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    Summary
    EudraCT Number:2007-000381-20
    Sponsor's Protocol Code Number:27820
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-02-28
    Trial results View 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 number2007-000381-20
    A.3Full title of the trial
    A Phase IIIb, Double-Blind, Placebo-Controlled, Multicenter, Parallel Group, Extension Trial to Evaluate the Safety and Tolerability of Oral Cladribine in Subjects with Relapsing-Remitting Multiple Sclerosis Who Have Completed Trial 25643 (CLARITY).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    CLARITY Extension Study
    A.3.2Name or abbreviated title of the trial where available
    CLARITY EXTENSION
    A.4.1Sponsor's protocol code number27820
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00641537
    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 SponsorMerck Serono S.A. - Geneva
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Serono S.A. - Geneva
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication Center Merck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+ 49 5151 72 5200
    B.5.5Fax number+ 49 5151 72 2000
    B.5.6E-mailservice@merck.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 No
    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 namecladribine
    D.3.2Product code Not Applicable
    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 4291638
    D.3.9.2Current sponsor codeEMD280922
    D.3.9.3Other descriptive name2-chloro-2’-deoxyadenosine (2-CdA)
    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
    Relapsing Remitting Multiple Sclerosis (RRMS)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 13.1
    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
    Safety Objectives:
    • Evaluate the safety of extended treatment with oral cladribine when administered according to a fixed annual dosing schedule to subjects who completed Trial 25643 (CLARITY)
    • To assess the safety of cladribine with an emphasis on cardiac repolarization as measured by changes in QT interval (in a subset of patients also partipating in the PK sampling and analysis).
    E.2.2Secondary objectives of the trial
    • Explore the long-term benefit of treatment with oral cladribine vs. placebo
    • Explore the relationship between oral cladribine treatments and various immunologic parameters, MRI measures of disease activity, clinical relapses and disease progression in subjects previously randomised in Trial 25643
    • Determine the benefit of continued oral cladribine treatment on health-related quality of life and economic outcome measures
    • Explore the association between genetic variants, clinical efficacy, MRI endpoints and groups of subject with adverse events (grade 3 and 4 toxicity)
    • Explore the effect of oral cladribine on gene expression profiles
    • Assess population pharmacokinetics
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ° Were randomised in Trial 25643 and satisfy one of the following:
    - Completed their randomised treatment course and scheduled visits for the full 96 weeks (a)(b); or
    - Did not complete the randomized treatment course in Trial 25643, but who elected to receive rescue treatment with Rebif or another beta-interferon or glatiramer acetate, and who completed scheduled clinic visits for the full 96 weeks; or
    - Did not complete the randomised treatment course in Trial 25643, declined rescue with Rebif or another beta-interferon or glatiramer acetate, and still completed scheduled clinic visits for the full 96 weeks; or
    - Did not complete the randomised treatment course in Trial 25643, were not eligible for rescue option with Rebif, and still completed scheduled clinic visits for the full 96 weeks.

    ° Be male or female and between 18 and 65 years of age (inclusive, at time of informed consent prior to entry into Trial 25643)

    ° Have no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test or chest X-ray;
    NOTE: For subjects with medical history or LTBI ot TB, please refer to Appendices L, M, N. Subjects who should be excluded from blinded medication could be proposed to be followed for safety according to the same scheduled visits

    ° All of the following laboratory hematologic parameters must be normal (as defined below, inclusively) within 28 days of first dosing of blinded study medication at SD1:
    - Hemoglobin = 11.6 – 16.2 G/DL
    - Leukocyctes (total white blood cells [WBC]) = 4.1 – 12.3 x 10E3/UL
    - Absolute lymphocytes = 1.02 – 3.36 x 10E3/UL
    - Absolute neutrophil count (ANC) = 2.03 – 8.36 x10E3/UL
    - Platelet count = 140-450 x 10E3/UL
    NOTE: For subjects with abnormal laboratory hematological parameters, please refer to section 6.2.1 for retesting guidelines. Subjects who should be excluded from blinded medication during the current yearly dosing could be proposed to be followed for safety according to the same scheduled visits.

    ° Female subjects must be neither pregnant nor breast-feeding and must lack child-bearing potential, as defined by either:
    - Be post-menopausal or surgically sterilized; or
    - Using a highly effective method of contraception throughout the entire duration of the study and for 6 months (6 menstrual cycles) following completion of the last dose of study medication. A highly effective method of contraception is defined as those which result in a low failure rate (i.e. less that 1% per year) when used consistently and correctly such as implants, injectables, comined with oral contraceptives, IUSs, sexual abstinence or vasectomised partner.
    - Treatment of pregnant and nursing women with cladribine is prohibited.

    ° If male, he must be willing to use contraception to avoid pregnancies throughout the entire duration of the study and for 90 days following the last dose of study medication or following early termination or early withdrawal.

    ° Voluntarily provide written informed consent, and for USA sites only, a subject authorization under Health Insurance Portability and Accountability Act (HIPAA)

    ° Absence of history or available abnormal laboratory results indicative of any significant or unstable cardiac, endocrinologic, hematologic (other than abnormal laboratory results consistent with prior exposure to oral cladribine), hepatic, immunologic (other than MS), metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric (including major depression), and/or other major disease,
    that would preclude the administration of oral cladribine over a 24-month course of treatment
    ° Absence of moderate to severe renal impairment
    E.4Principal exclusion criteria
    ° Have prior or current malignancy other than medically documented complete excision of basal cell skin cancer no less than 5 years prior to Screening;

    ° Have a history of chronic or clinically significant hematological abnormalities;

    ° Has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase > 2.5 times the upper limit of the normal values;

    ° Suffers from major medical illness such as cardiac, endocrinologic, hepatic, immunologic (other than MS), metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine.

    ° Suffers from major psychiatric illness (including history of, or current, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol;

    ° History of active or chronic infectious disease or any disease which compromises immune function (e.g. HIV+, HTLV-1, Lyme disease);

    ° Have an allergy or hypersensitivity to gadolinium, to cladribine or any of its excipients, or IFN-b or any of its excipient(s);

    ° Subject has any renal condition that would preclude to the administration of gadolinium (e.g.acute or chronic severe renal insufficiency (GFR <30 mL/min/1.73 m2)

    ° Have a positive stool heme-occult test at Pre-Study Evaluation (PSE);
    NOTE: For subjects with positive heme-occult test, please refer to section 6.4.6 for retesting guidelines. Subjects who should be excluded from blinded medication during the current yearly dosing could be proposed to be followed for safety according to the same scheduled visits.

    ° Subject has a history of seizures not adequately controlled by treatment.

    ° Concurrent enrolment in any other investigational drug trial with the exception of any Sponsor sub-trial of this protocol that is approved by the Medical Director

    ° Any other reason(s) that, in the opinion of the Investigator and/or the Sponsor, would indicate that the subject is unsuitable for inclusion in this extension trial

    ° Treatment with a beta-interferon or glatiramer acetate less than 3 months prior to Study Day 1 during any gap between completion of CLARITY Trial 25643 and CLARITY Extension Trial 27820

    ° Use of mitoxantrone, total lymphoid irradiation, myelosuppressive therapy, campath-1h, cyclophosphamide, azathioprine, methotrexate or natalizumab at anytime during and since Study 25643

    NOTE: For subjects who had to delay entry into the CLARITY Extension study or the 24-Week Supplemental Follow-up portion whereby there was a gap interval of varying duration, who subsequently, during the gap interval were treated with a DMD or Rebif should discontinue the DMD or Rebif for a period of at least 3 months prior to Study Day 1. For those subjects who are unable or are unwilling to discontinue their DMD, they may not be re- randomized to receive study medication. These subjects are encouraged to enter the study but will be followed for safety only.

    NOTE: For subjects who had to delay entry into the CLARITY Extension study or the 24-Week Supplemental Follow-up portion, whereby there was a gap interval of varying duration, who subsequently during the gap interval were treated with a prohibited medication (See exclusion criteria section 5.2.2.) will not be eligible for the enrollment in the future open-label study. These subjects are encouraged to enter the 24-Week Supplemental Follow-up, but will be followed for safety only.

