Title: A multicentre randomised trial of first line treatment pathways for newly diagnosed immune thrombocytopenia: Standard steroid treatment versus combined steroid and mycophenolate.
Funder: Department of Health and Social Care

Abstract: Immune thrombocytopenia (ITP) has an incidence of 2.9/100,000 person-years1. It is an autoimmune condition that presents with bleeding and bruising due to a low platelet count. There is increased consumption and reduced production of platelets due to both antibody and cell mediated autoimmune attack of platelets and megakaryocytes involving dysregulated autoreactive T and B cell lymphocytes2-13. Currently the standard care is initially to treat with high dose steroids and this has not been challenged for decades. Although 80% of patients respond, relapse rates are high when these steroids are reduced or stopped (70-90%) and steroid side effects are a major problem14,15. A published survey of ITP patients reported 98% had at least one side effect and 38% stopped or reduced dosage due to intolerable side effects16. Patients who relapse are at risk of bleeding, which occasionally can be severe including intracranial haemorrhage17. Fatigue is also associated with disease activity and can be severe18. Physical factors combine with psychological stress through fear of bleeding, need for time off work and lifestyle restrictions due to bleeding risk to adversely impact quality of life19,20. In the UK, mycophenolate (MMF) is becoming a popular second line agent due to its good side effect profile and efficacy, with response rates reported between 50- 80%21-27. However, as MMF has a slow onset of action (up to 2 months), patients may need bridging with further steroid. Mycophenolate has activity against both autoreactive T and B cells and has also shown efficacy in refractory ITP including steroid resistance suggesting a complimentary mechanism of action25. It is less expensive to the NHS than some other second line options costing approximately &pound;182/year (generic cost) compared to costs for average doses of romiplostim at &pound;25 000/year, Eltrombopag &pound;20 000/year or rituximab at &pound;8000 for a course of 4 infusions. We are proposing to bring forward the timing of MMF treatment from second to first line in the hope of preventing the almost inevitable first relapse. By giving patients a stable platelet count sooner we expect to improve other outcomes such as quality of life and fatigue. However, there will be some patients who will be treated with MMF who may have been successfully treated with steroids alone (10-30%). Similar to other immunosuppressives, MMF may slightly increase infection and cancer risk with long term use. This puts the trial in equipoise. The proposal includes a strategy to reduce and stop MMF at 6 months for patients in complete remission to prevent unnecessary long term use. This trial proposal has received support from clinicians and patients nationally (UK ITP forum and ITP support association). To ensure objective and meaningful outcomes, it will be a multicentre RCT recruiting 120 patients. Patients will be given up to one week of steroid prior to randomisation to enable sufficient time to read information, discuss and ask questions with informed consent in an appropriate setting. Patients will receive the usual follow up according to clinical need and local policy. Laboratory and clinical data will be collected from routine appointments. In addition, patient oriented outcomes will be recorded at diagnosis, 2, 4, 6, and 12 months using validated questionnaires for quality of life, fatigue and time off work. If the results challenge the current first line treatment, a change to the standard of care could be implemented within 5 years with potential to improve patients lives with a new diagnosis of ITP. Potential indirect benefits to the NHS include reduced need for hospital attendances and admissions. This will be the first UK multicentre ITP RCT and if successful represents a platform for future trials.

Lay abstract: Immune thrombocytopenia (ITP) is an illness that causes bruising and bleeding due to a low platelet count (blood cells essential for normal clotting). As treatment, patients are first given high dose steroids but most suffer side effects (e.g. difficulty sleeping, weight gain, moods swings, high blood pressure, diabetes etc). In addition, the illness doesn't get better for some patients, and the majority of others get ill again when the steroids are stopped. Only about 20% stay well long term. Mycophenolate (MMF) is often used as the next treatment for ITP and it works quite well. However, it can take up to 2 months to work. In these 2 months patients are at risk of bleeding, bruising, feeling tired and usually need more steroids which they loathe. They have to come to hospital each week for blood tests and most have to take time off sick. We want to find out whether more patients would feel better sooner if everyone takes MMF at diagnosis instead of what we do at the moment (waiting for the illness to come back). We plan to test this by comparing the current way we treat patients to a new way with all patients given MMF right at the start of their treatment. Patients from different hospitals will be asked to take part and half will be randomly chosen for the new pathway. Their normal hospital appointments will be used to record how well they are for a year. They will have no extra blood tests or appointments as a result of agreeing to take part. We have a group of local patients in Bristol who have helped us and we will continue to meet with them throughout. We expect the results will be able to improve care for patients with ITP within 5 years.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD