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

ChariotMS - A National (UK) Phase IIb, Multi-centre, Randomised, Double-blind, Placebo Controlled (1:1) Efficacy Trial With Cost-utility Analysis of Cladribine Tablets (3.5mg/kg Over Two Years) in People With Advanced Multiple Sclerosis. Is Cladribine Superior to Placebo in Protecting Upper Limb Function?

National Institute for Health Research, United Kingdom, Merck Serono Limited, UK, Multiple Sclerosis Society of Great Britain & Northern Ireland, National Multiple Sclerosis Society, Barts & The London NHS Trust

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).

Multiple Sclerosis, Progressive multiple sclerosis, Advanced multiple sclerosis, Upper limb function, Cladribine, Quality of life, Cognition, Health Economics, Biomarkers, Neurofilament light chain, B cells, Lymphocytes, Magnetic Resonance Imaging (MRI)

Cladribine (MAVENCLAD®) 3.5mg/kg, administered as weight-adjusted 10mg tablets in two treatment courses (12 months apart) lasting 8- 10 days each. Cladribine (MAVENCLAD®) 10mg available in blister packs of 1 tablet, 4 tablets and 6 tablets.

Placebo administered as weight adjusted tablets in two treatment courses (12 months apart) lasting 8-10 days each. Placebo 10mg available in blister packs of 1 tablet, 4 tablets and 6 tablets.

To establish whether there is efficacy superiority of cladribine tablets over placebo in reducing deterioration of upper limb function in pwAMS. To investigate whether cladribine tablets 3.5mg/kg over 24 months is an effective DMT in pwAMS as measured using the 9-hole peg test (9HPT) peg speed at 24 months.

The proportion of the cladribine versus placebo arms with an increase of >=0.5 in EDSS score over 24 months.

Lower Limb Function: The T25ftWT (Timed 25 foot walk test) will be collected in all pwAMS able to walk the required distance twice.

Cost-utility: Patient's generic health-related quality of life, measured using the EuroQoL EQ-5D-5L and, separately, carer's generic health-related quality of life, measured using the EuroQoL EQ-5D-5L, health and social care and other costs.

WPAI-GH (Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH) score

Safety: Any AEs/SAEs, Lymphopenia (peripheral blood lymphocyte counts), Severe infections, Malignancies. Pregnancies Special situations (e.g. overdose)

(MRI) Change over 24 months in brain volume assessed using the "Structural Image Evaluation, using Normalisation, of Atrophy" (SIENA) technique

To determine the perception of treatment allocation for both participants and trial teams at 24 months.

Memory B-Cell (total number and percentage of CD19+ cell count) and its association with upper limb function as measured using 9HPT speed.

To determine effects of IMP on cortical and deep grey matter volumes, thalamic, hippocampal and ventricular volumes (VIENA) and slowly expanding (i.e. chronically active) lesions.

To determine effects of IMP on cortical and deep grey matter volumes, thalamic, hippocampal and ventricular volumes (VIENA) and slowly expanding (i.e. chronically active) lesions.

To determine effects of IMP on cortical and deep grey matter volumes, thalamic, hippocampal and ventricular volumes (VIENA) and slowly expanding (i.e. chronically active) lesions.

To determine effects of IMP on cortical and deep grey matter volumes, thalamic, hippocampal and ventricular volumes (VIENA) and slowly expanding (i.e. chronically active) lesions.

Inclusion criteria: pwAMS aged 18+ years with an EDSS of 6.5-8.5 (inclusive) 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/. 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. Confirmation of MS diagnosis according to the McDonald Criteria (2017) Thompson et al. 2018). 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 Participants with known hypersensitivity to Cladribine of any grade (as per CTCAE grading system) should be excluded Any uncontrolled diabetes, arterial hypertension and hypercholesterolaemia as determined by PI or delegated sub-investigator A history of stroke, deep vein or sinus venous thrombosis (including pulmonary embolus) and/or myocardial infarction Moderate to severe renal impairment (creatinine clearance <60 ml/min) Moderate to severe hepatic impairment (Child-Pugh score >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. Pregnancy including planning to father a child or breastfeeding Body weight less <40kg Unwillingness to use effective contraception throughout the trial period until at least six months after the last administration of IMP. This is not applicable for post-menopausal women Acute infection (uncontrolled) Infection with Human Immunodeficiency Virus 1 and/or 2 Active chronic infection (Syphilis, Tuberculosis, Hepatitis). Patients with active TB will be excluded. However, patients who have a positive IGRA, Elispot or Quantiferon test, but exhibit no symptoms for TB and evidence of a normal Chest X Ray, can be included in the study as per judgement of the local PI and after clarification with the CI. Precancerous condition Total lymphocyte count <1.0*109/L Seronegativity for varicella zoster virus. Potential participants who are IgG negative may undergo vaccination, and can be screened again once full course has been completed. Seronegativity for all of the following: measles, mumps, rubella. Potential participants who are IgG negative for all 3 viruses, may undergo vaccination and can be screened again once full course has been completed. Relapse within six months before screening Inability to complete an MRI (contraindications for MRI, including but not limited to, MRI-non-compatible pacemaker, cochlear implants, intracranial vascular clips, surgery within 6 weeks of entry in the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, severe anxiety or claustrophobia etc.) or contraindication to Gd administration. Treatment with steroids due to MS relapse/progression within three months of screening. pwAMS who fall in this category may undergo a further screening visit once the three months' window has expired and may be included if no steroid treatment has been administered in the intervening period. Treatment with any interferon-beta, glatiramer acetate, teriflunomide or dimethyl-fumarate within three months before screening. Treatment with natalizumab, fingolimod, siponimod, ponesimod, ozanimod (or other Sphingosine-1-phosphate receptor modulators) within three months of screening. Treatment with azathioprine, methotrexate, or cyclosporine within six months before screening. pwAMS treated with teriflunomide will need to undergo accelerated elimination of the compound before being considered (Research and Case Medical Research 2019). Treatment with haematopoietic stem cell transplantation (HSCT), mitoxantrone, cyclophosphamide, cladribine, alemtuzumab or another B cell depleting compound, such as rituximab, ocrelizumab, ublitiuximab, ofatumumab, or biosimilars, unless the participant concerned has a memory B cell level of ≥20% of the CD19+ population in the peripheral blood. Such a level would normally not be expected earlier than a minimum of six months after the last drug administration. Participants who underwent such treatment will therefore have to be tested for their CD19+/CD27+ memory B cell level at screening. Treatment with fampridine: If they are already on treatment for at least six months, participants should continue throughout the trial. However, starting continuous fampridine treatment after signing the consent sheet will lead to exclusion from treatment with IMP/placebo. Concurrent participation or previous participation within the last 6 months in another clinical trial of an IMP or medical device. Unable to swallow tablets