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    Summary
    EudraCT Number:2018-005038-39
    Sponsor's Protocol Code Number:
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-09-29
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2018-005038-39
    A.3Full title of the trial
    ChariotMS – A national (UK), multi-centre, randomised, double-blind, placebo-controlled (1:1) phase IIb efficacy trial with cost-utility analysis of cladribine tablets (3.5mg/kg over two years) in people with advanced multiple sclerosis (EDSS 6.5-8.5). Is cladribine superior to placebo in protecting upper limb function?
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 2b study of Cladribine to halt deterioration in people with advanced multiple sclerosis
    A.3.2Name or abbreviated title of the trial where available
    ChariotMS - Cladribine for people with advanced multiple sclerosis
    A.4.1Sponsor's protocol code number
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorQueen Mary University of London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQueen Mary University of London
    B.5.2Functional name of contact pointKlaus Schmierer
    B.5.3 Address:
    B.5.3.1Street Address4 Newark Street
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeE1 2AT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02078826246
    B.5.6E-mailk.schmierer@qmul.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MAVENCLAD
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Europe B.V. Gustav Mahlerplein 102 1082 MA Amsterdam The Netherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMAVENCLAD
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCladribine
    D.3.9.1CAS number 4291-63-8
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Advanced Multiple Sclerosis (EDSS 6.5-8.5)
    E.1.1.1Medical condition in easily understood language
    Multiple sclerosis
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10052785
    E.1.2Term Multiple sclerosis acute and progressive
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10078558
    E.1.2Term Multiple sclerosis plaque
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.1
    E.1.2Level LLT
    E.1.2Classification code 10028246
    E.1.2Term Multiple sclerosis aggravated
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10078559
    E.1.2Term Multiple sclerosis brain lesion
    E.1.2System Organ Class 10028245 - Multiple sclerosis
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10063401
    E.1.2Term Primary progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10063401
    E.1.2Term Primary progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10064137
    E.1.2Term Progression of multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10053395
    E.1.2Term Progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10053395
    E.1.2Term Progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10067063
    E.1.2Term Progressive relapsing multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10067063
    E.1.2Term Progressive relapsing multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10063400
    E.1.2Term Secondary progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10063400
    E.1.2Term Secondary progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary clinical objective of the study is to establish whether there is efficacy superiority of cladribine tablets over placebo in reducing deterioration of upper limb function in pwAMS.
    E.2.2Secondary objectives of the trial
    The secondary objectives include establishing whether there is a difference in pwAMS between treatment with cladribine tablets or placebo in:

    - Protecting limb function
    - Safety/occurrence of adverse events
    - Blood/serum biomarkers of (i) inflammation (lymphocyte subsets) and/or (ii) neurodegeneration (serum neurofilament light chain)
    - Preventing loss of brain volume
    - Preventing loss of spinal cord cross sectional area
    - Preventing new focal demyelinating lesions and T2 burden of disease increase.
    - Preventing new hypo-intense lesions (“black holes”) on T1 weighted MRI
    - Degree of unblinding
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal exclusion criteria
    1. Known hypersensitivity to cladribine of Grade 3 or Grade 4 severity according to the Common Terminology Criteria for Adverse Events (CTCAE) grading system
    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
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is the 9-hole peg test (9HPT), a simple, sensitive and established test of upper limb function, which is well accepted among pwMS. To detect a 15% treatment effect in 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 is considered sufficient to address the primary objectives of the study.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The 9-HPT peg speed (tasks/second) at 24 months.
    E.5.2Secondary end point(s)
    Change over 24 months of the study in clinical outcome measures: EDSS, ARAT, T25ftWT, SLCVA and the questionnaires (including MSIS-29v2, 5NFI-MS, EuroQoL EQ-5D-5L, WPAI-GH and neurocognitive tests such as BICAMS).

    - 9-HPT proportion of patients who do not deteriorate at 24 months.
    - The proportion of the cladribine versus placebo arms with an increase of >=0.5 in EDSS score over 24 months.
    - ARAT (Upper Limb Function Test) upper limb function test score
    - ABILHAND score for manual ability
    - Lower Limb Function: The T25ftWT (Timed 25 foot walk test) will be collected in all pwAMS able to walk the required distance twice.
    - SLCVA (Sloan low contrast letter visual acuity) score.
    - BICAMS (Brief International Cognitive Assessment for MS) score
    - MSIS-29v2 (Multiple Sclerosis Impact Scale) quality of life score
    - NFI-MS (Neurological Fatigue Index-Multiple Sclerosis) score.
    - WPAI-GH (Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH) score
    - (MRI) Change over 24 months in brain volume assessed using the “Structural Image Evaluation, using Normalisation, of Atrophy” (SIENA) technique
    - (MRI) Change in the total cross-sectional area of spinal cord (at level C2) over 24 months
    - (MRI) Total number of new focal demyelinating brain lesions over 24 months
    - (MRI) Total number of new hypo-intense T1 lesions over 24 months
    - (MRI) Change over 24 months of the study in ventricular volume assessed using the VIENA technique.

    Safety:
    - Any AEs/SAEs,
    - Lymphopenia (peripheral blood lymphocyte counts),
    - Severe infections,
    - Malignancies.
    - Pregnancies
    - Special situations (e.g. overdose)
    - Cost-utility: Patient’s generic health-related quality of life, measured using the EuroQoL EQ-5D-5L and, separately, MSIS 8D, carer’s generic health-related quality of life, measured using the EuroQoL EQ-5D-5L, health and social care and other costs.
    - Blinding: To determine the perception of treatment allocation for both participants and trial teams at 24 months
    E.5.2.1Timepoint(s) of evaluation of this end point
    - 9-HPT proportion of patients who do not deteriorate at 24 months
    - (MRI) Change over 24 months of the study in brain volume assessed using the “Structural Image Evaluation, using Normalisation, of Atrophy” (SIENA) technique
    - (MRI) Change in the total cross-sectional area of spinal cord (at C2) over 24 months
    - (MRI) Total number of new focal demyelinating brain lesions over 24 months
    - (MRI) Total number of new hypo-intense T1 lesions over 24 months
    - (MRI) Change over 24 months of the study in ventricular volume assessed using the VIENA technique.

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned20
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state200
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 200
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After a subject has ended their participation in the trial they will return to standard of care treatment post-trial.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-11-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-02
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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