Award Title: ChariotMS - Cladribine to halt deterioration in people with advanced multiple sclerosis
Funder: Medical Research Council

Abstract: BACKGROUND. Multiple sclerosis (MS) is a chronic condition of the spinal cord and brain. MS affects over 120,000 people in the UK. It is caused when the immune system does not work well and the coating that protects the nerves (myelin) is damaged. Most people with MS (pwMS) suffer a range of problems such as, arm or leg movement, cognition. If untreated, MS will lead to serious disability within 10 years of onset, with about half of pwMS needing wheelchair assistance within 20 years._x000D_
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HEALTH NEED. MS disease modifying treatments (DMTs) to date have only been successful for early MS. They reduce inflammation (swelling), number of relapses and may slow disability. Trials of DMTs for pwMS with more advanced “progressive” disease (pwAMS) are few and there remains a MASSIVE unmet health need. pwAMS who are largely or entirely dependent on a wheelchair value keeping their upper limb function, swallowing, speech, and cognition - vital for their independence. There are no DMTs or trial options for pwAMS._x000D_
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WHY THE STUDY IS NEEDED. The ChariotMS trial is built on a strong science background, and cladribine pilot trial data in pwAMS. Results suggest long-term disability in MS may be due to the length of the nerve fibres. Such that, longer nerves, like those to the legs, have a higher chance of being damaged than short nerves, like those to the hands. This leads to earlier loss of lower limb use, while shorter nerves may still be able to be treated. There are also more nerve fibres to the upper limbs than the lower limbs; this may help keep their function for longer. Inflammation is seen in brain tissue from pwAMS under the microscope throughout the disease course. Cladribine is a drug that can pass into the brain and may be able to target brain inflammation and halt the disease._x000D_
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Cladribine has been used and licensed for more than 25 years to treat people with hairy cell leukaemia. A tablet form of cladribine (MAVENCLAD®) is now licensed for patients with early (relapsing) MS. We have pilot data that shows cladribine may work for pwAMS. This is exciting as no drugs are available for this patient group._x000D_
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AIM ChariotMS will test if cladribine tablets can effectively treat pwAMS compared to a dummy (placebo) drug._x000D_
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RESEARCH QUESTION. Does cladribine keep or improve upper limb performance in pwAMS over 24 and 48 months?_x000D_
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DESIGN. A national (UK), multi-centre, blinded, dummy drug-versus cladribine trial developed together with pwMS._x000D_
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INTERVENTION. Cladribine tablet provided free by the company Merck KGaA._x000D_
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CONTROL. Placebo, a “dummy” drug also provided free._x000D_
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POPULATION. pwAMS with an Expanded Disability Status Scale (EDSS) of 6.5-8.5 showing lower-limb loss of use, but still upper limb function._x000D_
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OUTCOMES. We will test if the treatments work by:_x000D_
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PRIMARY. 9-Hole Peg Test (upper limb function) after 24 months follow-up._x000D_
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SECONDARY. Cognitive function, fatigue, quality of life, biomarkers and health economics after 24 and 48 months._x000D_
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COLLABORATORS. Both the UK MS Society and the National MS Society (US), and Merck KGaA will support funding of ChariotMS. Further funding support, for the MRI proportion of the study, has been awarded by Barts Charity._x000D_
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PPI ChariotMS has been co-produced with PPI input, including a pwAMS who has undergone off-label treatment with cladribine (co-applicant of ChariotMS), the UK MS Society, Shift.ms and the MS Trust._x000D_
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DISSEMINATION. Alongside traditional outputs (publications), our PPI advisors will produce video info and a plain English trial summary. This will be shared with participants, pwMS and the wider community.

Lay Abstract: 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)._x000D_
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._x000D_
AIMS To test cladribine tablets 3.5mg/kg over 24 months for safety, efficacy, and cost-effectiveness, and to advance mechanistic understanding in pwAMS._x000D_
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._x000D_
SECONDARY OBJECTIVES To establish whether there is a difference in _x000D_
SAFETY (AEs/SUSARs; lymphopenia, severe infections, malignancies) and _x000D_
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._x000D_
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)._x000D_
METHODS Randomised, double-blind, placebo-controlled (1:1) trial cladribine vs placebo. _x000D_
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._x000D_
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._x000D_
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.

Research Activity Codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health Categories: NEUROLOGICAL