Title: Randomised trial of Haploidentical Transplantation compared to standard of care for Adults with Sickle Cell Disease
Funder: Department of Health and Social Care

Abstract: Sickle cell disease (SCD) is one of the most common serious inherited conditions worldwide. It is a disorder in which red blood cells become sickle shaped in conditions of stress. The sickle shape is unable to pass through blood vessels easily, resulting in a blockage. Patients with severe SCD may have many complications of their disease. These include repeated severe episodes of pain requiring frequent hospital admissions and strong pain medication, chronic pain, stroke, chest problems, increased risk of infection, impairment of brain function, kidney failure, low red blood counts causing severe tiredness, and leg ulcers. While advances in care have occurred in recent years, SCD is still associated with shortened life expectancy and early death. In addition, quality of life for those with severe SCD is affected with many patients suffering impacts on self-esteem, relationships, education and employment. Given the chronic nature of SCD, patients need to use significant NHS resources due to high need for medical care and hospital admissions. Standard treatment is limited, with regular blood transfusions and a drug called hydroxycarbamide the only options available. These treatment options do not offer cure and many patients will have complications of SCD while receiving these treatments._x000D_ _x000D_ Stem cell transplantation (SCT) is a procedure where healthy cells from a matched donor are given to a person with a blood disease. These healthy cells have the ability to re-populate the blood producing system and replace abnormal sickle cells. SCT is funded in the UK for children with cure estimated to be above 90%. Due to concerns about side effects of SCT, it has not been offered to adults. More recently, researchers have developed SCT protocols showing that SCT can be carried out safely in adults with high cure rates when receiving SCT from a 100% matched sibling. Patients can also receive SCT from relatives who are a 50% match, for example, from a sibling with whom they share one parent. This known as haploidentical (haplo) SCT. It is an important option as most patients do not have a 100% matched sibling. Initially there were concerns that haplo SCT would not work due to high rejection rates (this means that abnormal sickle cells were not replaced after receiving SCT), however recent research and new protocols mean it is now possible for haplo SCT to be done without rejection. The NHS has agreed funding for 100% sibling match SCT, however as most patients will not have a sibling donor, they will not have this option. The patient and public response to the NHS funding proposal suggested research into haplo SCT be considered. Therefore, we propose this clinical trial of haplo SCT compared to standard care. In this trial, 50% of patients would have SCT and 50% of patients would receive their normal care. _x000D_ _x000D_ The aims of this trial are to:_x000D_ - Assess whether haplo SCT is safe, show if haplo SCT improves outcomes such as frequency of pain episodes, quality of life, reduces the need for blood transfusions, and admission to hospital_x000D_ - Assess whether the cost of haplo SCT costs is less for the NHS than the current treatment_x000D_ _x000D_ In summary, current evidence suggests that haplo SCT could offer a curative treatment option, however this is not funded for adults in the UK at present due to lack of robust research. This research proposal will enable us to answer outstanding questions and then offer haplo SCT as a treatment option with the possibility of a cure for people living with sickle cell disease.

Lay abstract: Background: Sickle cell disease (SCD) is an inherited disease associated with shortened life expectancy, life-long intermittent severe acute and chronic pain and chronic multi-organ damage. SCD has negative impacts on quality of life, causes significant burden to the NHS due to high health-care utilisation and frequent hospitalisation. Haematopoietic stem cell transplantation (SCT) offers potentially curative treatment. The NHS has now routinely commissioned sibling SCT for patients with severe SCD, but most do not have a sibling donor. In recent years research has led to development of haploidentical (haplo) SCT which results in high initial rates of success (60-90%) and appears safe. _x000D_ Design: Multi-centre phase 3 randomised trial planned to evaluate both clinical, quality of life and cost efficacy when compared to current standard of care for adults with SCD. _x000D_ _x000D_ Setting: JACIE accredited hospital haematology departments with sickle cell and transplant physician expertise._x000D_ _x000D_ Target Population: Adult patients (>/=18 years) with severe SCD _x000D_ _x000D_ Health Technology Being Assessed: SCT is a procedure where a preparative protocol of chemotherapy and immunosuppressive drugs are given followed by stem cell infusion. This results in replacement of the recipient’s haematopoietic system (blood cell production) with the donor’s resulting in cure of the abnormal sickle cell production._x000D_ _x000D_ Measurement of Costs and Outcomes: We will undertake a model-based health economic analysis to compare haploidentical SCT versus current non-curative therapies for the treatment of severe SCD. The analysis will provide important information for decision-makers to determine whether haplo SCT for SCD represents good value for money for the NHS. The economic analysis will be undertaken from the perspective of the NHS and Personal Social Services over a lifetime horizon. Cost-effectiveness will be assessed in terms of the incremental cost per quality-adjusted life year (QALY) gained. Health outcomes and costs will be discounted at 3.5% per annum. Costs will be valued at current prices. The economic analysis will characterise trade-offs between potential improvements in longer term outcomes (e.g. survival and health-related quality of life [HRQoL]) and the potential for adverse effects with SCT._x000D_ _x000D_ Sample Size: 120 patients (60 haplo SCT, 60 controls). _x000D_ _x000D_ Project timetable: The project will last for 64 months with planned recruitment start in month 7. An internal pilot to determine the feasibility to proceed is planned in month 19. Recruitment will be completed by month 37, all patients will be followed up for 2 years until completion, last participant last visit is due in month 61. Data analysis and grant end will be by month 64. _x000D_ _x000D_ Patient and Public Involvement: Patient involvement is critical to ensure an important question for patients is successfully addressed. Ongoing patient involvement will allow us to adapt our protocol responsively and increase publicity and recruitment. We have identified a patient representative from the Sickle Cell Society (SCS), who has agreed to join the trial steering committee and is a co-applicant of the awarded grant. We will devise a patient advisory group to meet with investigators periodically throughout the trial. The chair of this group will be invited to attend the monthly trial management group meetings. The advisory group will assist with writing and review of patient material. Expenses incurred including travel, will be covered. We plan future public involvement events with the SCS to maintain patient awareness.

Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD