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    Summary
    EudraCT Number:2012-004334-42
    Sponsor's Protocol Code Number:31-08-252
    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:2012-12-18
    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 number2012-004334-42
    A.3Full title of the trial
    A 52-week, Multicenter, