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    Summary
    EudraCT Number:2011-000467-27
    Sponsor's Protocol Code Number:31-10-272
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-11-09
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2011-000467-27
    A.3Full title of the trial
    A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Safety and Efficacy of Flexible-Dose Once-weekly Oral Aripiprazole in Children and Adolescents with Tourette's Disorder
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A global study to see how safe and effective a Once-weekly tablet containing Aripiprazole is in Children and Adolecents with Tourette's Disorder
    A.3.2Name or abbreviated title of the trial where available
    AWARE 272
    A.4.1Sponsor's protocol code number31-10-272
    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 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 and Commercialization, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCovance
    B.5.2Functional name of contact pointDorota Plewicka, MD
    B.5.3 Address:
    B.5.3.1Street AddressStoretungrova 36
    B.5.3.2Town/ cityForde
    B.5.3.3Post code6800
    B.5.3.4CountryNorway
    B.5.4Telephone number+47 578 213 25
    B.5.5Fax number+48 22 627 69 40
    B.5.6E-maildorota.plewicka@covance.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAripiprazole ECER Tablets 52.5 mg
    D.3.2Product code not applicable
    D.3.4Pharmaceutical form Gastro-resistant prolonged-release 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 INNAripiprazole
    D.3.9.1CAS number 129722-12-9
    D.3.9.2Current sponsor codeOPC-14597
    D.3.9.3Other descriptive namenot applicable
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number52.5
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAripiprazole ECER Tablets 77.5 mg
    D.3.2Product code not applicable
    D.3.4Pharmaceutical form Gastro-resistant prolonged-release 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 INNAripiprazole
    D.3.9.1CAS number 129722-12-9
    D.3.9.2Current sponsor codeOPC-14597
    D.3.9.3Other descriptive namenot applicable
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number77.5
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAripiprazole ECER Tablets 110 mg
    D.3.2Product code not applicable
    D.3.4Pharmaceutical form Gastro-resistant prolonged-release 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 INNAripiprazole
    D.3.9.1CAS number 129722-12-9
    D.3.9.2Current sponsor codeOPC-14597
    D.3.9.3Other descriptive namenot applicable
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number110
    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 placeboGastro-resistant prolonged-release tablet
    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
    Tourette’s Disorder
    E.1.1.1Medical condition in easily understood language
    Tourette's syndrome is a neurological condition (a condition that affects the nervous system). It causes both physical and verbal tics, which are involuntary repetitive movements or sounds
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10044126
    E.1.2Term Tourette's disorder
    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
    Primary: To compare the efficacy of aripiprazole with placebo in the suppression of tics in children and adolescents (7-17 years) with a diagnosis of Tourette’s Disorder. The primary efficacy measure is change from Baseline to endpoint (Week 8) on the Total Tic score (TTS) of the Yale Global Tic Severity Scale (YGTSS). Secondary efficacy measures include Clinical Global Impressions Scale for Tourette’s Syndrome (CGI-TS) and Gilles de la Tourette Syndrome - Quality of Life Scale (GTS-QOL).
    E.2.2Secondary objectives of the trial
    Secondary: To evaluate the safety and tolerability of aripiprazole Once-weekly treatment with oral tablets in children and adolescents with a diagnosis of Tourette’s Disorder.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    There is an optional pharmacogenomic sub-study included within this protocol for CYP2D6 metabolic profiling. Please refer to the protocol for details.
    E.3Principal inclusion criteria
    1. The subject is a male or female child or adolescent, 7 to 17 years of age (inclusive) at the time of signing the informed consent/assent.
    2. The subject meets current DSM-IV-TR diagnostic criteria for Tourette’s Disorder, as confirmed by the K-SADS-PL, including the Diagnostic Supplement 5 (Substance Abuse and Other Diseases, i.e., Tic Disorders).
    3. The subject has a TTS ≥ 20 on the YGTSS at Screening and Baseline (randomization).
    4. The subject, a caregiver, and the investigator must all agree that the presenting tic symptoms cause impairment in the subject's normal routines, which include academic achievement, occupational functioning, social activities, and/or relationships.
    5. Females of childbearing potential (defined by menarche and not having undergone surgical sterilization/hysterectomy) must have a negative pregnancy test, must be practicing acceptable double-barrier methods of contraception (or can confirm abstinence at each scheduled visit), and must not be pregnant or lactating.
    6. Written informed consent must be obtained from a legally acceptable representative (eg, guardian or caregiver), in accordance with local law and the requirements of the trial center’s institutional review board (IRB) or independent ethics committee (IEC), prior to the initiation of any protocol-required procedures. In addition, the subject, as required by the trial center’s IRB/IEC, must provide informed assent at Screening and as such must be able to understand that he or she can withdraw from the trial at any time.
    7. The subject and the designated guardian(s) or caregiver(s) are able to comprehend and satisfactorily comply with the protocol requirements, as evaluated by the investigator.
    E.4Principal exclusion criteria
    1. The subject presents with a clinical presentation and/or history that is consistent with another neurologic condition that may have accompanying abnormal movements.
