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

NCT02229942 | Completed Phase 3 DMC

• 3 other identifiers: KTS-6-20142014-000795-25229035
• Study Type: interventional
• Target: 151
• Locations: 1 country
• Sites: 5

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.

Conditions

Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME)

Keywords

Chronic Fatigue Syndrome (CFS); Myalgic Encephalitis (ME); Rituximab; B-lymphocyte depletion; B-cell depletion

Outcome Measures

Primary Outcomes (1)

• 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.

  Course of Fatigue score during 24 months follow-up.

Secondary Outcomes (6)

• Short Form-36 (SF-36)

  Changes in SF-36 scores during 24 months follow-up

• Physical activity (Sensewear armband)

  Analyzed at baseline and at interval 17-21 months

• Self-recorded "Function level"

  Course during 24 months follow-up

• Fatigue Severity Scale

  24 months

• Clinical response duration

  During 24 months follow-up

Other Outcomes (1)

• Toxicity and side-effects

  During 24 months follow-up

Study Arms (2)

Rituximab

EXPERIMENTAL

Rituximab induction (two infusions two weeks apart) and maintenance (infusions at 3, 6, 9 and 12 months)

Drug: Rituximab

Placebo

PLACEBO COMPARATOR

Saline (with added albumin), two infusions two weeks apart, followed by infusions at 3, 6, 9 and 12 months.

Drug: Placebo

Interventions

Rituximab DRUG

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.

Also known as: Rituxan, Mabthera

Rituximab

Placebo DRUG

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.

Also known as: Saline

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Haukeland University Hospital: lead
• The Research Council of Norway: collaborator
• Norwegian Department of Health and Social Affairs: collaborator
• The Kavli Foundation: collaborator
• Oslo University Hospital: collaborator
• Trondheim University Hospital: collaborator
• University Hospital of North Norway: collaborator
• Sykehuset Telemark: collaborator
• MEandYou Foundation: collaborator
• The Norwegian ME association: collaborator

Study Sites (5)

Dept. of Oncology, Haukeland University Hospital

Bergen, N-5021, Norway

Location

Notodden Hospital

Notodden, N-3675, Norway

Location

CFS/ME centre, Oslo University Hospital

Oslo, N-0424, Norway

Location

Division of Rehabilitation Services, University Hospital of North Norway

Tromsø, N-9038, Norway

Location

Dept. of Pain and Complex Disorders, St. Olavs Hospital

Trondheim, N-7006, Norway

Location

Related Publications (3)

• 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.

  PMID: 19566965 BACKGROUND

• 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.

  PMID: 22039471 BACKGROUND

• 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.

  PMID: 30934066 DERIVED

MeSH Terms

Conditions

Fatigue Syndrome, Chronic

Interventions

Rituximab; Sodium Chloride

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Olav Mella, MD, PhD

  Dept. of Oncology, Haukeland University Hospital, Bergen, Norway

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• 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: August 29, 2014
• First Posted: September 3, 2014
• Study Start: September 1, 2014
• Primary Completion: September 1, 2017
• Study Completion: November 1, 2017
• Last Updated: May 11, 2021

Record last verified: 2018-02

Locations

NO (5)