Cytokine Inhibition in Chronic Fatigue Syndrome Patients

NCT ID: NCT02108210

Last Updated: 2016-05-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-06-30
• Study Completion Date: 2016-05-31

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.

Conditions

Chronic Fatigue Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Anakinra

This therapy will consist of once daily subcutaneous injections (100mg/day) during a period of 4 weeks. Patients will be monitored at week 1 and week 4 after starting medication for development of side effects. Therapy will be stopped in case of severe side effects, interfering disease or pregnancy. During the intervention period, use of co-medication is only allowed when used for ≤14 consecutive days, on the condition that there are no known interactions with anakinra. Oral contraceptives and/or paracetamol can be used without a limitation. During the follow-up period, there are no limitations regarding the use of medication. All co-medication will be registered precisely and reported afterwards.

Group Type: EXPERIMENTAL

Anakinra

Intervention Type: DRUG

Placebo

Patients in the placebo group will also receive once daily subcutaneous injection during a period of 4 weeks. Placebo injections will be identically in appearance compared to the Anakinra injections. Patients in the placebo group will have the same visits and monitoring for side effects as the patients randomized to the other treatment arm.

During the intervention period, use of co-medication is only allowed when used for ≤14 consecutive days, on the condition that there are no known interactions with anakinra. Oral contraceptives and/or paracetamol can be used without a limitation. During the follow-up period, there are no limitations regarding the use of medication. All co-medication will be registered precisely and reported afterwards.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

Anakinra

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Other Intervention Names

Kineret

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 59 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jos van der Meer, Prof, PhD, MD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

RadboudUMC

Nijmegen, Gelderland, Netherlands

Countries

Netherlands

References

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.

Reference Type: DERIVED

PMID: 29284500 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28265678 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26438161 (View on PubMed)

Other Identifiers

2013-005466-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL47571.091.14

Identifier Type: OTHER

Identifier Source: secondary_id

R0002198

Identifier Type: -

Identifier Source: org_study_id