Cytokine Inhibition in Chronic Fatigue Syndrome Patients

NCT02108210 | Completed Phase 2 DMC

• 3 other identifiers: R00021982013-005466-19NL47571.091.14
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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

Keywords

Chronic fatigue syndrome; Cytokines; Interleukin-1; Fatigue; Anakinra

Outcome Measures

Primary Outcomes (1)

• CIS (checklist individual strength, compared to baseline)

  To investigate the role of the cytokine IL-1 in the pathogenesis of CFS and to find leads for future treatment of CFS, a disorder for which there is no proven effective drug treatment. The primary outcome measure will be fatigue severity at 4 weeks measured with the Checklist Individual Strength (CIS).

  4 weeks, measurement will be repeated up to 26 weeks

Secondary Outcomes (7)

• SIP8 (sickness impact profile, change from baseline)

  4 weeks, measurement will be repeated up to 26 weeks

• SF-36 (subscale physical functioning and social functioning, compared to baseline)

  4 weeks, measurement will be repeated up to 26 weeks

• SCL-90 (symptom checklist-90, compared to baseline)

  4 weeks, measurement will be repeated up to 26 weeks

• VAS pain (visual analog scale, compared to baseline)

  4 weeks, measurement will be repeated up to 26 weeks

• Cortisol in saliva and hair (concentration compared to baseline)

  4 weeks

Other Outcomes (2)

• Body temperature

  4 weeks, measurement will be repeated up to 26 weeks

• pulse rate

  4 weeks, measurement will be repeated up to 26 weeks

Study Arms (2)

Anakinra

EXPERIMENTAL

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.

Drug: Anakinra

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Interventions

Anakinra DRUG

Also known as: Kineret

Anakinra

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years - 59 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

RadboudUMC

Nijmegen, Gelderland, 6500HB, Netherlands

Location

Related Publications (3)

• 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.

  PMID: 29284500 DERIVED

• 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.

  PMID: 28265678 DERIVED

• 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.

  PMID: 26438161 DERIVED

MeSH Terms

Conditions

Fatigue Syndrome, Chronic; Fatigue

Interventions

Interleukin 1 Receptor Antagonist Protein

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Encephalomyelitis; Neuroinflammatory Diseases; Nervous System Diseases; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Jos van der Meer, Prof, PhD, MD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 21, 2014
• First Posted: April 9, 2014
• Study Start: June 1, 2014
• Primary Completion: December 1, 2015
• Study Completion: May 1, 2016
• Last Updated: May 25, 2016

Record last verified: 2016-04

Locations

NL (1)