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

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ClinicalTrials.gov Identifier: NCT04695080
Recruitment Status : Recruiting
First Posted : January 5, 2021
Last Update Posted : June 10, 2022
Sponsor:
Collaborators:
National Institute for Health Research, United Kingdom
Merck Serono Limited, UK
Multiple Sclerosis Society of Great Britain & Northern Ireland
National Multiple Sclerosis Society USA
Barts & The London NHS Trust
Information provided by (Responsible Party):
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).


Condition or disease Intervention/treatment Phase
Advanced Multiple Sclerosis Progressive Multiple Sclerosis Drug: Cladribine (MAVENCLAD®) Drug: Placebo Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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?
Actual Study Start Date : June 25, 2021
Estimated Primary Completion Date : July 4, 2024
Estimated Study Completion Date : July 4, 2024


Arm Intervention/treatment
Active Comparator: Cladribine (MAVENCLAD®) Drug: Cladribine (MAVENCLAD®)

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 Comparator: Placebo Drug: Placebo

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.





Primary Outcome Measures :
  1. The 9-HPT peg speed (tasks/second) at 24 months [ Time Frame: 24 months ]

    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.


  2. 9-HPT proportion of patients who do not deteriorate at 24 months [ Time Frame: 24 months ]

Secondary Outcome Measures :
  1. Change over 24 months of the study in clinical outcome measure: EDSS [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    The proportion of the cladribine versus placebo arms with an increase of >=0.5 in EDSS score over 24 months.

  2. Change over 24 months of the study in clinical outcome measure: ARAT [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    ARAT (Upper Limb Function Test) upper limb function test score

  3. Change over 24 months of the study in clinical outcome measure: ABILHAND [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    ABILHAND score for manual ability

  4. Change over 24 months of the study in clinical outcome measure: T25ftWT [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    Lower Limb Function: The T25ftWT (Timed 25 foot walk test) will be collected in all pwAMS able to walk the required distance twice.

  5. Change over 24 months of the study in clinical outcome measure: SLCVA [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    SLCVA (Sloan low contrast letter visual acuity) score.

  6. Change over 24 months of the study in clinical outcome measure: MSIS-29v2 [ Time Frame: Screening, , Month 6, 12, 18 and 24 ]
    MSIS-29v2 (Multiple Sclerosis Impact Scale) quality of life score

  7. Change over 24 months of the study in clinical outcome measure: SDMT [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    SDMT (The Symbol Digit Modalities Test) score.

  8. Change over 24 months of the study in clinical outcome measure: NFI-MS [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    NFI-MS (Neurological Fatigue Index-Multiple Sclerosis) score.

  9. Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    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.

  10. Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    Cost-utility: Carer's generic health-related quality of life, measured using the EuroQoL EQ-5D-5L

  11. Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    Cost-utility: health and social care and other costs.

  12. Change over 24 months of the study in clinical outcome measure: WPAI-GH [ Time Frame: Baseline, Month 6, 12, 18 and 24 ]
    WPAI-GH (Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH) score

  13. Safety/occurrence of adverse events [ Time Frame: Through study completion, an average of 24 months ]

    Safety:

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

  14. Preventing loss of brain volume [ Time Frame: Screening, Month 6 and 24 ]
    (MRI) Change over 24 months of the study in ventricular volume assessed using the VIENA technique.

  15. Preventing loss of brain volume [ Time Frame: Screening, Month 6 and 24 ]
    (MRI) Change over 24 months in brain volume assessed using the "Structural Image Evaluation, using Normalisation, of Atrophy" (SIENA) technique

  16. Preventing loss of spinal cord cross sectional area [ Time Frame: Screening, Month 6 and 24 ]
    (MRI) Change in the total cross-sectional area of spinal cord (at level C2) over 24 months

  17. Preventing new focal demyelinating lesions and T2 burden of disease increase. [ Time Frame: Screening, Month 6 and 24 ]
    (MRI) Total number of new focal demyelinating brain lesions over 24 months

  18. Preventing new hypo-intense lesions ("black holes") on T1 weighted MRI [ Time Frame: Screening, Month 6 and 24 ]
    (MRI) Total number of new hypo-intense T1 lesions over 24 months

  19. Degree of unblinding [ Time Frame: Month 24 ]
    To determine the perception of treatment allocation for both participants and trial teams at 24 months.


Other Outcome Measures:
  1. To determine if cladribine correlates with memory Bcell count. [ Time Frame: Screening, Month 12 and 24 ]
    Memory B-Cell (total number and percentage of CD19+ cell count) and its association with upper limb function as measured using 9HPT speed.

  2. To determine association between Memory B cell count and 9HPT speed. [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    9HPT speed

  3. To determine association between Memory B cell count and 9HPT speed. [ Time Frame: Screening, Month 6, 12, 18 and 24 ]
    ARAT score

  4. To determine association between Memory B cell count, upper limb function and s-NfL level. [ Time Frame: Screening, Month 12 and 24 ]
    Serum-NfL at 6 and 24 months compared to baseline.

  5. 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. [ Time Frame: Screening, Month 6 and 24 ]
    (MRI) Change over 24 months of the study in cortical brain volume

  6. 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. [ Time Frame: Screening, Month 6 and 24 ]
    (MRI) Change over 24 months of the study in thalamic brain volume

  7. 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. [ Time Frame: Screening, Month 6 and 24 ]
    (MRI) Change over 24 months of the study in hippocampal brain volume

  8. 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. [ Time Frame: Screening, Month 6 and 24 ]
    (MRI) Change over 24 months of the study in new slowly expanding/evolving lesions (SELs)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04695080


Contacts
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Contact: Klaus Schmierer, PhD, FRCP +44 (0)20 7882 6246 k.schmierer@qmul.ac.uk
Contact: Svetlana Milca, MSc +44 (0)7907252008 chariot@qmul.ac.uk

Locations
Show Show 19 study locations
Sponsors and Collaborators
Queen Mary University of London
National Institute for Health Research, United Kingdom
Merck Serono Limited, UK
Multiple Sclerosis Society of Great Britain & Northern Ireland
National Multiple Sclerosis Society USA
Barts & The London NHS Trust
Layout table for additonal information
Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT04695080    
Other Study ID Numbers: 258909
2018-005038-39 ( EudraCT Number )
First Posted: January 5, 2021    Key Record Dates
Last Update Posted: June 10, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Queen Mary University of London:
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)
Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Sclerosis
Multiple Sclerosis, Chronic Progressive
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Cladribine
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs