Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME)Phase 3RituxMENCT02229942
B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III Study.
A Phase 3 study testing Rituximab in people with Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME), run by Haukeland University Hospital at 5 sites in Norway.
Trial summary
The hypothesis is that a subgroup of patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) have a chronically activated immune system and may benefit from B-lymphocyte treatment using the monoclonal anti-CD20 antibody rituximab with induction and maintenance treatment. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME)
- What is being tested?
- Rituximab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 151 participants
- Where
- 5 sitesNorway
- Study dates
- Sep 2014to Nov 2017
- Phase
- Phase 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 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) according to Canadian diagnostic criteria (Carruthers, 2003)
- Duration of CFS/ME disease 2-15 years. For patients with mild CFS/ME duration of disease must be 5-15 years.
- Mild, Mild/Moderate, Moderate, Moderate/Severe and Severe CFS/ME may be included
- Signed informed consent
Who cannot join
- Patients with fatigue, who do not comply with Canadian diagnostic criteria (2003)
- Duration of CFS/ME < 2 years or >15 years
- Patients with very severe CFS/ME
- Pregnancy or lactation.
- Previous malignant disease (except basal cell carcinoma in skin or uterine cervical dysplasia)
- Previous treatment with B-lymphocyte depleting therapeutic monoclonal antibodies, such as rituximab
Show all 15Show fewer
- Previous long-term systemic immunosuppressive treatment, including drugs such as cyclosporine, azathioprine, mycophenolate mofetil, but except steroid treatment e.g. for obstructive lung disease or for other autoimmune diseases such as ulcerative colitis
- Severe endogenous depression
- Lack of ability to adhere to protocol
- Known multi-allergy with clinically assessed risk from rituximab infusion
- Reduced kidney function (serum creatinine > 1,5x upper normal level)
- Reduced liver function (serum bilirubin or transaminases > 1,5x upper normal level)
- Known HIV positivity, previous hepatitis B or hepatitis C
- Evidence of ongoing, active and clinically relevant infection
- Known immunodeficiency with risk from therapeutic B-cell depletion, such as hypogammaglobulinemia
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Norway5 sites
Dept. of Oncology, Haukeland University Hospital
Bergen, N-5021
Notodden Hospital
Notodden, N-3675
CFS/ME centre, Oslo University Hospital
Oslo, N-0424
Division of Rehabilitation Services, University Hospital of North Norway
Tromsø, N-9038
Dept. of Pain and Complex Disorders, St. Olavs Hospital
Trondheim, N-7006
About this study
Official title: B-lymphocyte Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Multicentre, Randomized, Double-blind and Placebo Controlled Phase-III Study With Rituximab Induction and Maintenance Treatment.
The hypothesis is that a subgroup of patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) have a chronically activated immune system and may benefit from B-lymphocyte treatment using the monoclonal anti-CD20 antibody rituximab with induction and maintenance treatment.
Read the detailed description
We have published a case series of pilot patient observations with B-cell depletion in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) (Fluge and Mella, BMC Neurol, 2009). Subsequently, we published a small randomized and double-blind phase II study using rituximab induction two infusions two weeks apart (Fluge et al, Plos One, 2011).
We have completed an open label phase II study with 29 patients using rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished).
We hypothesize that a subgroup of patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) have a chronically activated immune system involving B-lymphocytes, possibly a variant of an autoimmune disease, and that patients may benefit from B-cell depletion therapy.
Three substudies will be performed:
Endothelial function: assessment of Flow-Mediated Dilation and skin microcirculation at baseline and repeated during the time interval 17-21 months.
Cardiopulmonary exercise test for two following days: assessment at baseline and repeated during the time interval 17-21 months.
Gastrointestinal function: assessment at baseline and repeated during the time interval 17-21 months.
- Being tested
- Rituximab, Placebo
- Keywords
- Chronic Fatigue Syndrome (CFS), Myalgic Encephalitis (ME), Rituximab, B-lymphocyte depletion, B-cell depletion
- Medical subject headings
- Fatigue Syndrome, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabDrug
Also called Rituxan, Mabthera
Induction with two infusions two weeks apart, rituximab 500 mg/m2 (max 1000 mg).
