but we do die earlier than the normal population, and we suffer every day.

 

[Snow Leopard]

Is it unethical? Perhaps, but so is doing nothing and leaving patients to rot and die. We don't die quickly but we do die earlier than the normal population, and we suffer every day.

It is not unethical to trial the treatment. It is unethical to tell patients that there is a known mechanism of action for this disease.

 

[Effi]

It's not uncommon for psychobabblers to be involved with these sorts of studies with the intent to disprove something. Usually they will ensure that with bad study design, such as using too small of a patient sample, or an inappropriate patient sample, or inappropriate timing of endpoints, or inappropriate outcome measurements.

The same people have done a drug-related study before (2007 - acclydine) with negative outcome. After that study was published they made sure the media would report *again* that CBT is the only proven treatment - sounds familiar, right? I don't know how to interpret this study, so I'll just add the link, in case someone else has some insights: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876596/

 

[Gijs]

It's not uncommon for psychobabblers to be involved with these sorts of studies with the intent to disprove something. Usually they will ensure that with bad study design, such as using too small of a patient sample, or an inappropriate patient sample, or inappropriate timing of endpoints, or inappropriate outcome measurements.

Though it can be fun watching them freak out when they still somehow come up with a result which would support biological disease theories and/or contradict psychological theories. The spin they apply then can be very inventive and highly entertaining

I am also a little sceptical but i don't believe that professor van der Meer wants to disprove Anakinra is working in CFS/ME patiënts. He really wants to find something that helps and wanted to know the real cause of this disease. I am 100% sure. Lets hope this drug will help. I would try it if i had the change. I think rituximab is a lot more dangerous to try but i would also use this. I want to feel better. I am very happy Radboud is testing this drug. We will see.

 

[Valentijn]

The same people have done a drug-related study before (2007 - acclydine) with negative outcome. After that study was published they made sure the media would report *again* that CBT is the only proven treatment - sounds familiar, right? I don't know how to interpret this study, so I'll just add the link, in case someone else has some insights: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876596/

It looks very underpowered for the amount of comparisons made. 29 and 26 patients were in the Acclydine and placebo group, with two drop-outs who had their data manufactured for later time points. So the Acclydine group scores for IGF1 dropped 5.5 points from 43.2 to 37.7, while the placebo group dropped only 1 point from 37.3 to 36.3, yet there was no statistical significance.

They also seem to have invented a completely new and random dosing method for the Acclydine. Instead of taking the same dose for 14 weeks, they started with the maximum dose and decreased it every 2-3 weeks. By the end they were taking the minimal dose every other day, though I don't see that low of a dose being used anywhere else.

 

[Effi]

They also seem to have invented a completely new and random dosing method for the Acclydine. Instead of taking the same dose for 14 weeks, they started with the maximum dose and decreased it every 2-3 weeks. By the end they were taking the minimal dose every other day, though I don't see that low of a dose being used anywhere else.

thanks @Valentijn . I also found the treatment protocol (in English) from the Dutch manufacturer of Acclydine. One part of the treatment seems to be GET! What about that? http://www.cfsnova.com/accyldineProtOct.pdf

In time the IGF-1 level will be high enough to normalize the intake of lipids
and carbohydrates. For this reason, the 14-week protocol starts with a high dose of
Acclydine. During the protocol the Acclydine is decreased and activity must be
increased. There is no schedule available as to how to increase your activity. The
level of exercise strongly depends on the patient’s level of activity at the start of the
protocol. However, there are some guidelines.

It is important to develop a routine. Rise at approximately 8 o’clock and exercise 3
times per day (controlled). Always listen to your body. Every one is unique. It is
advised to set a schedule together with your therapist.

For people who stay in bed most of the day, it is necessary to start with caution. Try to
exercise the same way every day if this is the case. It might be better to start your
exercise in bed. Please start only a few minutes per day. After this period you can
start using a home-trainer cycle. However, only if the resistance and/or the speed are
controllable. Also walking stairs is a possibility. It is preferred to start exercising in
your home so the patient can control the environment. Outside weather, wind, and
temperature are always different. If you already exercise, it is advisable to increase
your exercise in a controlled manner. Don’t force the activity level, especially in the
beginning of the protocol. The beginning is important to build up your reserves.

If your body mass increases by more than 4 pounds per month, you should increase
the level of exercise. The gaining of too much weight is a signal that the body has
reserves but they are not being fully utilized.
Guidelines for home trainer cycle use for those who have little energy from CFS:
1. A daily exercise in the morning of 60 to 80 rotations per minute (RPM), lowest
resistance for 2 or 3 minutes.
2. Increase the rotation to 100 RPM if you feel comfortable with this.
3. Also exercise during the evening. Start with only a few minutes.
4. Gradually increase the duration of the exercise to 15 minutes in the morning and in
the evening.
5. Start exercising in the afternoon for a few minutes. Increase the exercise to 3 times
15 minutes per day.
6. Increase the duration of the exercise to 30 to 45 minutes per day.
7. If you are comfortable with it, increase the resistance level during step 1 to 6

 

[Bob]

A very brief mention in Charles Shepherd's write-up of the recent UK conference...

This group also briefly discussed the role of cytokine-mediated neuroinflammation and the new clinical trial involving a drug called anakinra that inhibits the pro-inflammatory cytokine IL-1. A member of the clinical trials group from The Netherlands had also joined this workshop.

http://www.meassociation.org.uk/2015/10/global-mecfs-research-22-october-2015/

 

[Bob]

Cort Johnson has written about the trial, here (I don't think there's any new info):
http://www.cortjohnson.org/forums/t...drome-trial-indicates-changes-occurring.3175/

 

[Dolphin]

Lily Chu had a letter published in reply:

Ann Intern Med. 2017 Sep 19;167(6):447-448. doi: 10.7326/L17-0316.
Cytokine Inhibition in Patients With Chronic Fatigue Syndrome.
Chu L(1).
Author information:
(1)From Burlingame, California.
DOI: 10.7326/L17-0316
PMID: 28975326

Ann Intern Med. 2017 Sep 19;167(6):448. doi: 10.7326/L17-0317.
Cytokine Inhibition in Patients With Chronic Fatigue Syndrome.
Roerink ME(1), Van der Meer JWM(1).
Author information:
(1)From Radboud University Medical Centre, Nijmegen, the Netherlands.
DOI: 10.7326/L17-0317
PMID: 28975327