ChariotMS - Cladribine to Halt Deterioration in People With Advanced Multiple Sclerosis

MS is a chronic inflammatory and degenerative disease of the central nervous system (CNS) affecting more than 120,000 people in the UK.and 2.5 million people worldwide. Without disease modifying treatment (DMT),the majority of people with MS (pwMS) will develop significant disability within 10 years of onset, and 50% will require wheelchair assistance within 20 years. convenient, highly effective and CNS penetrant DMT for patients with relapsing multiple sclerosis (pwRMS) administered in short (8-10 days/year over 2 years) treatment courses. It effectively depletes B cells, particularly Memory B cells, a likely key mechanism of disease control in MS. Cladribine is the investigational product in this study as it not currently used to treat patients with an EDSS of 6.5 - 8.5. This is a multi-centre, randomised double-blind placebo-controlled phase IIb to test cladribine tablets (MAVENCLAD®) (3.5mg/kg over 24 months) for safety, efficacy, and cost effectiveness, and to advance mechanistic understanding of its action in people with advanced MS (pwAMS).

Inclusion criteria: 1. pwAMS aged 18+ years with an EDSS of 6.5-8.5 (inclusive) 2. History of bowel cancer screening for men, and women and cervical and breast cancer screening for women as per NHS recommended guidelines https://www.nhs.uk/conditions/nhs-screening/. 3. Ability to complete the 9HPT with at least one upper limb within 180 seconds. The average score of both attempts for each hand should be used to assess eligibility. 4. Confirmation of MS diagnosis according to the McDonald Criteria (2017) Thompson et al. 2018). 5. In the judgement of the investigator, evidence of deterioration of upper limb function during the 2 years running up to the screening date. Exclusion Criteria 1. Participants with known hypersensitivity to Cladribine of any grade (as per CTCAE grading system) should be excluded 2. Any uncontrolled diabetes, arterial hypertension and hypercholesterolaemia as determined by PI or delegated sub-investigator 3. A history of stroke and/or myocardial infarction 4. Moderate to severe renal impairment (creatinine clearance \6) 6. Significant comorbidity, e.g. cardiac failure, renal failure, malignancy, or other health condition that in the view of the PI or delegated sub-investigator precludes participation. Patients who, following discussion with their cancer treatment team, are deemed to be cured from malignancy, may be eligible to participate as per the clinical judgement of the local PI. 7. Pregnancy including planning to father a child or breastfeeding 8. Body weight less \