Title: STAR-MS: Autologous Stem Cell Transplantation versus Alemtuzumab or Ocrelizumab in Relapsing Remitting Multiple Sclerosis
Funder: Medical Research Council

Abstract: BACKGROUND_x000D_ Multiple Sclerosis (MS) is a chronic autoimmune condition, which causes an inflammatory response, which damages the brain and the spinal cord. In most cases, the illness runs a ‘relapsing remitting' course (RRMS), with relapses followed by periods of stability. Over time, RRMS typically progresses into a ‘secondary progressive’ phase, which results in a gradual accumulation of permanent disability. Current disease modifying therapies (DMTs) help to reduce relapses but their impact on disability is limited. There are no effective DMTs for progressive MS._x000D_ _x000D_ In recent years, autologous haematopoietic stem cell transplantation (aHSCT) has been increasingly used to treat RRMS by ‘rebooting’ the immune system and stopping it from attacking the brain and spinal cord. Autologous HSCT uses high doses of chemotherapy and is more intensive and higher risk than DMTs. The process is similar to intensive chemotherapy-based treatments which are routinely used in patients with cancer. Risks are significantly minimised if patients are treated in experienced units. _x000D_ _x000D_ Recent studies in RRMS suggest that aHSCT reduces relapse rates and improves disability and quality-of-life to a greater degree compared with most modern DMTs and is potentially more cost effective. Results from the MIST study, the only large randomised controlled trial which compares aHSCT with DMTs, suggests that aHSCT is safe and significantly more effective than standard DMTs in reducing relapse rates and stabilising the illness. Remarkably, there was a significant improvement in average disability scores in patients who received aHSCT compared with those who were treated with DMTs. However, Alemtuzumab and Ocrelizumab, some of the most effective DMTs, were not included in MIST. There is now a need to compare aHSCT with Alemtuzumab and Ocrelizumab. _x000D_ _x000D_ AIMS_x000D_ The aims of the StarMS trial are to compare the effectiveness and safety of aHSCT and highly effective DMTs (Alemtuzumab or Ocrelizumab) at stopping clinical and MRI disease activity in people with highly active RRMS who have failed at least one DMT and had at least two relapses in the previous year. Scientific studies will investigate the mechanism of ‘re-booting’ of the immune system in both groups of patients._x000D_ _x000D_ STUDY DESIGN_x000D_ The study will recruit 198 patients with highly active RRMS who will be randomly be allocated to the aHSCT or DMT (Alemtuzumab or Ocrelizumab) treatment arms to establish how effective and safe these two treatments are over 2 years. Assessments will be undertaken to evaluate disability, brain MRI activity, quality-of-life and side effects. Coordinated through our professional organisations, 19 large accredited NHS neurology and transplant centres will take part in this study, providing access for eligible patients across the UK. State-of-the-art science studies will be performed on blood samples collected from all participants to provide insights into why some patients respond better than others._x000D_ _x000D_ POTENTIAL IMPACT_x000D_ StarMS will be a well-balanced trial involving neurologists, haematologists, scientists and specialist nurses with Patient & Public Involvement support (provided by MS and aHSCT-treated patients who advised on study design) to clarify whether aHSCT is more effective than Alemtuzumab or Ocrelizumab for patients with RRMS and whether the treatment can be safely administered in experienced transplant centres. Comparing aHSCT to Alemtuzumab and Ocrelizumab, highly effective DMTs, in terms of benefits and risks will help to determine its place in the treatment pathway in patients with RRMS.

