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

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?

Sponsors

Lead Sponsor: Queen Mary University of London

Collaborator: University College, London
University of Plymouth
University of Edinburgh
University of Leeds
The Leeds Teaching Hospitals NHS Trust

Source Queen Mary University of London
Brief Summary

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).

Overall Status Not yet recruiting
Start Date 2021-05-31
Completion Date 2024-07-04
Primary Completion Date 2024-07-04
Phase Phase 2/Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
The 9-HPT peg speed (tasks/second) at 24 months 24 months
9-HPT proportion of patients who do not deteriorate at 24 months 24 months
Secondary Outcome
Measure Time Frame
Change over 24 months of the study in clinical outcome measure: EDSS Screening, Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: ARAT Screening, Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: ABILHAND Screening, Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: T25ftWT Screening, Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: SLCVA Screening, Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: MSIS-29v2 Screening, , Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: SDMT Screening, Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: NFI-MS Screening, Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L Screening, Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L Screening, Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L Screening, Month 6, 12, 18 and 24
Change over 24 months of the study in clinical outcome measure: WPAI-GH Baseline, Month 6, 12, 18 and 24
Safety/occurrence of adverse events Through study completion, an average of 24 months
Preventing loss of brain volume Screening, Month 6 and 24
Preventing loss of brain volume Screening, Month 6 and 24
Preventing loss of spinal cord cross sectional area Screening, Month 6 and 24
Preventing new focal demyelinating lesions and T2 burden of disease increase. Screening, Month 6 and 24
Preventing new hypo-intense lesions ("black holes") on T1 weighted MRI Screening, Month 6 and 24
Degree of unblinding Month 24
Enrollment 200
Condition
Intervention

Intervention Type: Drug

Intervention Name: Cladribine (MAVENCLAD®)

Description: 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.

Arm Group Label: Cladribine (MAVENCLAD®)

Intervention Type: Drug

Intervention Name: Placebo

Description: 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.

Arm Group Label: Placebo

Eligibility

Criteria:

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 either 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, deep vein or sinus venous thrombosis and/or myocardial infarction 4. Moderate to severe renal impairment (creatinine clearance <60 ml/min) 5. Moderate to severe hepatic impairment (Child-Pugh score >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 7. Pregnancy including planning to father a child or breastfeeding 8. Body weight less <40kg 9. 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 10. Acute infection 11. Infection with Human Immunodeficiency Virus 1 and/or 2 12. Active chronic infection (Syphilis, Tuberculosis, Hepatitis) 13. Precancerous condition or previous diagnosis of cancer 14. Total lymphocyte count <1.0*109/mL 15. Seronegativity for varicella zoster IgG, rubella, measles, mumps. Potential participants who fall in this category may undergo vaccination and can be screened (again) once full course has been completed. 16. Relapse within six months before screening 17. 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. 18. 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. 19. Treatment with any interferon-beta, glatiramer acetate, teriflunomide or dimethyl-fumarate within three months before screening. 20. Treatment with natalizumab, fingolimod, siponimod, ponesimod, ozanimod (or other Sphingosine-1-phosphate receptor modulators) within three months of screening. 21. Treatment with azathioprine, methotrexate, or cyclosporine within six months before screening. 22. pwAMS treated with teriflunomide will need to undergo accelerated elimination of the compound before being considered (Research and Case Medical Research 2019). 23. 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. 24. 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. 25. Concurrent participation or previous participation within the last 6 months in another clinical trial of an IMP or medical device. 26. Unable to swallow tablets

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Contact

Last Name: Klaus Schmierer, PhD, FRCP

Phone: +44 (0)20 7882 6246

Email: [email protected]

Location
Facility: Investigator:
Belfast Health and Social Care Trust | Belfast, BT12 6BA, United Kingdom Stella Hughs Principal Investigator
University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham | Birmingham, B15 2TH, United Kingdom Gordon Mazibrada Principal Investigator
The Princess Royal Hospital | Brighton, RH16 4EX, United Kingdom Leonora Fisniku Principal Investigator
North Bristol NHS Trust Southmead Hospital | Bristol, BS10 5NB, United Kingdom Mark Crossburn Principal Investigator
Cardiff University Hospital | Cardiff, CF14 4XW, United Kingdom Emma Tallantyre Principal Investigator
Anne Rowling Clinic, University of Edinburgh | Edinburgh, EH16 4SB, United Kingdom Don Mahad Principal Investigator
University Hospital Hairmyres, NHS Lanarkshire | Glasgow, G75 8RG, United Kingdom Niall MacDougall Principal Investigator
Leeds Teaching Hospitals | Leeds, LS1 3EX, United Kingdom Helen Ford Principal Investigator
Walton Centre NHS Trust | Liverpool, L9 7LJ, United Kingdom Carolyn Young Principal Investigator
Royal London Hospital | London, E1 1FR, United Kingdom Klaus Schmierer Principal Investigator
Royal Free London NHS Foundation Trust | London, NW3 2QG, United Kingdom Robert Brenner Principal Investigator
Queen's Hospital | London, RM7 0AG, United Kingdom Miriam Mattoscio Principal Investigator
St George's University Hospitals NHS Foundation Trust | London, SW17 0RE, United Kingdom Liquin Zhang Principal Investigator
Charing Cross Hospital | London, W6 8RF, United Kingdom Richard Nicolas Principal Investigator
University College London Hospitals NHS Foundation Trust | London, WC1N 3BG, United Kingdom Jeremy Chataway Principal Investigator
Luton and Dunstable Hospital | Luton, LU4 0DZ, United Kingdom Floriana DeAngelis Principal Investigator
Salford Royal Hospital NHS Trust | Manchester, M6 8HD, United Kingdom Tatiana Mihalova Principal Investigator
University Hospitals Plymouth | Plymouth, PL6 8DH, United Kingdom Jeremy Hobart Principal Investigator
Sheffield Teaching Hospitals NHS Foundation Trust | Sheffield, S10 2JF, United Kingdom Basil Sharrack Principal Investigator
Morriston Hospital, Swansea | Swansea, SA6 6NL, United Kingdom Owen Pearson Principal Investigator
Location Countries

United Kingdom

Verification Date

2020-10-01

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Cladribine (MAVENCLAD®)

Type: Active Comparator

Label: Placebo

Type: Placebo Comparator

Acronym ChariotMS
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

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