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    Summary
    EudraCT Number:2016-000401-36
    Sponsor's Protocol Code Number:DSC/14/2357/48
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-02-08
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-000401-36
    A.3Full title of the trial
    Randomised, double blind, placebo controlled, multicentre study to evaluate the efficacy and safety of givinostat in ambulant patients with Duchenne Muscular Dystrophy.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate the efficacy and safety of givinostat in ambulant patients with Duchenne Muscular Dystrophy.
    A.4.1Sponsor's protocol code numberDSC/14/2357/48
    A.5.4Other Identifiers
    Name:INDNumber:126598
    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 SponsorITALFARMACO S.p.A.
    B.1.3.4CountryItaly
    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 supportITALFARMACO S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationITALFARMACO S.p.A.
    B.5.2Functional name of contact pointClinical Research and Development
    B.5.3 Address:
    B.5.3.1Street AddressVia dei Lavoratori, 54
    B.5.3.2Town/ cityCinisello Balsamo (MI)
    B.5.3.3Post code20092
    B.5.3.4CountryItaly
    B.5.4Telephone number+390264431
    B.5.5Fax number+390264433554
    B.5.6E-mailp.bettica@italfarmaco.com
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/12/1009
    D.3 Description of the IMP
    D.3.1Product nameGivinostat (hydrochloride monohydrate)
    D.3.2Product code ITF2357
    D.3.4Pharmaceutical form Oral suspension
    D.3.4.1Specific paediatric formulation Yes
    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 INNGivinostat (hydrochloride monohydrate)
    D.3.9.1CAS number 732302-99-7
    D.3.9.2Current sponsor codeITF2357
    D.3.9.3Other descriptive nameGIVINOSTAT
    D.3.9.4EV Substance CodeSUB30834
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 placeboOral suspension
    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
    Duchenne Muscular Dystrophy (DMD)
    E.1.1.1Medical condition in easily understood language
    A neuromuscular disease characterized by rapidly progressive muscle weakness and wasting
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level PT
    E.1.2Classification code 10013801
    E.1.2Term Duchenne muscular dystrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To establish the effects of givinostat versus placebo administered chronically over 18 months to slow disease progression in ambulant DMD subjects
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of givinostat versus placebo administered chronically in DMD subjects.
    To evaluate the pharmacokinetic (PK) profile of givinostat administered chronically in the target population.
    To evaluate the impact on quality of life and activities of daily living of givinostat versus placebo administered chronically.

    Exploratory objectives:
    To evaluate the correlation between PK profile of givinostat and pharmacodynamics (PD) data.
    To explore whether the effects of givinostat versus placebo administered chronically may be related to the type of DMD mutation or to the biomarkers.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Are ambulant males aged ≥6 years at randomisation with DMD characteristic clinical symptoms or signs (e.g., proximal muscle weakness, Gowers’ maneuver, elevated serum creatinine kinase level) already present at screening;
    2. Have DMD diagnosis confirmed by genetic testing;
    3. Are able to give informed assent and/or consent in writing signed by the subject and/or parent/legal guardian (according to local regulations);
    4. Are able to complete 2 Four Stairs Climb test (4SC) screening assessments; the results of these tests must be within ±1 second of each other;
    5. Have the mean of 2 screening 4SC assessments ≤8 seconds;
    6. Have time to rise from floor of <10 seconds at screening;
    7. Have manual muscle testing (MMT) of quadriceps at screening ≥ Grade 3;
    8. Are eligible according to the protocol-specified functional algorithm predictive of vastus lateralis muscle fat fraction (VL MFF) that should be in the range >10% but <30%;
    9. Have used systemic corticosteroids for a minimum of 6 months immediately prior to the start of study treatment, with no significant change in dosage or dosing regimen (excluding changes related to body weight change) for a minimum of 6 months immediately prior to start of study treatment and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study.
    10. Subjects must be willing to use adequate contraception.
    Contraceptive methods must be used from Randomization Visit 3 through 3 months after the last dose of study drug, and include the following:
    • True abstinence (absence of any sexual intercourse), when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
    • Condom with spermicide and the female partner must use an acceptable method of contraception, such as an oral, transdermal, injectable or implanted steroid-based contraceptive, or a diaphragm or a barrier method of contraception in conjunction with spermicidal jelly such as for example cervical cap with spermicide jelly.
    E.4Principal exclusion criteria
    1. Have exposure to another investigational drug within 3 months prior to the start of study treatment;
    2. Have exposure to idebenone within 3 months prior to the start of study treatment;
    3. Have exposure to any dystrophin restoration product (e.g., Ataluren, Exon-skipping) within 6 months prior to the start of study treatment;
    4. Use of any pharmacologic treatment, other than corticosteroids, that might have had an effect on muscle strength or function within 3 months prior to the start of study treatment (e.g., growth hormone); Vitamin D, calcium, and any other supplements will be allowed;
    5. Have surgery that might have an effect on muscle strength or function within 3 months before study entry or planned surgery at any time during the study;
    6. Ankle joint contractures due to a fixed loss of ≥10 degrees of dorsiflexion from plantagrade assuming a normal range of dorsiflexion of 20 degree;
    7. Change in contracture treatment such as serial casting, contracture control devices, night splints, stretching exercises (passive, active, self) within 3 months prior to enrollment, or expected need for such intervention during the study;
    8. Have presence of other clinically significant disease, which, in the Investigator’s opinion, could adversely affect the safetyof the subject, making it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results;
    9. Have a diagnosis of other neurological diseases or presence of relevant somatic disorders that are not related to DMD;
    10. Have platelets count, White Blood Cell and Hemoglobin at screening <Lower Limit of Normal (LLN) (for abnormal screening laboratory test results (<LLN), the platelets count, White Blood Cell and Hemoglobin will be repeated once; if the repeat test result is still <LLN, then exclusionary);
    11. Have symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction <50% at screening;
    12. Have a current or history of liver disease or impairment; including but not limited to an elevated total bilirubin (i.e. > 1.5 x ULN), unless secondary to Gilbert disease or pattern consistent with Gilbert's;
    13. Have inadequate renal function, as defined by serum Cystatin C >2 x the upper limit of normal (ULN). If the value is >2 x ULN, the serum Cystatin C will be repeated once; if the repeated test result is still >2 x ULN, the subject should be excluded);
    14. Have a positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening;
    15. Have a baseline corrected QT interval, Fridericia’s correction (QTcF) >450 msec, (as the mean of 3 consecutive readings 5 minutes apart) or history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, or family history of long QT syndrome);
    16. Have a psychiatric illness/social situations rendering the potential subject unable to understand and comply with the muscle function tests and/or with the study protocol procedures;
    17. Have any hypersensitivity to the components of study medication;
    18. Have a sorbitol intolerance or sorbitol malabsorption, or have the hereditary form of fructose intolerance.

