Clinical and cost-effectiveness of eculizumab withdrawal in atypical haemolytic uraemic syndrome: the SETS aHUS multi-centre, open-label, prospective and single-arm study.

Background: Atypical haemolytic uraemic syndrome is a rare disease (incidence: 0.4 cases per million per year) which, without treatment, is 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 (£360,000 per year for an adult) has not been established. Objective: Establish the safety of eculizumab withdrawal and the effectiveness of a monitoring protocol to detect disease relapse and reintroduction of treatment if relapse occurs. Setting: Fifteen hospitals in the United Kingdom. Design: SETS aHUS is a multicentre, open label, prospective, single arm study of the safety and impact of eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome using Bayes single arm analysis with a health economic analysis and qualitative study. Participants: Patients over 2 years of age with atypical haemolytic uraemic syndrome who were receiving eculizumab therapy for at least 6 months. Two study arms are described with 28 participants recruited to the withdrawal arm and 11 additional participants recruited to the standard of care arm of the study. Intervention: Withdrawal of eculizumab treatment and replacement with monitoring to assess disease activity with reintroduction of treatment if relapse occurs. Main outcome measures: The primary outcome measure was to determine the safety of eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome during the 2-year study period. Patients met a primary outcome of 'safety event occurred' if there was a permanent reduction in estimated glomerular filtration rate or requirement for renal replacement therapy or significant extra-renal manifestation of disease. The health economic analysis compared the cost and health outcomes on and off eculizumab treatment. The qualitative study explored the experiences of patients on living with atypical haemolytic uraemic syndrome and eculizumab treatment, views on withdrawing from treatment and the proposed monitoring plan. Results: One of 28 patients (3.6%) who withdrew from treatment met a primary outcome. Based on the pre-study analysis plan, withdrawal from treatment is not associated with a greater risk to patients compared to remaining on treatment. Of 17 patients with an abnormality in complement regulation, 4 relapsed. Of 11 patients with no abnormality in complement regulation, 0 relapsed. It was possible, by monitoring and rapid patient access, to reintroduce eculizumab treatment when relapse was identified. Most patients welcomed the opportunity to withdraw from treatment but identified concerns about monitoring and the risk of relapse, informed by initial experience at presentation. Withdrawing a patient from treatment saves £4.2M in healthcare costs (80 years time horizon). Limitations: Reflecting the low prevalence, participant numbers are low, particularly in the standard of care group. Conclusions: Withdrawal of eculizumab treatment with monitoring of disease activity exhibited a favourable safety profile compared to continuation of eculizumab, was acceptable to patients and carers and is associated with significant cost savings. Future work: More real-world data should be generated by continued assessment of patients after treatment withdrawal including risk of relapse, renal outcomes, real-world economic analysis and a better understanding of communicating change to patients and carers. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 15/130/94.