B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III Study. (RituxME)
Primary Purpose
Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME)
Status
Completed
Phase
Phase 3
Locations
Norway
Study Type
Interventional
Intervention
Rituximab
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME) focused on measuring Chronic Fatigue Syndrome (CFS), Myalgic Encephalitis (ME), Rituximab, B-lymphocyte depletion, B-cell depletion
Eligibility Criteria
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
- 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
Sites / Locations
- Dept. of Oncology, Haukeland University Hospital
- Notodden Hospital
- CFS/ME centre, Oslo University Hospital
- Division of Rehabilitation Services, University Hospital of North Norway
- Dept. of Pain and Complex Disorders, St. Olavs Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Rituximab
Placebo
Arm Description
Rituximab induction (two infusions two weeks apart) and maintenance (infusions at 3, 6, 9 and 12 months)
Saline (with added albumin), two infusions two weeks apart, followed by infusions at 3, 6, 9 and 12 months.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
Full Information
NCT ID
NCT02229942
First Posted
August 29, 2014
Last Updated
May 10, 2021
Sponsor
Haukeland University Hospital
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
1. Study Identification
Unique Protocol Identification Number
NCT02229942
Brief Title
B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III Study.
Acronym
RituxME
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.
Study Type
Interventional
2. Study Status
Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
September 2014 (Actual)
Primary Completion Date
September 2017 (Actual)
Study Completion Date
November 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Haukeland University Hospital
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
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME)
Keywords
Chronic Fatigue Syndrome (CFS), Myalgic Encephalitis (ME), Rituximab, B-lymphocyte depletion, B-cell depletion
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
151 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Rituximab
Arm Type
Experimental
Arm Description
Rituximab induction (two infusions two weeks apart) and maintenance (infusions at 3, 6, 9 and 12 months)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Saline (with added albumin), two infusions two weeks apart, followed by infusions at 3, 6, 9 and 12 months.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan, Mabthera
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Saline
Intervention Description
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.
Primary Outcome Measure Information:
Title
Fatigue score, selfreported.
Description
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.
Time Frame
Course of Fatigue score during 24 months follow-up.
Secondary Outcome Measure Information:
Title
Short Form-36 (SF-36)
Description
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.
Time Frame
Changes in SF-36 scores during 24 months follow-up
Title
Physical activity (Sensewear armband)
Description
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.
Time Frame
Analyzed at baseline and at interval 17-21 months
Title
Self-recorded "Function level"
Description
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.
Time Frame
Course during 24 months follow-up
Title
Fatigue Severity Scale
Description
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.
Time Frame
24 months
Title
Clinical response duration
Description
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.
Time Frame
During 24 months follow-up
Title
Sustained clinical response at 24 months
Description
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.
Time Frame
Assessment at 24 months
Other Pre-specified Outcome Measures:
Title
Toxicity and side-effects
Description
Toxicity and side effects will be recorded throughout 24 months follow-up, as specified in the protocol.
Time Frame
During 24 months follow-up
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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
Exclusion Criteria:
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
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Olav Mella, MD, PhD
Organizational Affiliation
Dept. of Oncology, Haukeland University Hospital, Bergen, Norway
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dept. of Oncology, Haukeland University Hospital
City
Bergen
ZIP/Postal Code
N-5021
Country
Norway
Facility Name
Notodden Hospital
City
Notodden
ZIP/Postal Code
N-3675
Country
Norway
Facility Name
CFS/ME centre, Oslo University Hospital
City
Oslo
ZIP/Postal Code
N-0424
Country
Norway
Facility Name
Division of Rehabilitation Services, University Hospital of North Norway
City
Tromsø
ZIP/Postal Code
N-9038
Country
Norway
Facility Name
Dept. of Pain and Complex Disorders, St. Olavs Hospital
City
Trondheim
ZIP/Postal Code
N-7006
Country
Norway
12. IPD Sharing Statement
Citations:
PubMed Identifier
19566965
Citation
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.
Results Reference
background
PubMed Identifier
22039471
Citation
Fluge 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.
Results Reference
background
PubMed Identifier
30934066
Citation
Fluge 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.
Results Reference
derived
Learn more about this trial
B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III Study.
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