    For the subgroup of subjects who will perform the magnetic resonance imaging (MRI) and spetroscopy (MRS) (i.e., MR Cohort):
    19.Have contraindications to MRI or MRS (e.g., claustrophobia,
    metal implants, or seizure disorder).
    E.5 End points
    E.5.1Primary end point(s)
    Mean change in 4SC before and after 18 months of treatment of givinostat versus placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    18 months
    E.5.2Secondary end point(s)
    Key endpoints (all subjects):
    Mean change in time to rise from floor before and after 18 months of treatment of givinostat versus placebo;
    Mean change in 6MWT before and after 18 months of treatment of givinostat versus placebo;
    Mean change in muscle strength evaluated by knee extension, elbow flexion as measured by HHM, before and after 18 months of treatment of givinostat versus placebo.

    Key endpoints (MR cohort):
    • Mean change in fat fraction of vastus lateralis muscles comparing the MRS before and after 12 months of treatment of givinostat versus placebo;
    • Mean change in 4SC before and after 12 months of treatment of givinostat versus placebo;
    • Mean change in time to rise from floor before and after 12 months of treatment of givinostat versus placebo;
    • Mean change in 6MWT before and after 12 months of treatment of givinostat versus placebo;
    • Mean change in muscle strength evaluated by knee extension before and after 12 months of treatment of givinostat versus placebo;
    • Mean change in fat fraction of vastus lateralis muscles comparing the MRS before and after 18 months of treatment of givinostat versus placebo

    Safety endpoints:
    - Number of subjects experiencing treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) (Baseline through end of study [EOS]);
    - Type, incidence, and severity of TEAEs and SAEs (Baseline through EOS);
    - Changes from baseline to end of study of:
    o Vital signs and clinical laboratory tests (blood chemistry and hematology);
    o Respiratory function evaluated by forced vital capacity (FVC), forced expiratory volume at 1 second (FEV1), FVC/FEV1, Peak Expiratory Flow (PEF);
    o Cardiac function evaluated by ECG and ECHO;
    o Cognitive function evaluated by the Raven progressive matrices;
    o Weight, height, and body mass index (BMI).
    o Evaluation of acceptability/palatability of the oral suspension.

    Pharmacokinetic Endpoints:
    - Description of the PK of givinostat and its major metabolites:
    ITF2374 and ITF2375 in the subject population;
    - Identification of the relevant demographic and pathophysiological covariates influencing the PK of givinostat.

    Exploratory endpoints:
    • Mean changes before and after 12 months of treatment of givinostat versus placebo of:
    o time to 4SC;
    o time to rise from floor;
    o 6MWT;
    o muscle strength.
    • Mean changes before and after 12 and 18 months of treatment of givinostat as compared to placebo of:
    o time to walk/run 10 meters;
    o physical function as measured by NSAA;
    o PODCI scores.
    • Mean changes before and after 18 months of treatment of givinostat as compared to placebo of:
    o %-predicted 6MWT;
    o Only in the MR cohort: MRI parameters (e.g., fat fraction of thigh muscles, CSA of vastus lateralis and other thigh muscles).
    • Time to 10% persistent worsening in 6MWT (Baseline through end of study);
    • Proportion of subjects with ≥10% worsening in 6MWT at end of study;
    • Time to loss of standing (Baseline through end of study);
    • Proportion of subjects who loose ambulation during the study;
    • PK-PD analyses: relationships between metrics of exposure and efficacy/safety endpoints of givinostat.
    E.5.2.1Timepoint(s) of evaluation of this end point
    timepoint given in endpoint
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Quality of life and daily activities
    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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Belgium
    Canada
    France
    Germany
    Israel
    Italy
    United Kingdom
    United States
    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
    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
    E.8.9.2In all countries concerned by the trial years4
    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 Yes
    F.1.1Number of subjects for this age range: 192
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 150
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 42
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female No
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    male paediatric subjects aged ≥6 years
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 192
    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)
    A follow up visit will be performed 4 weeks after the last dose is administered (± 7 days) and only in cases where the subject or parent/legal guardian do not provide assent/consent to participate in long-term study.
    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 Decision2016-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-24
    P. End of Trial
    P.End of Trial StatusCompleted
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