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    Summary
    EudraCT Number:2007-000381-20
    Sponsor's Protocol Code Number:27820
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-01-15
    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 ConcernedPortugal - INFARMED
    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.4.1Sponsor's protocol code number27820
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Information not present in EudraCT
    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.3.9.3Other 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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 9.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    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)
    • Determine the effect of oral cladribine on QTc interval.
    E.2.2Secondary objectives of the trial
    • Explore the long-term benefit (rate of disease progression as reflected by rate of change in Expanded Disability Status Score [EDSS] score) 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
    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 DMD, and who completed scheduled clinic visits for the full 96 weeks (a)(b); or
    - Did not complete the randomised treatment course in Trial 25643, declined rescue with Rebif or another DMD, and still completed scheduled clinic visits for the full 96 weeks (a)(b); 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 (a)(b).

    ° 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 90 days following completion of the last dose of study medication or following early termination or early withdrawal. 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. [Note: for Danish sites only, subjects should use a hormonal contraceptive or intrauterine device for the duration of the trial]

    ° 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.

    ° Subject must be willing and able to participate in the trial and have provided written, informed consent

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

    Females of childbearing potential, who are either subjects in the trial or who are partners to male subjects in the trial, must use one of the above means of contraception for the entire trial period and for at least 12 weeks after the last dose of trial medication. For the purposes of this trial, women of childbearing potential is defined as: “All female subjects after puberty unless they are postmenopausal for at least two years, are surgically sterile or are sexually inactive.”

    (a) - For subjects who had to delay entry into the CLARITY Extension study 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.
    (b) - For subjects who had to delay entry into the CLARITY Extension study, whereby there was a gap interval of varying duration, who subsequently during the gap interval were treated with a prohibited medication (See exclusion criteria) are not able to be re-randomized to receive study medication in the CLARITY Extension study. These subjects are encouraged to enter the study, but will be followed for safety only.
    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);

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

    ° Have a positive stool heme-occult test at Pre-Study Evaluation (PSE);
    NOTE: For subjects with positive heme-occult test, please refer to section 6.2.1 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.

    ° 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 DMD 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 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, 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.) are not able to be re-randomized to receive study medication in the CLARITY Extension study. These subjects are encouraged to enter the study, 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)
    Note that the safety endpoints and some other endpoints of this trial will utilise observations from the antecedent Trial 25643 and this extension Trial 27820 (if data are available). The specific time points or the following endpoints will be detailed in the statistical analysis section.

    ° 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 time to recovery from hemtological and liver toxicity

    ° Median time to nadir of absolute lymphocyte count and mean time to recovery to normal values

    ° Mean change in QTc interval from baseline
    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.8.3 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 Yes
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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.1.3Elderly (>=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 state3
    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)
    Prior to the end of the trial, the Sponsor will determine if there will be any further extensions to the trial. Should there be any extensions to the protocol, the Sponsor will notify the trial sites as to the implementation and timing of such an extension. Any extension to the protocol will need to be submitted as a protocol amendment or separate protocol to Ethics Committees and Regulatory Authorities.
    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 Decision2008-04-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-04-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-02-16
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