Maintenance with rituximab infusions (500 mg fixed dose) at 3, 6, 9 and 12 months.
PlaceboDrug
Also called Saline
Saline (NaCl 0,9%) added human albumin (Flexbumin) 0,4 mg/ml, two infusions two weeks apart. Maintenance infusions after 3,6, 9 and 12 months.
| Study group | Role | What they receive |
|---|---|---|
| Rituximab | Experimental | Rituximab induction (two infusions two weeks apart) and maintenance (infusions at 3, 6, 9 and 12 months) Receives: Drug: Rituximab |
| Placebo | Placebo comparator | Saline (with added albumin), two infusions two weeks apart, followed by infusions at 3, 6, 9 and 12 months. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Fatigue score, selfreported.
Selfreported Fatigue score is registered every second week, as the mean score for the four symptoms: "Post-exertional malaise", "Fatigue", "Need for rest", "Daily functioning" (scale 0-6). Mean Fatigue scores for the time intervals 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 months are recorded for each patient. These data are used for statistical analysis. The difference in course of Fatigue score during 24 months follow-up, between the rituximab and placebo groups, will constitute the primary endpoint.
Overall response is recorded as the effect on CFS/ME symptoms during 24 months follow-up. The overall response is not predefined to a specific time interval, but is defined as mean Fatigue score at least 4.5 for at least 8 consecutive weeks for moderate response, and mean Fatigue score at least 5.0 for at least 8 consecutive weeks for major response. Single response periods and the sum of response periods during 24 months follow-up will be recorded.
Measured: Course of Fatigue score during 24 months follow-up.
Secondary outcomes (6)
Short Form-36 (SF-36)
SF-36 (ver 1.2) are selfreported by patients at baseline, and at 3, 6, 9, 12, 15, 18, 21 and 24 months follow-up. Changes in Physical health summary score, Physical function, and "Mean of five subdimensions" (Physical function, Bodily pain, Vitality, Social function, General health) are recorded. The difference in course during 24 months follow-up, between the rituximab and placebo groups, will constitute secondary endpoints.
Also, the difference between rituximab and placebo groups, in changes from baseline to recording at 18 months, for Physical health summary score, Physical function, and "mean of five SF-36 subdimensions", constitute secondary endpoints.
Measured: Changes in SF-36 scores during 24 months follow-up
Physical activity (Sensewear armband)
The patients' physical activity level, in a home setting for 7 consecutive days, is recorded using Sensewear armbands, with registration at baseline and repeated in the time interval 17-21 months follow-up. Changes from baseline to analysis during the time interval 17-21 months, for mean number of steps per 24h, maximum number of steps per 24h, mean duration per 24h with activity level at least 3.5 METs, max duration per 24h with activity level at least 3.5 METs, are recorded. The difference between rituximab and placebo groups will constitute secondary endpoints.
Measured: Analyzed at baseline and at interval 17-21 months
Self-recorded "Function level"
Self-recorded "Function level" (scale 0-100, compared to healthy state, according to a set of examples) are registered every second week. Mean "Function level" for the time intervals 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 months are calculated. The difference in course of "Function level", between the rituximab and placebo groups, constitute a secondary endpoint.
Also, the differences between the rituximab and placebo groups, for changes in selfreported "Fatigue score" and in selfreported "Function level", calculated from baseline to the mean value during the time interval 16-20 months, constitute secondary endpoints.
Measured: Course during 24 months follow-up
Fatigue Severity Scale
Fatigue Severity Scale (FSS) is self-recorded at baseline and at 6, 12, 18, 24 months. The difference between the rituximab and placebo groups, in changes in FSS from baseline to 18 months follow-up, constitutes a secondary endpoint.
Measured: 24 months
Clinical response duration
Clinical response periods, defined as consecutive self-recorded Fatigue score at least 4.5 (scale 0-6) for a minimum of 8 weeks, during 24 months follow-up, are recorded.
The difference in the longest consecutive clinical response period, between rituximab and placebo groups, constitutes a secondary endpoint.
Measured: During 24 months follow-up
Sustained clinical response at 24 months
The difference between rituximab and placebo groups, in fraction of patients with sustained clinical response (defined as Fatigue score of at least 4.5) at 24 months, constitute a secondary endpoint.
