A bone marrow transplant will be tested head-to-head against two leading drugs to see which better stops multiple sclerosis from flaring up. For people with relapsing-remitting MS who keep having attacks despite taking first-line treatments, the choice between a one-off stem cell transplant and long-term drug therapy is a real dilemma. The drugs alemtuzumab and ocrelizumab are highly effective but require repeated infusions and carry their own risks. Autologous haematopoietic stem cell transplantation (aHSCT) resets the immune system by wiping out faulty cells and regrowing healthy ones from the patient’s own stem cells, but it is an intensive procedure with serious potential side effects. No large randomised trial has directly compared aHSCT to these modern drugs. If aHSCT proves superior, patients could gain a durable, one-time treatment that eliminates the need for ongoing medication and monitoring. The NHS could also see significant cost savings, as the transplant procedure is less expensive than two years of either drug. Even if aHSCT is not superior, the trial’s mechanistic studies will reveal why the transplant works in some patients, guiding future therapies. The results will directly inform clinical guidelines for managing aggressive relapsing-remitting MS.
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A. AIMS: 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. 2. To advance understanding of mechanisms of action of aHSCT by hypothesis-driven laboratory studies. B. DESIGN: Multicentre parallel-group rater-blinded RCT 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. D. INTERVENTIONS: 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). Comparator: Alemtuzumab or Ocrelizumab, depending on current guidelines and clinician/participant preference, given and monitored as per licence. E. PRIMARY OUTCOME: Maintained No Evidence of Disease Activity (NEDA, 14) at 2 years. SECONDARY & EXPLORATORY OUTCOMES: 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 2) DISABILITY: Patient and physician outcome measures. 3) Quality of Life (QoL)/Health Economic measures. 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). 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). 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. 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.
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