Journal of IiMER previous Phase II studies with the B-cell depleting CD20 monoclonal antibody rituximab, a decision was made to conduct a Norwegian multicenter, Phase III, double blind, placebo controlled intervention study with rituximab, given mainly as outpatient treatment at Day 0 and 14, and at 3, 6, 9 and 12 mths, with follow-up for 24 mths. The number of patients filling Canadian criteria to be recruited at each hospital was predefined, and there was block-randomization to reduce possible practice differences between institutions. The first of the patients started infusion in September 2014, the last patient in September 2015. One primary endpoint is the course in changes of subjectively measured fatigue over 24 mths, with retrospective registration of symptom changes from baseline, every two week periods through follow-up. The other primary endpoint is number of patients achieving clinical response according to predefined criteria. Secondary endpoints are quality of life (SF 36, FSS), changes in physical performance (electronically recorded for 5-7 consecutive days), physical function level at 6, 12, 18 and 24 mths, length of response duration, and patients still in response 24 mths after inclusion. Toxicity is also a secondary endpoint. There is external monitoring of the trial, with full insight into the data. 152 patients were enrolled, but one withdrew before start, leaving 151 evaluable patients. The trial has been performed according to the protocol. There have been hospital admissions, but the safety committee has reported no serious and unexpected toxicity. The randomization and data handling was done through a professional trials company (Viedoc) and the quality of data is judged good by the external monitors. The final follow-up of the last included patient in the trial will be at the end of September 2017. After that the data quality will be checked and locked, thereafter the trial key unlocked and the study analysed. Publication is expected in 2018. Based on a small pilot study, the open-label Phase II (CycloME) cyclophosphamide intervention study with 40 patients at two centers was initiated in March 2015. The trial includes patients previously exposed to rituximab, and patients without previous immune manipulation. The patients were given infusions of the cytotoxic agent cyclophosphamide 600-700 mg/m2 every 4th week, given 6 times. Endpoints were as in the RituxME study, with follow-up for 18 mths. The last patient will have finished follow-up in July 2017 and the data then analyzed. Compliance has been good, with practically no hematologic toxicity. However, acute nausea and vomiting was experienced to a greater extent than seen in cancer patients at the same drug level, and some patients reported initial and transient worsening of ME-symptoms after infusions. Patients reporting improvement from ME-symptoms generally did so after the final infusion. Although the data has not officially been analyzed, a preliminary observation is that also a more unspecific, immune modulating agent than rituximab can improve the clinical course, in a subgroup of ME patients. Trial sponsors: Norwegian Research Council, Norwegian Ministry of Health and Care Services, the Regional Health Trusts, MEandYou fundraising, the Norwegian ME Association, private donations, the Kavli Foundation www.investinme.org Page 75 of 82
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