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    Summary
    EudraCT Number:2018-004557-24
    Sponsor's Protocol Code Number:UKM17_0056
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2019-06-18
    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 ConcernedGermany - BfArM
    A.2EudraCT number2018-004557-24
    A.3Full title of the trial
    Clarifying the mechanism of action of cladribine in relapsing multiple sclerosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clarifying the mechanism of action of cladribine in relapsing multiple sclerosis
    A.3.2Name or abbreviated title of the trial where available
    ClaiMS, Cladribine in MS
    A.4.1Sponsor's protocol code numberUKM17_0056
    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 SponsorWestfälische Wilhelms-Universität Münster c/o Universitätsklinikum Münster, Geschäftsbereich Recht u. Drittmittel
    B.1.3.4CountryGermany
    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 supportMerck Serono GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinik für Neurologie mit Institut für translationale Neurologie am UKM
    B.5.2Functional name of contact pointProf. Dr. med. Luisa Klotz
    B.5.3 Address:
    B.5.3.1Street AddressAlbert-Schweizer-Campus 1, Gebäude A1
    B.5.3.2Town/ cityMünster
    B.5.3.3Post code48149
    B.5.3.4CountryGermany
    B.5.4Telephone number00492518344452
    B.5.5Fax number00492518345379
    B.5.6E-mailluisa.klotz@ukmuenster.de
    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 10 mg tablets
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical 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 CodeSUB06635MIG
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple Sclerosis
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Analysis of the T cell receptor repertoire of CD4 and CD8 T cells, and the B cell receptor repertoire of CD19 B cells before and during the first year after onset of cladribine treatment initiation.
    E.2.2Secondary objectives of the trial
    - Analysis of the T cell receptor repertoire of CD4 and CD8 T cells, and the B cell receptor repertoire of CD19 B cells before and during the second year after onset of cladribine treatment Initiation
    - Analysis of the impact of cladribine treatment on the transcriptional profile of CD4, CD8 and CD19 cells using unbiased RNAseq of sorted cells and PBMCs
    - Analysis of the impact of cladribine treatment on immune cell subsets (T cells, B cells, monocytes, NK cells, dendritic cells, CD4, CD8 T cells)
    - Analysis of the impact of cladribine treatment on immune cell activation status, markers of cell death and immune senescence
    - Analysis of the impact of cladribine treatment on mitochondrial energy metabolism (i.e. oxidative phosphorylation) of CD4 and CD8 T cells
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed informed consent form (ICF)
    2. Age 18 to 60 years old (inclusive) as of the date the ICF is signed
    3. Diagnosis of MS according to the McDonald criteria 2017 and cranial MRI scan demonstrating white matter lesions attributable to MS
    4. Therapy with cladribine is indicated (according to label)
    5. EDSS score 0.0 to 6.0 (inclusive)
    6. Patient did not receive cladribine treatment before and is cladribine treatment naive at time point of inclusion and first blood draw
    E.4Principal exclusion criteria
    1. Hypersensitivity to the active substance or to any of the excipients of the study medication
    2. Acute infection
    3. Infection with human immunodeficiency virus (HIV)
    4. Active chronic infection (tuberculosis or hepatitis)
    5. Suspected progressive multifocal leukoencephalopathy (PML) (a baseline magnetic resonance imaging (MRI) should be performed within 3 months before start of treatment with cladribine)
    6. Varicella zoster virus antibody-negative patients
    7. Immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy
    8. Patients with significant disposition for infections
    9. Abnormal lymphocyte count
    10. Vaccination with live or attenuated live vaccines within 4 to 6 weeks before start of treatment with cladribine and also during and after cladribine treatment until normalization of white blood cell counts
    11. Moderate or severe renal impairment (creatinine clearance <60 mL/min)
    12. Patients with impaired liver function (Child-Pugh-Score >6)
    13. Patients with active malignancies
    14. Patients with hereditary problems of fructose intolerance
    15. Pregnancy and breast-feeding
    16. For female and male patients of reproductive potential: Unwilling to agree to use a highly effective method of contraception (Pearl index <1) within a period of 6 month after the last cladribine treatment.
    17. Medical, psychiatric, cognitive, or other condition that, in the Investigator´s opinion, compromise the patient´s ability to understand the patient information, to give informed consent, or to complete the study
    18. Participation in another interventional clinical trial during this trial or within 4 weeks before entry into this trial resp. 5 half-lives of the previously applied investigational medicinal product depending on which period is longer. Simultaneous inclusion of patients in the clinical trial MAGNIFY (EudraCT-No. 2017-002631-42, Sponsor: Merck KgaA) is permitted. There may be other exceptions at the discretion of the (coordinating) investigator.
    19. Therapy with teriflunomide, ozanimod, ponesimod or fingolimod within 4 weeks before start of treatment with cladribine
    20. Therapy with natalizumab within 6 weeks before start of treatment with cladribine
    21. Therapy with mitoxantron, azathioprin, methotrexat, ciclosporin A or cyclophosphamid within 3 months before start of treatment with cladribine
    22. Therapy with alemtuzumab, rituximab or ocrelizumab within 6 months before start of treatment with cladribine
    E.5 End points
    E.5.1Primary end point(s)
    Changes in the T cell receptor repertoire (CD4 and CD8 T cells) and B cell receptor repertoire (CD19 B cells) 3 and 12 months after start of first treatment course (as compared to baseline) will be assessed using thawed PBMC by deep sequencing of the T cell receptor and the B cell receptor repertoire.
    E.5.1.1Timepoint(s) of evaluation of this end point
    3 and 12 months after start of first treatment course
    E.5.2Secondary end point(s)
    • Changes in the T cell receptor repertoire (CD4 and CD8 T cells) and B cell receptor repertoire (CD19 B cells) 12 months after start of second treatment course (as compared to baseline) will be assessed using thawed PBMC by deep sequencing of the T cell receptor and the B cell receptor repertoire.
    • Changes in the transcriptional profiles of CD4 and CD8 T cells as well as CD19 B cells 3 and 12 months after start of first treatment course (as compared to baseline) will be assessed by RNAseq of sorted CD4, CD8, and CD19 expressing cells and PBMCs in a subgroup of 10 patients.
    • Changes in proportions and absolute counts of immune cell subsets (T cells, B cells, monocytes, NK cells, dendritic cells, CD4, CD8 T cells) 3 and 12 months after start of first treatment course (as compared to baseline), and 12 months after start of second treatment course (as compared to baseline), analyzed by flow cytometry.
    • Changes in the immune cell activation status, in markers of cell death and immune senescence 3 and 12 months after start of first treatment course (as compared to baseline), and 12 months after start of second treatment course (as compared to baseline), analyzed by flow cytometry.
    • Changes in the mitochondrial energy metabolism (i.e. oxidative phosphorylation) of CD4 and CD8 T cells, 3 and 12 months after start of first treatment course (as compared to baseline), and 12 months after start of second treatment course (as compared to baseline), assessed by maximal respiratory capacity using seahorse agilent technology (oxygen consumption rate in pmol/min).
    E.5.2.1Timepoint(s) of evaluation of this end point
    see above
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    Due to the time-consuming laboratory examinations the study will end at data base lock, presumably 6 months after the last visit of the last patient.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state30
    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)
    As agreed upon with the patient further medical care after individual study termination is provided by the study site or by the primary care physician. Particular attention should be paid to the lasting side effects of cladribine therapy, e.g. low lymphocyte counts, immunosuppression with resulting susceptibility to infections.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-29
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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