Measured: Assessment at 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Sep 2014 (estimated)
- Study startSep 2014
- Primary completionSep 2017
- Study completionNov 2017
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 Syndrome/ Myalgic Encephalitis (CFS/ME)Studies of the same condition, open and under way.
- More trials run by Haukeland University HospitalThe 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 151 participants (actual)
Sponsor and investigators
- Lead sponsor
- Haukeland University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- The Research Council of Norway, Norwegian Department of Health and Social Affairs, The Kavli Foundation, Oslo University Hospital, Trondheim University Hospital, University Hospital of North Norway, Sykehuset Telemark, MEandYou Foundation, The Norwegian ME association
- Responsible party
- Sponsor
- Investigators
- Olav Mella, MD, PhD, Principal investigator, Dept. of Oncology, Haukeland University Hospital, Bergen, Norway
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02229942
- Sponsor's protocol ID
- KTS-6-2014
- Other IDs
- 2014-000795-25, 229035, 2014
- Acronym
- RituxME
- Status last verified
- Feb 2018
- First submitted
- 29 Aug 2014
- Last updated
- 11 May 2021
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Fluge O, Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28. doi: 10.1186/1471-2377-9-28.
PubMed 19566965Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Naess H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358. doi: 10.1371/journal.pone.0026358. Epub 2011 Oct 19.
PubMed 22039471Fluge O, Rekeland IG, Lien K, Thurmer H, Borchgrevink PC, Schafer C, Sorland K, Assmus J, Ktoridou-Valen I, Herder I, Gotaas ME, Kvammen O, Baranowska KA, Bohnen LMLJ, Martinsen SS, Lonar AE, Solvang AH, Gya AES, Bruland O, Risa K, Alme K, Dahl O, Mella O. B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Ann Intern Med. 2019 May 7;170(9):585-593. doi: 10.7326/M18-1451. Epub 2019 Apr 2.
PubMed 30934066
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- B-lymphocyte Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Multicentre, Randomized, Double-blind and Placebo Controlled Phase-III Study With Rituximab Induction and Maintenance Treatment.
- ClinicalTrials.gov ID
- NCT02229942
- Acronym / sponsor ID
- RituxME / KTS-6-2014
- Keywords
- Chronic Fatigue Syndrome (CFS), Myalgic Encephalitis (ME), Rituximab, B-lymphocyte depletion, B-cell depletion
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 151 participants (actual)
- Lead sponsor
- Haukeland University HospitalUniversity, hospital or other
- Collaborators
- The Research Council of Norway, Norwegian Department of Health and Social Affairs, The Kavli Foundation, Oslo University Hospital, Trondheim University Hospital, University Hospital of North Norway, Sykehuset Telemark, MEandYou Foundation, The Norwegian ME association
- Study start
- Sep 2014 (actual)
- Primary completion
- Sep 2017 (actual)
- Study completion
- Nov 2017 (actual)
- First posted
- 3 Sep 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.
The hypothesis is that a subgroup of patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) have a chronically activated immune system and may benefit from B-lymphocyte treatment using the monoclonal anti-CD20 antibody rituximab with induction and maintenance treatment.
Detailed description
We have published a case series of pilot patient observations with B-cell depletion in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) (Fluge and Mella, BMC Neurol, 2009). Subsequently, we published a small randomized and double-blind phase II study using rituximab induction two infusions two weeks apart (Fluge et al, Plos One, 2011).
We have completed an open label phase II study with 29 patients using rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished).
We hypothesize that a subgroup of patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) have a chronically activated immune system involving B-lymphocytes, possibly a variant of an autoimmune disease, and that patients may benefit from B-cell depletion therapy.
Three substudies will be performed:
Endothelial function: assessment of Flow-Mediated Dilation and skin microcirculation at baseline and repeated during the time interval 17-21 months.
Cardiopulmonary exercise test for two following days: assessment at baseline and repeated during the time interval 17-21 months.
Gastrointestinal function: assessment at baseline and repeated during the time interval 17-21 months.
