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    Summary
    EudraCT Number:2012-004473-25
    Sponsor's Protocol Code Number:242-12-232
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-09-14
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2012-004473-25
    A.3Full title of the trial
    Phase 1, Open-label, Multiple-dose, and Age De-escalation Trial to
    Assess the Pharmacokinetics, Safety, and Tolerability of Delamanid (OPC 67683) in
    Pediatric Multidrug-resistant Tuberculosis Patients on Therapy With an Optimized
    Background Regimen of Antituberculosis Drugs
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 1, Open-label, Multiple-dose, and Age De-escalation Trial to Assess the how the drug is processed by the body to determine safety, and Tolerability of Delamanid (OPC 67683) in Pediatric patients with Multidrug-resistant Tuberculosis on Therapy With a Background
    Regimen of Antituberculosis Drugs
    A.4.1Sponsor's protocol code number242-12-232
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/281/2014
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOtsuka Pharmaceutical Development & Commercialization, Inc.
    B.1.3.4CountryUnited States
    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 supportOtsuka Pharmaceutical Development & Commercialization, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOtsuka Europe Development and Commercialisation Ltd (OEDC)
    B.5.2Functional name of contact pointPharmacovigilance Region Europe
    B.5.3 Address:
    B.5.3.1Street AddressEuropa-Allee 52
    B.5.3.2Town/ cityFrankfurt am Main
    B.5.3.3Post code60327
    B.5.3.4CountryGermany
    B.5.6E-mailGlobal_Intake@otsuka-us.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/3/07/524
    D.3 Description of the IMP
    D.3.2Product code OPC-67683
    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 INNDELAMANID
    D.3.9.1CAS number 681492-22-8
    D.3.9.2Current sponsor codeOPC-67683
    D.3.9.4EV Substance CodeSUB33761
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 2
    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/3/07/524
    D.3 Description of the IMP
    D.3.2Product code OPC-67683
    D.3.4Pharmaceutical form Dispersible tablet
    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 INNDELAMANID
    D.3.9.1CAS number 681492-22-8
    D.3.9.2Current sponsor codeOPC-67683
    D.3.9.4EV Substance CodeSUB33761
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.IMP: 3
    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/3/07/524
    D.3 Description of the IMP
    D.3.2Product code OPC-67683
    D.3.4Pharmaceutical form Dispersible tablet
    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 INNDELAMANID
    D.3.9.1CAS number 681492-22-8
    D.3.9.2Current sponsor codeOPC-67683
    D.3.9.4EV Substance CodeSUB33761
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    Pediatric patients with multidrug-resistant tuberculosis (MDRTB) who are receiving an optimized background regimen (OBR) of Antituberculosis Drugs
    E.1.1.1Medical condition in easily understood language
    Pediatric patients who received other treatments that did not work and who are receiving treatment of Antituberculosis Drugs
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the pharmacokinetics (PK) of delamanid and its metabolites in combination with an OBR in pediatric MDR-TB patients
    E.2.2Secondary objectives of the trial
    - To determine the safety and tolerability of delamanid in combination with an OBR in pediatric MDR-TB patients
    - To determine the palatability of the delamanid pediatric
    formulation
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Key Inclusion Criteria:
    - Male or female
    - Age birth to 17 years, inclusive
    - Confirmed diagnosis of MDR-TB, ie, culture positive
    for Mycobacterium tuberculosis (MTB) with isoniazid
    and rifampicin resistance on drug-susceptibility testing,
    or a positive rapid test demonstrating resistance to
    rifampicin alone or to rifampicin and isoniazid
    OR
    - Presumptive diagnosis of pulmonary or extrapulmonary
    MDR-TB such that the treating physician has decided to
    treat for MDR-TB the patient who has one of the following:
    - Clinical specimen (eg, cerebral spinal fluid, pleural
    fluid, ascitic fluid, lymph node aspirate, or other
    tissue specimen) suggestive of tuberculosis (TB)
    disease
    - Persistent cough lasting > 2 weeks
    - Fever, weight loss, and failure to thrive
    - Findings on recent chest radiograph or other
    imaging studies (prior to Visit 1) consistent with TB
    AND
    - Household contact of a person with known
    MDR-TB or a person who died while appropriately
    taking drugs for drug-sensitive TB
    OR
    - On first-line TB treatment but with no clinical
    improvement
     Negative urine pregnancy test for female patients who
    have reached menarche
     Study-specific written informed consent/assent obtained
    from a parent(s) or guardian or legally acceptable
    representative, as applicable for local laws prior to the
    initiation of any protocol-required procedures. In
    addition, for patients in Groups 1 and 2 the patient must
    provide informed assent at screening and must be able
    to fully understand that he or she can withdraw from the
    study at any time.
    E.4Principal exclusion criteria
    Key Exclusion Criteria:
     Children with laboratory evidence of active hepatitis B
    or C
     Children with body weight < 5.5 kg
     For patients with HIV co-infection, CD4 cell count ≤
    1000/mm3 for children 1-5 years old, and ≤
    1500/mm3 for children less than 1 year old
    History of allergy to metronidazole and any disease or
    condition in which metronidazole is required
     Use of amiodarone within 12 months prior to the first
    dose of investigational medicinal product (IMP) or use
    of other predefined antiarrhythmic medications within
    30 days prior to the first dose of IMP
     Serious concomitant conditions (cardiovascular
    disorders, severe respiratory disease, severe diarrheal
    disease, renal, hepatic, or neurological impairment)
     Preexisting cardiac conditions including but not limited
    to structural cardiac disease including suspected TB
    involvement of the heart on clinical or radiographic
    grounds
     Abnormalities in screening electrocardiogram (ECG)
    (including atrioventricular block, bundle branch block
    or hemi-block, QRS prolongation > 120 msec, or QT
    interval corrected using Fridericia’s method (QTcF)
    > 450 msec in both males and females)
     A concomitant condition such as renal impairment
    characterized by serum creatinine levels > 1.5 mg/dL,
    hepatic impairment (alanine aminotransferase or
    aspartate aminotransferase > 3 times the upper limit of
    normal [ULN]), or hyperbilirubinemia characterized by
    total bilirubin > 2x ULN
     Concurrent diagnosis of severe malnutrition or
    kwashiorkor
     Positive urine drug screen (Groups 1 and 2 only)
     Use of rifampicin and/or moxifloxacin within 1 week
    prior to the first dose of IMP and/or any prior or
    concurrent use bedaquiline
     Lansky Play Performance Score < 50 (not applicable for
    children < 1 year old) or Karnofsky Score < 50
     Administered an IMP within 1 month prior to Visit 1
     Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the informed consent form (Groups 1 and 2 only)
    E.5 End points
    E.5.1Primary end point(s)
    Pharmacokinetic parameters of delamanid and its main metabolites

