Title: Multicentre, open label, prospective, single arm study of the safety and impact of Eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome
Funder: Department of Health and Social Care

Abstract: Research Question: In patients on Eculizuamb treatment for aHUS (P) does withdrawal of treatment with monitoring (I) lead to equivalent rates adverse event compared to patients who remain on treatment (C)? If so this would change the way Eculizumab is used for the treatment of aHUS (O). Design: Single arm, open label study Setting: Secondary Care Population: Patients with a diagnosis of aHUS (www.rarerenal.org) receiving Eculizumab to treat disease in native or transplanted kidneys. Inclusion criteria: On Eculizumab treatment for at least 6 months, in remission with no evidence of ongoing disease activity and stable renal function with normal function or CKD stage 1-3. Exclusion criteria: Severe non-renal disease manifestations, loss of a previous transplant kidney to recurrent aHUS, pregnancy, unable to comply with monitoring protocol, pathogenic mutation in a transplant recipient. Health Technology: Withdrawal of Eculizumab replacing treatment with a system of medical and self-monitoring and treatment re-introduction if required. Measurement of Outcomes: The primary outcome is the number of withdrawal attributable adverse events during a two-year follow-up period. These events will be monitored continuously using the Bayes factor single arm design of Johnson and Cook. The trial will be stopped if the posterior probability that the primary outcome rate is equal to or higher than a pre-specified threshold (2 fold observed rate in patients on treatment). 6% of patients on Eculizumab experience a treatment related adverse event (observed in patients on treatment in the UK). The cost per successful withdrawal of Eculizumab and the incremental cost per quality adjusted life year over the 2 year follow-up period and patient life time will be estimated. The qualitative component of the study will provide an understanding of the factors that influence the decision of a patient (or carer) to withdraw from Eculizumab. Sample size: 30 patients. More than 100 patients will be on treatment in England during the study period and we will also recruit from devolved nations. Most will be eligible and we predict >30% of those eligible will agree to participate in the withdrawal study (based on PPI insights). An additional 20 patients who agree to participate in the qualitative and economic assessments (but not to withdraw from Eculizumab) will also be recruited. These patients will act as a comparator for the qualitative and health economic strands. Project timetable: Ethical, HRA and MHRA approvals, month -3-6; Site set up, month 6-12; Recruitment, month 6-21; Follow up, health economic and qualitative data collection, month 6-45; Data analysis, month 6-48; final analysis and write up, month 45-48. Team Expertise: The team includes clinicians with experience in the treatment of aHUS and conducting clinical trials in this disease. Co-applicants have expertise in trial design and analysis, qualitative research and health economics. Patients and the patient group have been involved in trial design and dissemination of information about the trial and collection of patient feedback.

Lay abstract: Aims: To assess whether patients with Atypical haemolytic uraemic syndrome (aHUS) on Eculizumab can safely withdraw from treatment and test a method to monitor those patients. Background: aHUS is a rare, life threatening disease caused by excess activation of part of the immune system. In 2011 a new drug, Eculizumab, was approved in Europe and the USA to treat aHUS. This drug is an effective treatment and controls the disease in 90% of patients. It is known that aHUS has the potential to relapse and therefore lifelong treatment is recommended. This will control disease but lifelong treatment is not without problems, most importantly the potential risk of a severe meningococcal infection (3 cases in the UK recorded so far). Patients also find the treatment a burden (hospital-based intravenous injection every 2 weeks) and the drug is very expensive to the NHS, currently £360,000 per patient per year. We know that of those patients who do not develop kidney failure in the first presentation of the disease, only a minority will relapse in the next 10 years. Therefore many patients currently on Eculizumab may be able to stop treatment. This view is supported by a report of a group of 16 Italian patients, 11 of whom successfully withdrew from the drug. Patients who relapsed after being withdrawn restarted treatment with no evidence of long-term harm. These issues were recognised by NICE which recommended the use of Eculizumab to treat the disease on the condition of there being a research programme with robust methods to evaluate when withdrawing treatment or reducing the dose might occur, a condition that this study will fulfil. Design and methods: The drug will be withdrawn and patients regularly monitored throughout the study with blood and urine tests to check for signs of relapse. If relapse occurs Eculizumab will be restarted immediately. If a serious health problem occurs while the patient is not on the drug this will be reported immediately to the trial organisers. A maximum number of allowable problems will be set before the study begins. If this pre-set number is exceeded the trial will be stopped and we will conclude that it is not safe to stop treatment. This rate will not be set at zero as complications, including death, occur even while on the drug. Using interviews we will explore patients’ views on stopping Eculizumaab and what is acceptable in terms of level of monitoring. This will help us undertand why people might choose not to stop taking the drug. We will also assess the costs to the NHS and patients of drug withdrawal, replacing treatment with a system of (self)monitoring and re-initiation of treatment on relapse Patient and public involvement : A representative of the patient organisation, aHUSUK, will sit on the trial management committee. The national patient group, patients and carers have advised on the design of this trial and some have already agreed to participate. Dissemination: The results will be published in journals, presented to scientific and patient meetings, reported to commissioners and lay summaries written for patients. Potential impact: As recognised by NICE, there is a need for high quality research into the optimal use of Eculizumab. This patient safety-centred study will generate a protocol that will allow the safe withdrawal of Eculizumab treatment in a proportion of patients, explore patients’ attitudes to withdrawal and the resource impact of substituting monitoring for treatment.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD