Clinical trial NCT02108210: Cytokine Inhibition in Chronic Fatigue Syndrome Patients
Official title: Cytokine Inhibition in Chronic Fatigue Syndrome Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Chronic Fatigue Syndrome
Keywords: Chronic fatigue syndrome
Cytokines
Interleukin-1
Fatigue
Anakinra
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2014-04-09
Enrollment: 50
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Rationale: 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. Although derangements of the cytokine network in CFS are controversial, a major problem is that many studies did not use adequate controls. In addition, all studies have been performed on peripheral venous blood of the patients. As cytokines mainly act in the tissues, e.g., the brain, the information that can be derived from peripheral blood cells is limited. The only information regarding the possible role of cytokines in the pathophysiology of CFS could come from intervention studies in which pathogenetically important cytokines are inhibited. A potentially relevant cytokine which can be blocked in humans without severe side effects is IL-1. Although it is plausible that these cytokines play a role in CFS, there is limited evidence for this.

Objective: To investigate the effect on symptomatology of interference with IL-1 in CFS patients.

Study design: A randomized placebo controlled study will be performed to determine whether interference with IL-1 is able to reduce fatigue and disabilities in CFS patients.

Study population: Female CFS patients without psychiatric co-morbidity will be included in this study. Patients of the outpatient clinic of the Department of General internal medicine and the Expert Centre for Chronic Fatigue (ECCF) will be asked to participate in the study. Patients will be asked to bring a healthy neighbourhood control to their first study visit.

Intervention: After inclusion patients will be randomized to receive one of the following treatments:

* interleukin-1 inhibitor Anakinra (IL-1Ra) for 4 weeks (N=25);
* placebo for 4 weeks (N=25).

Main study parameters/endpoints: The primary outcome measure will be fatigue severity measured with the Checklist Individual Strength (CIS) at 4 weeks, measurement will be repeated up to 26 weeks.

Secondary outcome measures will be:

* level of functional impairment measured with the Sickness Impact Profile (SIP8) total score;
* physical and social functioning assessed with the subscale physical functioning and social functioning of the SF-36;
* level of psychological distress assessed with the total score on the Symptom Checklist-90 (SCL-90);
* pain severity assessed with a Visual Analog Scale (VAS);
* cytokine measurement in blood (plasma and blood in Pax-gene tubes) and saliva (at protein and mRNA level);
* cortisol measurement in saliva and hair;
* microbiome determination in faeces;
* body temperature and pulse rate.


Eligibility criteria: Inclusion Criteria:

* CDC-diagnosed CFS-patients;
* female, between 18 and 59 years old;
* fatigue duration ≤10 years, or significant increase of complaints during the last 10 years
* score of ≥40 on the subscale fatigue severity of the CIS (Checklist Individual Strength);
* marked functional impairment assessed with the Sickness Impact Profile (SIP-8) and operationalised as a total score of ≥700.

Exclusion Criteria:

* pregnant or nursing women;
* women who intend to get pregnant during the study;
* fatigue duration \>10 years;
* patients who use or have used psychotropic medication in the past month;
* substance abuse in the past 3 months;
* patients taking any medication except oral contraceptives and/or paracetamol;
* patients with evident somatic co-morbidity;
* previous or current engagement in CFS research;
* inability to understand the nature and the extent of the trial and the procedure required;
* psychiatric co-morbidity (major depression, psychosis, eating disorders, anxiety disorders, bipolar disease and post traumatic stress disorder) assessed with the MINI;
* live vaccination during the past four weeks;
* current engagement in a legal procedure with respect to disability claims.

Primary outcomes:
measure: CIS (checklist individual strength, compared to baseline)
timeFrame: 4 weeks, measurement will be repeated up to 26 weeks
Secondary outcomes:
measure: SIP8 (sickness impact profile, change from baseline)
timeFrame: 4 weeks, measurement will be repeated up to 26 weeks
measure: SF-36 (subscale physical functioning and social functioning, compared to baseline)
timeFrame: 4 weeks, measurement will be repeated up to 26 weeks
measure: SCL-90 (symptom checklist-90, compared to baseline)
timeFrame: 4 weeks, measurement will be repeated up to 26 weeks
measure: VAS pain (visual analog scale, compared to baseline)
timeFrame: 4 weeks, measurement will be repeated up to 26 weeks
measure: Cortisol in saliva and hair (concentration compared to baseline)
timeFrame: 4 weeks
measure: microbiome determination faeces
timeFrame: at baseline
measure: cytokine concentrations in blood and saliva (compared to baseline)
timeFrame: 4 weeks
Other outcomes:
measure: Body temperature
timeFrame: 4 weeks, measurement will be repeated up to 26 weeks
measure: pulse rate
timeFrame: 4 weeks, measurement will be repeated up to 26 weeks
Locations:
city: Nijmegen
country: Netherlands
facility: RadboudUMC
state: Gelderland
Study officials:
affiliation: Radboud University Medical Center
name: Jos van der Meer, Prof, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Roerink ME, Knoop H, Bronkhorst EM, Mouthaan HA, Hawinkels LJAC, Joosten LAB, van der Meer JWM. Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment. J Transl Med. 2017 Dec 29;15(1):267. doi: 10.1186/s12967-017-1371-9.
citation: Roerink ME, Bredie SJH, Heijnen M, Dinarello CA, Knoop H, Van der Meer JWM. Cytokine Inhibition in Patients With Chronic Fatigue Syndrome: A Randomized Trial. Ann Intern Med. 2017 Apr 18;166(8):557-564. doi: 10.7326/M16-2391. Epub 2017 Mar 7.
citation: Roerink ME, Knoop H, Bredie SJ, Heijnen M, Joosten LA, Netea MG, Dinarello CA, van der Meer JW. Cytokine inhibition in chronic fatigue syndrome patients: study protocol for a randomized controlled trial. Trials. 2015 Oct 5;16:439. doi: 10.1186/s13063-015-0971-z.