Abstract
BACKGROUND: Atypical Haemolytic Uraemic Syndrome is a rare disease, associated with high morbidity and mortality. Eculizumab, a monoclonal complement inhibitor, is an effective treatment but the optimal way to use this high-cost medication has not been determined. The SETS aHUS trial aimed to establish the safety of eculizumab withdrawal and the effectiveness of a monitoring protocol to detect disease relapse and reintroduction of treatment if relapse occurs. METHODS: The SETS aHUS multicentre, open label, prospective, single-arm trial enrolled participants from 15 UK hospitals. Patients over two years of age with aHUS who were receiving eculizumab therapy for at least six months were eligible to withdraw from treatment, replacing it with monitoring to assess disease activity and treatment re-introduction if relapse occurred. The primary outcome measure was harm to a participant as a consequence of eculizumab withdrawal. Participants met a primary outcome if there was a permanent reduction in estimated glomerular filtration rate, requirement for kidney replacement therapy or significant extra-renal manifestation of disease. The Bayes factor single arm binary model was used to monitor and analyse the trial data, applying pre-trial stopping rules. The trial is registered with the European Union Drug Regulating Authority (EudraCT 2017-003916-37) and is closed for recruitment. FINDINGS: One of 28 participants (3.6%) who withdrew from treatment met a primary outcome. Four of the 28 participants (14.3%) relapsed. Only participants with an identified cause of complement dysregulation relapsed. It was possible, by monitoring and rapid participant access, to reintroduce eculizumab treatment. Based on the pre-trial analysis plan, withdrawal from treatment may represent no greater risk to patients. INTERPRETATION: In this single arm study, for patients fulfilling trial entry criteria, which excluded some high-risk patients, withdrawal of eculizumab treatment with monitoring of disease activity was not associated with an increased risk of harm compared to continuation of eculizumab. FUNDING: National Institute for Health and Care Research Health Technology Assessment programme.