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    Summary
    EudraCT Number:2020-005762-34
    Sponsor's Protocol Code Number:MGCDB001
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-03-04
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2020-005762-34
    A.3Full title of the trial
    A phase 2 clinical trial assessing the efficacy and safety of adding cladribine for treatment modifying course of seropositive myasthenia gravis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Cladribine therapy in Myasthenia
    A.4.1Sponsor's protocol code numberMGCDB001
    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 SponsorMedical University of Lublin
    B.1.3.4CountryPoland
    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 supportMedical University of Lublin
    B.4.2CountryPoland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedical University of Lublin,Konrad Rejdak
    B.5.2Functional name of contact pointCountry Clinical Trial Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressJaczewskiego 8
    B.5.3.2Town/ cityLublin
    B.5.3.3Post code20-059
    B.5.3.4CountryPoland
    B.5.4Telephone number+48817244720
    B.5.5Fax number+48817447540
    B.5.6E-mailkonradrejdak@umlub.pl
    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.2.5The 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 name Cladrybine
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous 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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Myasthenia gravis
    E.1.1.1Medical condition in easily understood language
    Myasthenia gravis is an autoimmune disease manifesting itself in
    increasing post-stress weakness of the muscles of the eyes, mouth,
    throat and limbs, with periods of life-threatening exacerbations
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10028417
    E.1.2Term Myasthenia gravis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of the trial is to evaluate the efficacy and safety of cladribine
    added to the treatment modifying the course of seropositive
    pseudoparalytic myasthenia gravis.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The clinical trial consists of three parts:
    - The first part conducted in the primary cohort over the basic trial period - a double-blind placebo-controlled trial involving the group of patients treated immunoactively with oral steroids, 48 weeks (the basic duration of the trial for an individual participant);
    - The second part conducted in the complementary cohort over the basic trial period - a double-blind placebo-controlled trial in the group of patients with newly-diagnosed myasthenia / previously untreated immunoactively; 48 weeks (the basic duration of the trial for an individual participant);
    - The third part conducted over the additional time – the open-arm (only the active group – the study drug) This part will be a continuation of the trial conducted over the basic time, an additional 48 weeks for an individual participant.
    In the blinded phase of the trial, the following will be assessed:
    -the clinical effect of cladribine in patients treated immunoactively with oral steroids (the primary cohort),
    - the clinical effect of cladribine in patients with newly-diagnosed myasthenia / previously untreated immunoactively (the complementary cohort).

    In the open phase, the clinical effect of cladribine is assessed in patients treated immunoactively with oral steroids who received placebo (the primary cohort) during the blinded phase.
    E.3Principal inclusion criteria
    GENERAL CRITERIA:
    1. Age > 18 years (no border).
    2. Obtaining informed consent for the patient's participation in the entry.
    3. The characteristic clinical picture of myasthenia gravis with non-painful movement of typical striated muscle groups with the intensity of professional development changing throughout the day.
    4. Increased cut-off titer of anti-acetylcholine receptor (anti-AchR-ab) or muscle tyrosine kinase (anti-MUSK-ab) involved in the pathogenesis of myasthenia gravis (historical result: untimed).
    5. The known status of thymus pathology based on the chest radiological examination (CT) (historical up to 5 years prior to qualifying visit or performed at qualifying visit) and / or the hist-path results of the removed thymus if the patient underwent a thymectomy.
    6. Corticosteroid dose stabilised ≥ 4 weeks prior to randomisation and a minimum 4-week withdrawal period from other immunosuppressive agents (cytostatic or biological) in the absence of lymphopenia and drug-induced parenchymal organ damage (liver, kidney).
    7.AChEI dose stabilised ≥ 4 weeks prior to randomisation (W1D1).
    8. Electrophysiological test result of the myasthenia test (historical up to 5 years before the qualifying visit)or the test can be performed at the qualifying visit (W0).
    9. MRI result of head with contrast (archived up to 5 years prior to qualifying visit or performed at qualifying visit).

    DETAILED CRITERIA:
    - the main cohort: validity of second-line immunoactive treatment indicated by failure to achieve pharmacological remission according to MGFA post-interventional status despite symptomatic acetylcholinesterase inhibitor treatment at optimal doses combined with chronic oral steroid therapy with achievement of stable 4 weeks prior to the randomisation visit (W1D1) prednisone equivalent dose.
    - complementary cohort: no immunoactive treatment (acceptable symptomatic treatment with acetylcholinesterase inhibitors) and non-acceptance of the patient's side for the sick steroid therapy dictated by the disease before side effects.
    E.4Principal exclusion criteria
    1. Unusual distribution of muscle weakness or lack of apocamnosis effect with other diagnosis (such as LEMS, OPMD).
    2. Negative results (below the cut-off threshold) of determinations of acetylcholine receptor auto-aggressive antibodies (anti-AChR-ab) or muscle tyrosine kinase (anti-MUSK-ab).
    3. Electrophysiological exponents of presynaptic disorders of neuromuscular conduction (facilitation phenomenon in electromyographic myasthenia gravis test).
    4. Coexistence of diseases that make it impossible to assess the disease state in the context of the severity of myasthenia gravis (e.g. cardiovascular or respiratory diseases clinically manifested by fatigue).
    5. Coexistence of diseases that reduce resistance to opportunistic infection, which may be the cause of complications of immunoactive treatment of myasthenia gravis (e.g. HIV, hepatitis B or C, tuberculosis) or recurrent herpes zoster in treatment.
    6. Tumour disease active at the time of the qualifying visit (W0) for the study, or completed non-deferred temporal
    (< 6 months) oncological treatment.
    7. Significant deviation in basic research:
    - peripheral blood count: leukopenia < 1.5 x 109/l;
    - neck functions: creatinine > 1.4 mg/dl in women and > 1.5 mg/dl in men;
    - liver function: AST or ALT > 3x ggn;
    - anti-IgA infection in people with IgA deficiency (in case emergency treatment is needed due to intravenous administration of human immunoglobulins *IVIG).
    If there is improvement in follow-up, deviations from the above criteria are acceptable based on the patient's clinical presentation ( to be at the decision of the Investigator).
    8. Hypersensitivity to cladribine or to any of them has been helpful:
    - mechanical obstruction of the urinary tract (with attention to AChEI);
    - pregnancy (patients of childbearing age will be required to declare use of an effective method of contraception [Pearl index ≤2 ] from the qualifying visit (W0) during the trial and 6 months after its completion);
    - breastfeeding.
    9. No use of an effective method of contraception [Pearl index ≤ 2] by patients of childbearing age at the time of eligibility (visit W0) for the study until 6 months after the last dose of study medicinal product.
    10. No use of barrier contraception by patients at the time of study eligibility (W0 visit) until 6 months after the last dose of study medicinal product.
    11. Other contraindications which, in the opinion of the Investigator, exclude the patient from participating in the study.
    E.5 End points
    E.5.1Primary end point(s)
    Changes in the evaluation of the effects of intensified myasthenia symptoms on the daily living activities according to the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale. SIMPLIFIED TRIAL DESIGN (compatible with text documents without graphics) BLINDED PHASE (BASIC TRIAL PERIOD):
    In the blinded phase, the following will be assessed:
    1. the clinical effect of cladribine in patients treated immunoactively
    with oral steroids (the primary cohort),
    2. the clinical effect of cladribine in patients with newly diagnosed
    myasthenia / previously untreated immunoactively (the complementary
    cohort of the clinical trial).
    W0 (week 0) – preliminary evaluation
    The duration of immunoactive therapy with the use of the therapeutic
    product studied
    W1 (week 4) – administration of the therapeutic product in question
    W2 (week 6) – search for the symptoms of early adverse side effects
    W3 (week 16) –administration of the therapeutic product studied
    W4 (week 18), W5 (week 28), W6 (week 34), W7 (week 40), W8 (week
    48) – neurological exams with the evaluation of increased symptoms of
    myasthenia, revision of steroid demands with the dose correction in the
    primary cohort/ emergency therapy, if required.
    OPEN PHASE (additional trial time):
    Patients who completed the blinded phase of the study as scheduled
    or as a result of a significant intensification of the symptoms of myasthenia gravis defined in 2 points exclusion criteria after the use of IVIG salvage therapy and a 4-week grace period eliminating the impact of IVIG on the assessment of the effects of cladribine
    they can begin the open-label phase with cladribine (visits W9 and W11 / weeks 54 and 66, respectively) and follow-up with a simplified follow-up (visits W10 and W12 - W15 / weeks 56 and 68 - 96).