    These include, but are not limited to:
    • Transient Tic disorder
    • Huntington's disease
    • Parkinson's disease
    • Sydenham's chorea
    • Wilson's disease
    • Mental retardation
    • Pervasive developmental disorder
    • Traumatic brain injury
    • Stroke
    • Restless Legs Syndrome
    2. The subject has a history of schizophrenia, bipolar disorder, or other psychotic disorder.
    3. Subjects who receive psychostimulants for the treatment of ADD/ADHD and who have developed and/or had exacerbations of the tic disorder after the initiation of stimulant treatment. (Note that subjects with ADD/ADHD who are treated with psychostimulants and have not developed new tics or a worsening of their current tics can be included if all other enrollment obligations are met).
    4. The subject currently meets DSM-IV-TR criteria for a primary mood disorder.
    5. The subject has severe obsessive-compulsive disease (OCD), as evidenced by a Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score > 16.
    6. The subject has taken aripiprazole within 1 month (30 days) of the Screening visit.
    7. Subjects who received any investigational agent in a clinical trial within 30 days prior to Screening or who were randomized into a clinical trial with Once-weekly aripiprazole at any time.
    8. The subject has a history of neuroleptic malignant syndrome.
    9. Sexually active males who will not commit to utilizing 2 of the approved birth control methods or who will not remain abstinent during the trial and for 90 days following the last dose of study drug, or sexually active females of childbearing potential who will not commit to utilizing 2 of the approved birth control methods or who will not remain abstinent during the trial and for 30 days following the last dose of study drug. Abstinence will be permitted if it is confirmed and documented at every trial visit. If employing birth control, 2 of the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pill, birth control depot injections, implant, condom or sponge with spermicide.
    10. Females who are breast-feeding and/or who have a positive serum pregnancy test result prior to receiving trial drug.
    11. The subject represents a significant risk of committing suicide based on history (suicide attempt in past 1 year), routine psychiatric status examination, investigator’s judgment, or who have an answer of “yes” on any question other than 1-3 (current or over the last 30 days) on the Baseline/Screening version of the Columbia-Suicide Severity Rating Scale (C-SSRS).
    12. Body weight is lower than 16 kg.
    13. Subjects who have taken neuroleptic or antiparkinson drugs less than 14 days prior to randomization.
    14. Subjects requiring cognitive-behavioral therapy (CBT) for Tourette’s Disorder during the trial period. CBT for other non-exclusionary disorders must remain consistent throughout the trial.
    15. The subject has met DSM-IV-TR criteria for any significant psychoactive substance use disorder (abuse, dependence, and/or withdrawal) within the past 3 months.
    16. A positive drug screen for cocaine, alcohol, or other drugs of abuse (excluding caffeine, nicotine, or prescribed psychostimulants for ADD/ADHD). Investigators can chose to repeat a positive drug screen one time during Screening period after concurrence with the Medical Monitor. A second positive test for any drug of abuse would be exclusionary.
    17. Subject requiring medication not allowed per protocol.
    18. Use of any Cytochrome P450 (CYP)2D6 and CYP3A4 inhibitors or CYP3A4 inducers within 14 days prior to dosing and for the duration of the trial (see list provided in Section 4.1).
    19. The inability to swallow tablets or tolerate oral medication.
    20. The following laboratory test results, vital sign, measurements, and electrocardiogram (ECG) results are exclusionary:
    1) Platelets ≤ 75,000/mm3
    2) Hemoglobin ≤ 9 g/dL
    3) Neutrophils, absolute ≤ 1000/mm3
    4) Aspartate aminotransferase (AST) > 3x upper limit of normal as defined by the central laboratory
    5) Alanine aminotransferase (ALT) > 3x upper limit of normal as defined by the central laboratory
    6) Creatinine ≥ 2 mg/dL
    7) Diastolic blood pressure > 105 mmHg
    8) QTc ≥ 450 msec on either the QTcB (Bazett’s) or QTcF (Fridericia) corrections on 2 of 3 time points (see NOTE on page 42 of the protocol)
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint: Change from Baseline to endpoint (Week 8) in YGTSS Total Tic Score.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 8
    E.5.2Secondary end point(s)
    Key Secondary Endpoints:
    • Mean CGI-TS Change score at endpoint
    • Mean changes from Baseline to endpoint in GTS-QOL overall score
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 8
    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 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 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 concerned2
    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 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
    Canada
    Hungary
    Korea, Republic of
    Taiwan
    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
    The end of the trial is the final subject follow-up telephone call 30 days after last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    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 Yes
    F.1.1Number of subjects for this age range: 126
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 38
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 88
    F.1.2Adults (18-64 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children and Adolescents under 18 years old
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 126
    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)
    Subjects who discontinue and are withdrawn by the investigator for “lack of efficacy” at or after the Week 5 visit, and subjects who complete the trial through the Week 8 visit may be offered entry into an open-label safety trial of aripiprazole (Protocol 31-10-274) for an additional 52 weeks of open-label treatment with a 30-day follow-up. All subjects who do not enter the open-label trial will be followed up for safety reasons 30 days (± 3 days) after the last trial visit.
    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 Decision2011-11-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-10-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-11-06
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