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

[Marky90]

Look at this guys,

http://www.ncbi.nlm.nih.gov/pubmed/26438161

Seems like good research?

 

[snowathlete]

I think the idea of trialing various cytokine inhibitory drugs is potentially a good idea. They are talking about starting with a trial of anakinra which is used in RA to inhibit IL-1. @Jonathan Edwards - is this a worthwhile endeavour in your opinion?

 

[John Mac]

" The results of this study may expand treatment options for patients with CFS, for whom graded exercise therapy and cognitive behavioral therapy are the only evidence-based interventions that exist at this moment."

Really? What about Rituximab?

 

[Marky90]

" The results of this study may expand treatment options for patients with CFS, for whom graded exercise therapy and cognitive behavioral therapy are the only evidence-based interventions that exist at this moment."

Really? What about Rituximab?

Yeah... I hope they just haven`t heard of it. This kinda proves what i already fear: that most people don`t actually read the studies that are supposed to prove that CBT and graded exercise therapy works.. They seem to often take the conclusion for fact.

 

[lansbergen]

Yeah... I hope they just haven`t heard of it. This kinda proves what i already fear: that most people don`t actually read the studies that are supposed to prove that CBT and graded exercise therapy works.. They seem to often take the conclusion for fact.

This lot is in bed with the weasel.

 

[snowathlete]

" The results of this study may expand treatment options for patients with CFS, for whom graded exercise therapy and cognitive behavioral therapy are the only evidence-based interventions that exist at this moment."

Really? What about Rituximab?

Although it's annoying, I think their point is that GET and CBT are the only approved treatments at the moment (even though the eveidence for them is actually shockingly bad - wish they had therefore not referred to them as "evidence-based") and although Rituximab already has better evidence than all the GET and CBT studies put together it is not a recognised, approved treatment yet, and it wont be until at least the Norwegian phase 3 study is out.

 

[Simon]

Note this is a protocol for a planned study.

I actually think the idea is pretty good idea, not least because of what it might reveal about mechanisms (as opposed to treatment options). If the IL-1 inhibitor anakinra reduces fatigue, it's evidence that IL-1 plays a role in fatigue. And anakinra apparently crosses the blood brain barrier, so if IL-1 plays a pathological role in the brain, anakinra could help identify that too.

The information regarding the possible role of cytokines in the pathophysiology could come from intervention studies in which the activities of relevant cytokines are reduced, for example, reducing interleukin-1, interleukin-6 or tumor necrosis factor.

Cytokine inhibition in chronic fatigue syndrome patients: study protocol for a randomized controlled trial.
Roerink ME1, Knoop H2, Bredie SJ3, Heijnen M4, Joosten LA5, Netea MG6, Dinarello CA7, van der Meer JW8.
Author information
Abstract
BACKGROUND:
Chronic fatigue syndrome (CFS) is a medically unexplained syndrome for which no somatic or pharmacological treatment has been proven effective. Dysfunction of the cytokine network has been suspected to play a role in the pathophysiology of CFS. The disturbances of the cytokine network detected in CFS patients are highly variable, in part due to the lack of adequate controls in many studies. Furthermore, all studies have been performed on peripheral venous blood of patients. As cytokines mainly act in tissues, for example, the brain, the information that can be derived from peripheral blood cells is limited. The information regarding the possible role of cytokines in the pathophysiology could come from intervention studies in which the activities of relevant cytokines are reduced, for example, reducing interleukin-1, interleukin-6 or tumor necrosis factor. In this study, the clinical usefulness of anakinra, an IL-1 antagonist, will be assessed in patients with CFS.

METHODS/DESIGN:
A randomized placebo-controlled, double-blind trial will be conducted. Fifty adult female patients meeting the Centers for Disease Control (CDC) criteria for CFS and without psychiatric co-morbidity will be included. After inclusion, patients will be randomized between treatment with anakinra (recombinant human interleukin-1 receptor antagonist) or placebo. Each group will be treated for 4 weeks. Outcome measures will be assessed at baseline, after 4 weeks of intervention, and 6 months after baseline assessment. The primary outcome measure will be fatigue severity at 4 weeks, measured with the validated Checklist of Individual Strength (CIS). Secondary outcome measures are functional impairment, physical and social functioning, psychological distress, pain severity, presence of accompanying symptoms, and cytokine and cortisol concentrations.

DISCUSSION:
This is the first randomized placebo-controlled trial that will evaluate the effect of interference with IL-1 on the experience of fatigue in patients with CFS. The results of this study may expand treatment options for patients with CFS, for whom graded exercise therapy and cognitive behavioral therapy are the only evidence-based interventions that exist at this moment.