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 |
|---|---|---|
| Rituximab | Experimental | Drug: RituximabRituximab induction (two infusions two weeks apart) and maintenance (infusions at 3, 6, 9 and 12 months) |
| Placebo | Placebo comparator | Drug: PlaceboSaline (with added albumin), two infusions two weeks apart, followed by infusions at 3, 6, 9 and 12 months. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) according to Canadian diagnostic criteria (Carruthers, 2003)
- Duration of CFS/ME disease 2-15 years. For patients with mild CFS/ME duration of disease must be 5-15 years.
- Mild, Mild/Moderate, Moderate, Moderate/Severe and Severe CFS/ME may be included
- Signed informed consent
Key exclusion criteria (15 listed)
- Patients with fatigue, who do not comply with Canadian diagnostic criteria (2003)
- Duration of CFS/ME < 2 years or >15 years
- Patients with very severe CFS/ME
- Pregnancy or lactation.
- Previous malignant disease (except basal cell carcinoma in skin or uterine cervical dysplasia)
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 |
|---|---|---|
| RituximabAlso: Rituxan, MabtheraInduction with two infusions two weeks apart, rituximab 500 mg/m2 (max 1000 mg). Maintenance with rituximab infusions (500 mg fixed dose) at 3, 6, 9 and 12 months. | Drug | Rituximab |
| PlaceboAlso: SalineSaline (NaCl 0,9%) added human albumin (Flexbumin) 0,4 mg/ml, two infusions two weeks apart. Maintenance infusions after 3,6, 9 and 12 months. | Drug | Placebo |
Primary outcome
Fatigue score, selfreported.
Time frame: Course of Fatigue score during 24 months follow-up.
Selfreported Fatigue score is registered every second week, as the mean score for the four symptoms: "Post-exertional malaise", "Fatigue", "Need for rest", "Daily functioning" (scale 0-6). Mean Fatigue scores for the time intervals 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 months are recorded for each patient. These data are used for statistical analysis. The difference in course of Fatigue score during 24 months follow-up, between the rituximab and placebo groups, will constitute the primary endpoint. Overall response is recorded as the effect on CFS/ME symptoms during 24 months follow-up. The overall response is not predefined to a specific time interval, but is defined as mean Fatigue score at least 4.5 for at least 8 consecutive weeks for moderate response, and mean Fatigue score at least 5.0 for at least 8 consecutive weeks for major response. Single response periods and the sum of response periods during 24 months follow-up will be recorded.
6 secondary outcomes
Short Form-36 (SF-36)
Time frame: Changes in SF-36 scores during 24 months follow-up
Physical activity (Sensewear armband)
Time frame: Analyzed at baseline and at interval 17-21 months
Self-recorded "Function level"
Time frame: Course during 24 months follow-up
Fatigue Severity Scale
Time frame: 24 months
Clinical response duration
Time frame: During 24 months follow-up
Sustained clinical response at 24 months
Time frame: Assessment at 24 months
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 11 May 2021.
- Background: PubMed 19566965Fluge O, Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28. doi: 10.1186/1471-2377-9-28.
- Background: PubMed 22039471Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Naess H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358. doi: 10.1371/journal.pone.0026358. Epub 2011 Oct 19.
- Derived from this study: PubMed 30934066Fluge O, Rekeland IG, Lien K, Thurmer H, Borchgrevink PC, Schafer C, Sorland K, Assmus J, Ktoridou-Valen I, Herder I, Gotaas ME, Kvammen O, Baranowska KA, Bohnen LMLJ, Martinsen SS, Lonar AE, Solvang AH, Gya AES, Bruland O, Risa K, Alme K, Dahl O, Mella O. B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Ann Intern Med. 2019 May 7;170(9):585-593. doi: 10.7326/M18-1451. Epub 2019 Apr 2.
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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.
Olav Mella, MD, PhD principal investigator
Dept. of Oncology, Haukeland University Hospital, Bergen, Norway
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Rituximab in people with Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME), run by Haukeland University Hospital at 5 sites in Norway.
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 4 inclusion and 15 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 11 May 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Norway. 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 phase mean?
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?
Fatigue score, selfreported. (time frame: Course of Fatigue score during 24 months follow-up.). 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 NCT02229942, 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 11 May 2021.