    E.5.1.1Timepoint(s) of evaluation of this end point
    Plasma samples will be performed in Day 1 (first dose), Day 10 (last dose) and Day 17

    For children with tuberculosis meningitis, CSF concentrations of delamanid will be determined after lumbar puntcure
    E.5.2Secondary end point(s)
    Safety assessments including:
    - Vision and neurologic assessments
    - Standard 12-lead ECG, intensive ECG monitoring.
    - Laboratory testing, including coagulation testing
    - Monitoring of electrolytes especially from birth to 2 years of age
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Safety assessments on Days 1, 10 (Groups 1 and 2 only),
    and 18

    Follow-up Period: Day 19 to Day 40 (2 days)
    - All patients who complete their last scheduled visit will be contacted by telephone 28 to 30 days after the last dose of delamanid to assess any new or ongoing adverse events.

    - Patients who terminate from the trial prior to their last scheduled visit will be contacted by telephone or home visit 14 days (2 days) after the last dose of delamanid to assess for any new or ongoing adverse events.
    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 No
    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 Yes
    E.6.13.1Other scope of the trial description
    Palatability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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) No
    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.8.2.4Number of treatment arms in the trial4
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Philippines
    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
    November 2017
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial days17
    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: 36
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 6
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 18
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    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 Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients No
    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
    Subjects aged birth to 17 years old
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 36
    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)
    Follow-up Period: Day 19 to Day 40 (+/-2 days)
    On Day 40 (+/-2 days), patients who complete their last scheduled visit will be
    contacted by phone 28 to 30 days after the last dose of
    delamanid to assess new or ongoing adverse events.

    Patients who terminate from the trial prior to their last
    scheduled visit will be contacted by telephone or home visit
    14 days (+/-2 days) after the last dose of delamanid to assess for
    any new or ongoing adverse events.
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: Philippines
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