A randomised, single-blind, placebo-controlled, dose-finding safety and tolerability study of the anti-CD3 monoclonal an
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ARTICLE
A randomised, single-blind, placebo-controlled, dose-finding safety and tolerability study of the anti-CD3 monoclonal antibody otelixizumab in new-onset type 1 diabetes Bart Keymeulen 1,2 & André van Maurik 3 & Dave Inman 3 & João Oliveira 4 & Rene McLaughlin 5 & Rachel M. Gittelman 6 & Bart O. Roep 7,8 & Pieter Gillard 9 & Robert Hilbrands 1,2 & Frans Gorus 1,2 Chantal Mathieu 9 & Ursule Van de Velde 1,2 & Nicolas Wisniacki 3 & Antonella Napolitano 3
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Received: 14 May 2020 / Accepted: 9 September 2020 # The Author(s) 2020
Abstract Aims/hypothesis Numerous clinical studies have investigated the anti-CD3ɛ monoclonal antibody otelixizumab in individuals with type 1 diabetes, but limited progress has been made in identifying the optimal clinical dose with acceptable tolerability and safety. The aim of this study was to evaluate the association between dose–response, safety and tolerability, beta cell function preservation and the immunological effects of otelixizumab in new-onset type 1 diabetes. Methods In this randomised, single-blind, placebo-controlled, 24 month study, conducted in five centres in Belgium via the Belgian Diabetes Registry, participants (16–27 years old, 10,000 copies/106 peripheral blood mononuclear cells (PBMCs) or who were IgG negative for EBV were excluded. Dose escalation (i.e. initiation of treatment in next participant cohort) was decided upon pre-established stopping criteria around in-stream, real-time data review of CRS variables based on the maximum number of participants experiencing CRS symptoms of grade 3 or worse (three out of eight participants on active treatment) (ESM Table 2) and the number of participants showing clinical and virological EBV reactivation (Table 1). The study was carried out with the approval of the ethics committees of all participating hospitals, the Belgian Diabetes Registry and the Belgian national regulatory agency. Written consent was obtained from all participants older than 18 years, and from participants aged 16–18 years and their parents/ guardians.
Diabetologia Table 1 Protocol-defined doseescalation EBV reactivation stopping criteria
EBV reactivation
Criteriaa
Clinical symptoms of mononucleosis Change in viral load Change in serology
Fever, fatigue, malaise, myalgia, pharyngodynia, lymphadenopathy EBV by PCR >10,000 copies/106 PBMCs Emergence of IgM for EBV on otherwise EBV IgG-positive participants
a
Stopping criteria: If three or more of eight participants on active treatment within a cohort developed symptoms of clinical EBV reactivation, otelixizumab dosing was stopped and no further dosing was carried out on any other participants; participants who had been dosed were followed up as per protocol
Safety The primary study objective was to assess the safety and tolerability of otelixizumab over 24 months. Safety assessments, including clinical laboratory tests (haematology, clinical chemistry and serology), vital signs, ECGs and physical examinations were conducted every day during the dosing period and at regular intervals dur
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