ChariotMS - Cladribine to halt deterioration in people with advanced multiple sclerosis

RESEARCH QUESTION Are cladribine tablets 3.5mg/kg over 24 months an effective disease modifying treatment (DMT) to protect upper limb function in people with advanced multiple sclerosis (pwAMS; EDSS 6.5-8.5). BACKGROUND MS is a chronic inflammatory and degenerative disease of the CNS affecting >120,000 people in the UK. Without DMT, majority of people with MS (pwMS) develop significant disability within 10 years of onset; 50% will require a wheelchair by year 20. The resulting cost (>£3 billion/year) is mainly spent on pwAMS. Whilst introduction of DMTs has transformed the management of people with early/relapsing MS (pwRMS), neurologists are mandated to withdraw/withhold DMTs once pwMS reach EDSS >6.5. However, evidence suggests CNS inflammation remains key driver of functional decline beyond this cut-off, and that effective DMT may halt this process. Cladribine is a safe, convenient, highly effective and CNS penetrant DMT for pwRMS given in short courses. It effectively depletes B cells, particularly memory B cells, a likely key mechanism of disease control. Evidence suggesting that (i) a significantly higher number of CNS axons supply upper compared to lower limbs and (ii) longer axons are more vulnerable to the effects of MS than shorter ones corroborate our hypothesis that upper limb function can be protected even beyond EDSS 6.5. AIMS To test cladribine tablets 3.5mg/kg over 24 months for safety, efficacy, and cost-effectiveness, and to advance mechanistic understanding in pwAMS. PRIMARY CLINICAL OBJECTIVE To establish whether there is efficacy superiority of cladribine over placebo in preventing deterioration of upper limb function in pwAMS at 24 months. SECONDARY OBJECTIVES To establish whether there is a difference in SAFETY (AEs/SUSARs; lymphopenia, severe infections, malignancies) and EFFICACY including further clinical indices and “patient reported outcome measures” (PROMS) of upper limb function, cognition, fatigue, and cost-utility from the patients’ and carers’ perspectives, as well as MRI measures of lesion volume and brain atrophy between pwAMS randomised to cladribine tablets versus placebo. MECHANISTIC OBJECTIVES To investigate whether in pwAMS any beneficial effect of cladribine on clinical outcomes is mediated by blood/serum biomarkers of inflammation (lymphocyte subsets) and can be predicted through changes in indices of neurodegeneration including serum neurofilament light chain level, MRI detectable grey matter loss and slowly-expanding lesions (as a marker of chronic lesion activity). METHODS Randomised, double-blind, placebo-controlled (1:1) trial cladribine vs placebo. PRIMARY OUTCOME 9-hole peg test (9HPT) speed at 24 months. 9HPT is a simple, sensitive, well established and accepted test of upper limb function among pwMS. To detect a clinically important 15% treatment effect using 9HPT peg speed, adjusting for baseline, with 90% power at 5% significance and 20% drop-out we calculated a sample size of n=200 over 24 months. TIMELINES Total project duration 57 month: 9 months set-up; 18 months recruitment across 20 UK centres, 24 months follow-up leaving 6 months for close out, analysis, reporting. IMPACT AND DISSEMINATION ChariotMS is the first DMT RCT in pwAMS offering potential for widespread NHS adoption of cladribine thereby addressing significant unmet health/social need. This would have major impact on the lives of pwAMS, their family and carers, and on medical as well as social services since maintaining upper limb function will preserve independence for longer. Results will be published in high-impact journals, meetings, and social media, further catalysed by our strong relationship with the MS Societies, MS Trust, Shift.ms, and the wider community.