Chronic Fatigue SyndromePhase 2/3CiCFSNCT02108210
Cytokine Inhibition in Chronic Fatigue Syndrome Patients
A Phase 2/3 study testing Anakinra in people with Chronic Fatigue Syndrome, run by Radboud University Medical Center at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 59 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Chronic Fatigue Syndrome
- What is being tested?
- Anakinra
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 50 participants
- Where
- 1 siteNetherlands
- Study dates
- Jun 2014to May 2016
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 59 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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;
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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
- Being tested
- Anakinra, Placebo
- Keywords
- Chronic fatigue syndrome, Cytokines, Interleukin-1, Fatigue, Anakinra
- Medical subject headings
- Fatigue Syndrome, Chronic, Fatigue
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AnakinraDrug
Also called Kineret
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 4 weeks, measurement will be repeated up to 26 weeks
Secondary outcomes (7)
SIP8 (sickness impact profile, change from baseline)
level of functional impairment
Measured: 4 weeks, measurement will be repeated up to 26 weeks
SF-36 (subscale physical functioning and social functioning, compared to baseline)
physical and social functioning assessed with the subscale physical functioning and social functioning of the SF-36
Measured: 4 weeks, measurement will be repeated up to 26 weeks
SCL-90 (symptom checklist-90, compared to baseline)
level of psychological distress assessed with the total score on the Symptom Checklist-90
Measured: 4 weeks, measurement will be repeated up to 26 weeks
VAS pain (visual analog scale, compared to baseline)
pain severity assessed with a Visual Analog Scale
Measured: 4 weeks, measurement will be repeated up to 26 weeks
Cortisol in saliva and hair (concentration compared to baseline)
Because of the possible role of the hypothalamus-pituitary-adrenal axis we will also measure the cortisol concentration in saliva and hair. For the baseline assessment, comparison will be made with matched neighbourhood controls.
Measured: 4 weeks
microbiome determination faeces
A new field of great interest in pathophysiology is the role of the microbial flora of the host (microbiome). The availability of well defined patients with CFS and matched controls is a great opportunity in an unexplored area of CFS research, to assess whether the microbiome of CFS patients is peculiar.
Measured: at baseline
cytokine concentrations in blood and saliva (compared to baseline)
In addition to the cytokine intervention, we will assess cytokines (at the transcriptional level and as proteins) in serum and saliva at baseline and after 4 weeks of intervention. For the baseline assessment, comparison will be made with matched neighbourhood controls.
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2014 (estimated)
- Study startJun 2014
- Primary completionDec 2015
- Study completionMay 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Chronic Fatigue SyndromeStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jos van der Meer, Prof, PhD, MD, Principal investigator, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02108210
- Sponsor's protocol ID
- R0002198
- Other IDs
- 2013-005466-19, NL47571.091.14
- Acronym
- CiCFS
- Status last verified
- Apr 2016
- First submitted
- 21 Mar 2014
- Last updated
- 25 May 2016
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 29284500Roerink 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.
PubMed 28265678Roerink 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.
PubMed 26438161
Study at a glance
From the registry record, last updated by the sponsor on 25 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cytokine Inhibition in Chronic Fatigue Syndrome Patients
- ClinicalTrials.gov ID
- NCT02108210
- Acronym / sponsor ID
- CiCFS / R0002198
- Conditions
- Chronic Fatigue Syndrome
- Keywords
- Chronic fatigue syndrome, Cytokines, Interleukin-1, Fatigue, Anakinra
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- Jun 2014
- Primary completion
- Dec 2015 (actual)
- Study completion
- May 2016 (actual)
- First posted
- 9 Apr 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Anakinra | Experimental | Drug: AnakinraThis 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. |
| Placebo | Placebo comparator | Drug: PlaceboPatients 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. |
Who may qualify
- Ages
- 18 to 59 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (12 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AnakinraAlso: Kineret | Drug | Anakinra |
| Placebo | Drug | Placebo |
Primary outcome
CIS (checklist individual strength, compared to baseline)
Time frame: 4 weeks, measurement will be repeated up to 26 weeks
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).
7 secondary outcomes
SIP8 (sickness impact profile, change from baseline)
Time frame: 4 weeks, measurement will be repeated up to 26 weeks
SF-36 (subscale physical functioning and social functioning, compared to baseline)
Time frame: 4 weeks, measurement will be repeated up to 26 weeks
SCL-90 (symptom checklist-90, compared to baseline)
Time frame: 4 weeks, measurement will be repeated up to 26 weeks
VAS pain (visual analog scale, compared to baseline)
Time frame: 4 weeks, measurement will be repeated up to 26 weeks
Cortisol in saliva and hair (concentration compared to baseline)
Time frame: 4 weeks
microbiome determination faeces
Time frame: at baseline
cytokine concentrations in blood and saliva (compared to baseline)
Time frame: 4 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 May 2016.
- Derived from this study: PubMed 29284500Roerink 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.
- Derived from this study: PubMed 28265678Roerink 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.
- Derived from this study: PubMed 26438161Roerink 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jos van der Meer, Prof, PhD, MD principal investigator
Radboud University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Anakinra in people with Chronic Fatigue Syndrome, run by Radboud University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 May 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
CIS (checklist individual strength, compared to baseline) (time frame: 4 weeks, measurement will be repeated up to 26 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02108210, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 May 2016.