Journal of IiME Volume 9 Issue 1 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and PlaceboControlled Study" Abstract: Rituximab: a multicenter, double blind, placebo-controlled study of rituximab induction and maintenance treatment in ME/CFS Øystein Fluge and Olav Mella, Haukeland University Hospital, for the Norwegian cooperative study group (Haukeland University Hospital, Oslo University Hospital Notodden Hospital, St. Olav University Hospital, University Hospital of Northern Norway). ME is a debilitating disease, often long-lasting, with a high sickness burden and a low quality of life, in addition to costing the patients, their families and society vast amounts of money. There is no established or generally accepted drug treatment. Based on observation of a patient with ME with marked symptom improvement when she was treated for lymphoma with cytotoxic drugs, we did a case study, followed by a small, double blind, placebo-controlled study with the anti-CD20, monoclonal antibody rituximab, that acts by depleting B-lymphocytes. These positive studies were followed by a phase II study of rituximab in 29 patients, exploring rituximab induction followed by maintenance rituximab up to 15 months, with 36 months observation time. That study confirmed that B-cell depletion with rituximab resulted in clinical responses in 2 of 3 patients and that about half of the patients still experienced sustained responses at the end of the observation. Based on these studies, there is from September 2014 an on ongoing, Norwegian multicenter study of rituximab induction and maintenance. The study is double blind, placebo (saline and May 2015 albumin) controlled, and has by May 2015 recruited more than 120 of the projected 152 patients. The patients fulfill the Canadian criteria, with sickness duration from 2-15 years. The study is block randomized by treatment center, with a predetermined number of included patients in each center. Induction is with rituximab 500mg/m2 day 1 and 15, maintenance with 500mg flat dose at 3, 6, 9 and 12 months. Observation time is 24 months. The primary end points are temporal development of self-reported fatigue score, and number of patients reaching predetermined, clinical criteria for response. Secondary endpoints are quality of life measured by SF36, levels of physical activity registered by electronic armbands for 7 consecutive days before and after intervention, total level of self-reported function at 6, 12, 18 and 24 months, and number of patients still in response at 24 months. Toxicity will be analyzed. Based on the assumption that declined ability for blood flow regulation is an important element in symptom maintenance in ME, substudies to investigate endothelial dysfunction in large arteries (flow-mediated vasodilation) before and after intervention will be performed in Bergen and Notodden, microcirculatory changes in addition in Bergen. Ergo-spirometry day 1 and 2 before and after intervention will be done in Bergen, Oslo and Notodden in patients sufficiently well to perform ramp bicycle exertion. In Bergen, patients with gastrointestinal symptoms are offered a gastroenterology sub-study before and after intervention. The study will be unblinded for analysis when the last recruited patient has been observed for 24 months, hopefully in early autumn 2017. Throughout the study, systematic blood tests are drawn for a central biobank with the aim of elucidating molecular mechanisms behind the symptom maintenance in ME. This part of the Invest in ME (Charity Nr. 1114035) www.investinme.org Page 53 of 57

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