B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III Study. (RituxME)

• ClinicalTrials.gov Identifier: NCT02229942
• Recruitment Status: Completed
• First Posted: September 3, 2014
• Last Update Posted: May 11, 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
• Information provided by (Responsible Party): Haukeland University Hospital

Tracking Information

• First Submitted Date: August 29, 2014
• First Posted Date: September 3, 2014
• Last Update Posted Date: May 11, 2021
• Actual Study Start Date: September 2014
• Actual Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 29, 2014)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 29, 2014)

• Short Form-36 (SF-36) [ Time Frame: Changes in SF-36 scores during 24 months follow-up ]
  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) [ Time Frame: Analyzed at baseline and at interval 17-21 months ]
  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" [ Time Frame: Course during 24 months follow-up ]
  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 [ Time Frame: 24 months ]
  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 [ Time Frame: During 24 months follow-up ]
  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 [ Time Frame: Assessment 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.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: August 29, 2014)

Toxicity and side-effects [ Time Frame: During 24 months follow-up ]

Toxicity and side effects will be recorded throughout 24 months follow-up, as specified in the protocol.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III 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.
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME)

Intervention

• Drug: Rituximab

  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.

  Other Names:

  • Rituxan
  • Mabthera
• Drug: Placebo
  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.
  Other Name: Saline

Study Arms

• Experimental: Rituximab
  Rituximab induction (two infusions two weeks apart) and maintenance (infusions at 3, 6, 9 and 12 months)
  Intervention: Drug: Rituximab
• Placebo Comparator: Placebo
  Saline (with added albumin), two infusions two weeks apart, followed by infusions at 3, 6, 9 and 12 months.
  Intervention: Drug: Placebo

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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 10, 2021): 151
• Original Estimated Enrollment (submitted: August 29, 2014): 152
• Actual Study Completion Date: November 2017
• Actual Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Norway

Administrative Information

• NCT Number: NCT02229942
• Other Study ID Numbers: KTS-6-2014; 2014-000795-25 ( EudraCT Number ); 229035 ( Other Grant/Funding Number: Research Council of Norway: project no 229035 )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Haukeland University Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Haukeland University Hospital
• Original Study Sponsor: Same as current

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

Investigators

• Principal Investigator: Olav Mella, MD, PhD; Dept. of Oncology, Haukeland University Hospital, Bergen, Norway

• PRS Account: Haukeland University Hospital
• Verification Date: February 2018