    The visits will be carried out in the same way as in the double-blind phase, according to the schedule.

    The duration of immunoacive therapy with the use of the therapeutic
    product studied
    W9 (week 54) – administration of the therapeutic product studied,
    W10 (week 56) – search for the symptoms of early adverse side effects,
    W11 (week 66) – administration of the therapeutic product studied.
    W12 (week 68), W13 (week 78), W14 (week 84), W15 (week 96) –
    neurological exams with the evaluation of increased symptoms of myasthenia, emergency therapy, if required.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Assessment of plasma cladribine pharmacokinetics at visits W1 and W2 according to the procedure schedule.
    During visits evaluating the efficacy of treatment:
    -W2 – W8 during the basic trial period and
    -W10 – W15 during the additional trial period in relations to the baseline result (W1 during the basic period and W9 during the additional period of the trial).
    E.5.2Secondary end point(s)
    Reduction in the requirement for simultaneous oral corticosteroids used in immunotherapy (steroid-sparing effect). Stabilized ≥ 4 weeks prior to study entry, systematically revised and adjusted to the need at follow-up visits. The endpoint will only be assessed in the core cohort. Evaluation of W4-W8 during the primary study duration and W12-W15 during the additional study duration.
    Frequency of occurrence of the need for salvage therapy due to
    An exacerbation of myasthenia gravis with respiratory failure at any
    time
    observation time during the study, separately in the primary and
    secondary duration
    research.
    Changed antibodies to acetylcholine receptors (anti-AChR-ab) and specific muscle tyrosine kinase (anti-MUSK-ab) in serum baseline result (on W1 at baseline and
    18
    on W9 during the additional study duration). Grade for W3 and W6 in
    basic
    study duration, and W11 and W15 in the additional study duration.
    Change in the concentration of complement components (C3, C4)
    relative to the result
    baseline time (on W1 at the base time of the study and on W9 at the
    additional time
    the duration of the study). Assessment of W3 and W6 in the basic
    duration of the study and W11 i
    W15 during the additional study duration.
    Change in cytokine concentrations from baseline (to W1 at baseline time
    study and on W9 in an additional study duration). Grade on W3 and W6
    in
    baseline study duration and W11 and W15 in additional study duration
    research.
    Change in the percentage of individual lymphocyte populations in
    immunophenotyping
    lymphocytes from baseline (on W1 at baseline and on
    W9 during the additional study duration). Assessment for W3 and W6 at
    the basic time
    the duration of the study and W11 and W15 in the additional study
    duration.
    Regarding treatment safety:
    The frequency of adverse events.
    Change in safety parameters (complete blood count, creatinine, urea,
    bilirubin,
    alanine aminotransferase (ALT), aspartate aminotransferase (AST),
    gammaglutamyltranspeptidase (GGTP), C-reactive protein (CRP), PCT
    procalcitonin, urinalysis) relative to baseline (W1 at baseline
    study and on W9 in an additional study duration). Grade on W3-W8
    during the primary study duration and W11-W15 during the additional
    study duration
    research.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Effectiveness of treatment:
    Change in the demand for oral glucocorticosteroids: Evaluation of W4-
    W8 plus W12-W15. Relevant to baseline (W1 or W9 respectively).
    The need for rescue therapy for exacerbations of myasthenia gravis: The
    endpoint will be assessed at any time during the study.
    Change in the titre of antibodies to acetylcholine receptors; Change in
    the concentration of complement components (C3, C4); Change in
    cytokine concentrations; Change in the percentage of specific
    lymphocyte populations: The endpoint will be assessed as W3 and W6
    plus W11 and W15. Relevant to baseline (W1 or W9 respectively).
    Incidence of adverse events: The endpoint will be assessed at any time
    during the study.
    Change in safety parameters: The endpoint will be assessed at W3-W8
    plus W11-W15.
    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 Yes
    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 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) Yes
    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 concerned6
    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 Yes
    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 (Last Visit Last Subject)
    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 months0
    E.8.9.1In the Member State concerned 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.1.2.1Number of subjects for this age range: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Written consent may be given by the patient's legal representative, in accordance with the guidelines of the site,however the patient must be able to understand and comply with the protocol requirements and willingness to participate in the study.
    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.4.2.2In 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)
    None
    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 Decision2021-07-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-01-28
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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