TRIAL REGISTRATION:
Clinicaltrials.gov: NCT02108210 . Clinicaltrials.gov registration date: 8 April 2014. EudraCT: 2013-005466-19.

 

[snowathlete]

This lot is in bed with the weasel.

Knoop's name is on a few dodgy papers, as is Van der Meer's. The others don't seem to have much history, and I don't know anything about them.

 

[snowathlete]

http://arni.uk.com/pdf/CIS.pdf this appears to be the primary endpoint.

 

[Sidereal]

Free full text:

http://www.trialsjournal.com/content/16/1/439

 

[Valentijn]

The primary outcome measure will be fatigue severity at 4 weeks, measured with the validated Checklist of Individual Strength (CIS).

Useless bullshit. It's a cytokine treatment trial, but cytokines are only a secondary measure, and all of the focus is on fatigue. Get rid of the psychobabbler and use your brains.

 

[Gijs]

Why don't they measure these cytokines before and after treatment? This is how real objective science works. Otherwise it is sloppy science. Still i do hope it works but i doubt it.

 

[Bob]

Fukuda!

Also, will they only select patients who test for abnormal levels of IL-1 or will there be no attempt at a rigorous trial methodology? Are they just going to randomly include all Fukuda CFS patients (without psychiatric comorbidity) whatever their cytokine levels? If so then... Doh! Fail! #yetanotherwasteofresources

 

[Jonathan Edwards]

I think the idea of trialing various cytokine inhibitory drugs is potentially a good idea. They are talking about starting with a trial of anakinra which is used in RA to inhibit IL-1. @Jonathan Edwards - is this a worthwhile endeavour in your opinion?

I think this has to be worth trying, although the absence of raised CRP in ME suggests that symptoms are probably not generated by a typical IL-1 and TNF cytokine drive. TNF inhibitors have already been tried and I think the trials were discontinued for unpromising results.

 

[Jonathan Edwards]

Yeah... I hope they just haven`t heard of it. This kinda proves what i already fear: that most people don`t actually read the studies that are supposed to prove that CBT and graded exercise therapy works.. They seem to often take the conclusion for fact.

The authors will be well aware of the quality of data for CBT and GET, of the recent debate about that and the rituximab data. I think it is fair to say that we do not yet have a formal evidence base for rituximab, but that probably applies to CBT and GET as well.

 

[Jonathan Edwards]

Knoop's name is on a few dodgy papers, as is Van der Meer's. The others don't seem to have much history, and I don't know anything about them.

Charles Dinarello more or less discovered IL-1 - i.e. he sort of invented cytokines. If he is taking an interest in IL-1 in ME that should be worth a glass of Cava, if not Champagne.

 

[Jonathan Edwards]

Why don't they measure these cytokines before and after treatment? This is how real objective science works. Otherwise it is sloppy science. Still i do hope it works but i doubt it.

I am not sure I agree about that. IL-1 might well be acting locally, with nothing to find in the blood. Doing blood levels would be sensible and I expect they will do them, but they certainly should not be the primary outcome measure. If you think about it showing that an IL-1 inhibitor inhibits IL-1 in PWME tells you nothing whatsoever about ME - just that you put the right drug in the bottle. The end point is designed to show that in PWME the inhibitor benefits symptoms - i.e. fatigue, so fatigue is precisely the right endpoint!

 

[Bob]

This is from the full protocol. It's a secondary outcome to be measured at baseline, and directly following the intervention, and at 6 months...

6. Cytokine concentration in blood. The cytokine concentrations in blood (plasma and blood in Pax-gene tubes) will be determined. Our study can provide additional information regarding cytokine levels because we have the opportunity to compare cytokine concentrations with healthy neighborhood controls. Also we will compare pre-treatment concentrations with post-treatment concentrations.

 

[Effi]

Knoop's name is on a few dodgy papers, as is Van der Meer's. The others don't seem to have much history, and I don't know anything about them.

They're all from Radboud Nijmegen (the Netherlands). They're the ones who throw CBT at everything (MS, post-cancer fatigue, post-polio syndrome, cfs, ...). One patient who was in this trial said that they offered voluntary CBT to everyone in the trial, almost like an incentive I guess in their minds?

 

[Valentijn]

I think this has to be worth trying, although the absence of raised CRP in ME suggests that symptoms are probably not generated by a typical IL-1 and TNF cytokine drive.

My CRP was raised the one time it was tested