Lay abstract: A. AIMS:_x000D_ 1. To determine whether autologous haematopoietic stem cell transplantation (aHSCT) has superior clinical efficacy to highly effective Disease Modifying Therapy (DMT; Alemtuzumab or Ocrelizumab) with acceptable safety profile, in patients with relapsing remitting multiple sclerosis (RRMS) who continued to relapse on first line DMT._x000D_ 2. To advance understanding of mechanisms of action of aHSCT by hypothesis-driven laboratory studies._x000D_ _x000D_ B. DESIGN: Multicentre parallel-group rater-blinded RCT_x000D_ _x000D_ C. POPULATION: patients with RRMS with 2 or more relapses, or 1 relapse and evidence of MRI activity at a separate time point, in the preceding 12 months despite being on first line DMT, age 16-55, EDSS 0-6.0 (EDSS 0-1.5 must be accompanied by poor prognosis, EDSS 6.0 must be due to relapse rather than progressive disease), clinically stable for >30 days following last relapse. Exclusion of primary or secondary progressive MS, disease duration >10 years, previous treatment with Alemtuzumab, Ocrelizumab, Cladribine or aHSCT, or specific medical co-morbidity._x000D_ _x000D_ D. INTERVENTIONS: _x000D_ Investigative arm: aHSCT (Cyclophosphamide 2g/m2 mobilization and harvest followed by Cy/ATG followed by unselected autologous graft); patients will otherwise receive routine standard of supportive care according to EBMT and IDSA guidelines (2.42). _x000D_ Comparator: Alemtuzumab or Ocrelizumab, depending on current guidelines and clinician/participant preference, given and monitored as per licence._x000D_ _x000D_ E. PRIMARY OUTCOME: Maintained No Evidence of Disease Activity (NEDA, 14) at 2 years. _x000D_ SECONDARY & EXPLORATORY OUTCOMES: _x000D_ 1) SAFETY i) Serious adverse events ii) mortality rate iii) combined grade 4 and 5 SAE rates iv) number of SAEs per participant in the 100 days post-randomisation v) total number of adverse events vi) long term safety events to 2 years _x000D_ 2) DISABILITY: Patient and physician outcome measures. _x000D_ 3) Quality of Life (QoL)/Health Economic measures._x000D_ _x000D_ F. ASSESSMENTS: Patients will be assessed for eligibility at a baseline visit (BLV) & followed up with clinical & safety assessments at 3,6,9,12,18 and 24 months (m) post randomisation, MRI (BLV,6,12 & 24m), pulmonary function & cardiovascular effects (BLV,12 & 24m), disability assessments & QoL evaluations (at BLV,3,6,9,12,18 & 24m). We will collect blood samples (all visits) for the mechanistic study. (Ongoing data will be recorded for aHSCT participants via routine EBMT registry follow up with analysis subject to additional funding and support). _x000D_ _x000D_ G. SAMPLE SIZE & STATISTICAL ANALYSIS: Primary outcome is No Evidence of Disease Activity (NEDA) at 2 years. Assuming 40% NEDA in the control arm, and that an absolute increase of 25% to 65% NEDA is of clinical importance [see changes from first stage for justification], to have 90% power to detect this difference at the 5% (two-sided) level 90 patients per group are required (180 in total). Adjusting for a predicted drop-out rate of 10%, the project aims to recruit 198 patients. Statistical analysis will be performed on an intention-to-treat-basis and reported according to CONSORT guidelines (50). NEDA (14), will be compared between the two groups (Control & aHSCT)._x000D_ _x000D_ H. DURATION & RECRUITMENT RATE: 66m project: 12m set-up; 24m recruitment (incl. 6m internal pilot to test recruitment feasibility); 24m follow-up; 6m close-out, analysis & write-up. Recruitment window based on availability of eligible participants at 19 centres & adjusted for capacity of sites to deliver aHSCT procedure/likely refusal rate (all sites confirmed recruitment rate 8-10 pts/site/yr achievable) i.e. a rate of around 1.25 patients/month at anchor sites or 0.5 patients/month at other sites._x000D_ _x000D_ I. ECONOMIC BENEFIT:The one off cost of aHSCT is approx. £30,000. The cost for a 2 year course of Alemtuzumab is approx. £70,000 (with additional yearly dosing for emerging disease activity), and the cost for a 2 year course of Ocrelizumab is approx. £38,000; therefore the potential cost saving to the NHS is significant.

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;6.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL