B-lymphocyte depletion with Rituximab induction and maintenance in ME/CFS. A multicenter, randomized, double blind, placebo-controlled study

The RituxME randomized, double-blind and placebo-controlled multi center study will evaluate B-cell depletion using the monoclonal anti-CD20 antibody rituximab (or placebo) with maintenance treatment (six infusions during the first 12 months) and follow-up for 24 months, as treatment for Myalgic Encephalopathy/ Chronic fatigue Syndrome (ME/CFS). 152 patents were projected to be included, aged 18-65 years, according to Canadian inclusion criteria. The protocol has been approved by the authorities, and the inclusion period started September 1st, 2014. Substudies will be performed for Endothelial function, Ergospirometry for two consecutive days, and Gastrointestinal function, all three by evaluation at baseline and repeated at the follow-up interval 17-21 months. The code for intervention will be revealed 24 months after the last patient was included, expected during October 2017. Blood samples have been collected in a biobank with serial samples during follow-up, and will be used for laboratory experiments aiming to elucidate the pathogenesis of ME/CFS. The final inclusion was 151 patients (one patient withdrew after inclusion, before intervention). No results concerning the effect of the intervention can be provided so far (blinded study). The analysis of biobank material (where the samples from the current study represents the biggest patient cohort) before intervention started has already given results that will shed light on disease mechanisms in ME/CFS.

ME/CFS is a disease with considerable morbidity, often with longstanding or life-lasting disability, presently without known etiology or recognized pharmacological treatment. Immune dysregulation is by many believed to be an underlying cause. After an ini tial case series, the monoclonal anti-CD20 B-lymphocyte depleting antibody rituximab was used in a small double-blinded and placebo-controlled study, showing benefit and significantly altered course for symptom score in the rituximab arm. Ten of the 15 pa tients in the rituximab group, and 2 of 15 in the placebo group responded. The present study is national, led from Haukeland University Hospital, with participation from Oslo University Hospital, St. Olav’s Hospital in Trondheim, University of Northern No rway in Tromsø and Notodden Hospital. The aim is to verify or refute the results of the initial placebo-controlled study. 152 ME/CFS patients fulfilling Canadian criteria will be selected for inclusion. Block-randomization by site will be performed in a 1 :1 manner between rituximab and placebo, given at 0 and 2 weeks, with maintenance infusions at 3, 6, 9 and 12 months. Primary endpoints will be difference between groups for course of self-reported Fatiguescore during follow-up, analyzed by general linear model for repeated measures, and difference in overall response. Secondary endpoints include changes in SF36 subdimentions between intervention and control groups during follow-up, changes in physical activity measured by Sensewear armband for 7 days, co urse of changes in self-reported function level compared with premorbid condition, effects on Fatigue Severity Scale, longest period of continuous response, and patients without symptom recurrence at 24 months. Side effects will be monitored. The sample o f the main study is based an estimated 50% response in the rituximab group and 25% in the placebo, giving 85-90% strength to detect a difference between groups (alpha 0.05). Three substudies to elucidate disease mechanisms will be performed before by ass essment before and after 17-21 months: endothelial function (flow-mediated vasodilatation), ergospirometry, and irritable bowel disease/ functional dyspepsia. Biobank material sampled during inclusion and follow-up may also contribute to enlighten pathoph ysiology.