Clinical trial NCT02229942: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME)
Keywords: Chronic Fatigue Syndrome (CFS)
Myalgic Encephalitis (ME)
Rituximab
B-lymphocyte depletion
B-cell depletion
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
Collaborators: name: The Research Council of Norway
name: Norwegian Department of Health and Social Affairs
name: The Kavli Foundation
name: Oslo University Hospital
name: Trondheim University Hospital
name: University Hospital of North Norway
name: Sykehuset Telemark
name: MEandYou Foundation
name: The Norwegian ME association
First posted: 2014-09-03
Enrollment: 151
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: 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rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished).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.

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

Primary outcomes:
measure: Fatigue score, selfreported.
timeFrame: Course of Fatigue score during 24 months follow-up.
Secondary outcomes:
measure: Short Form-36 (SF-36)
timeFrame: Changes in SF-36 scores during 24 months follow-up
measure: Physical activity (Sensewear armband)
timeFrame: Analyzed at baseline and at interval 17-21 months
measure: Self-recorded "Function level"
timeFrame: Course during 24 months follow-up
measure: Fatigue Severity Scale
timeFrame: 24 months
measure: Clinical response duration
timeFrame: During 24 months follow-up
measure: Sustained clinical response at 24 months
timeFrame: Assessment at 24 months
Other outcomes:
measure: Toxicity and side-effects
timeFrame: During 24 months follow-up
Locations:
city: Bergen
country: Norway
facility: Dept. of Oncology, Haukeland University Hospital
city: Notodden
country: Norway
facility: Notodden Hospital
city: Oslo
country: Norway
facility: CFS/ME centre, Oslo University Hospital
city: Tromsø
country: Norway
facility: Division of Rehabilitation Services, University Hospital of North Norway
city: Trondheim
country: Norway
facility: Dept. of Pain and Complex Disorders, St. Olavs Hospital
Study officials:
affiliation: Dept. of Oncology, Haukeland University Hospital, Bergen, Norway
name: Olav Mella, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.