    ° Use of cytokine or anti-cytokine therapy, intravenous immunoglobulin (IVIG) or plasmapheresis since their completion of Trial 25643

    ° Treatment with oral or systemic corticosteroids or adrenocorticotropic hormone within 28 days before Study Day 1
    E.5 End points
    E.5.1Primary end point(s)
    Safety endpoints:
    ° Proportion of subjects with at least one grade 4 CTCAE toxicity on the following parameters of hematologic and hepatic function: absolute lymphocyte count (ALC),
    hemoglobin level, white blood cell (WBC) count, absolute neutrophil count (ANC), platelets, alanine transaminase (ALT), aspartate transaminase (AST) and bilirubin
    ° Proportion of subjects with grades 3 or 4 adverse events (AEs) for hematologic and hepatic indices
    ° Mean change in absolute lymphocyte count, hemoglobin level, WBC, ANC, platelets, ALT, AST, and bilirubin
    ° Incidence of all treatment emergent AEs and SAEs
    ° Proportion of subjects developing infections, infection-related AEs and malignancies
    ° Time to first grade 3 and 4 hematological toxicity or liver toxicity
    ° Median and mean time to recovery from hemtological and liver toxicity
    ° Median and mean time to nadir of absolute lymphocyte count and mean time to recovery to normal values
    ° Mean change in QTc interval from baseline

    Clinical Efficacy Endpoints:
    ° Proportion of subjects relapse free (qualifying and/or non-qualifying)
    ° Disability progression. The following three progression endpoints will be used:
    o Time to confirmed EDSS progression, confirmed after 3 months
    o Time to confirmed EDSS progression, confirmed after 6 months
    o Confirmed progressions (sustained over a period of at least 3 months) assessed at annual intervals
    ° Time to treatment start with rescue medication
    ° Annualized relapse rate (qualifying and/or non-qualifying)
    ° Time to first relapse (qualifying and/or non-qulaifying)
    ° Time to second relapse (qualifying and/or non-qualifying)

    MRI endpoints:
    ° Number of new T1 gadolinium-enhanced lesions
    ° Number of active T2 lesions
    ° Number of combined unique (CU) lesions defined as 1) new T1 gadoliniumenhancing, or 2) new T2 non-enhancing or enlarging lesions, or 3) both, without double-counting
    ° Total T2 lesion volume (the proton density/T2-weighted (T2) burden of disease (BOD))
    ° Proportion of T1 gadolinium-enhanced lesions assessed at Baseline of Trial 25643
    transformed in T1 hypointense lesions (black holes)
    ° Percent brain volume changes
    ° Proportion of subjects with no new T1 gadolinium-enhanced lesions
    ° Proportion of subjects with no active T2 lesions
    ° Proportion of subjects with no combined unique lesions
    ° Number of new T1 hypointense lesions
    ° Mean change in volume of T1 hypointense lesions
    E.5.1.1Timepoint(s) of evaluation of this end point
    96 weeks and 120 weeks
    E.5.2Secondary end point(s)
    Not Applicable
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) Yes
    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 Yes
    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 Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Brazil
    Bulgaria
    Canada
    Croatia
    Czech Republic
    Denmark
    Estonia
    Finland
    France
    Germany
    Greece
    Italy
    Latvia
    Lebanon
    Lithuania
    Morocco
    Netherlands
    Poland
    Portugal
    Russian Federation
    Saudi Arabia
    Serbia
    Switzerland
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 700
    F.4.2.2In the whole clinical trial 1100
    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)
    Following completion of the study, the treating physician should discuss available treatment options
    with the subject. Given cladribine’s mechanism of action (lymphocytotoxicity), caution must be
    exercised regarding choice of post-study treatment. Any treatment that has a different mechanism
    of action from that of cladribine but which is myelosuppressive must be used with caution in order
    to minimize potential toxicity.
    Please refer to the protocol section 6.2.6 for more information.
    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 Decision2008-02-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-03-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-02-16
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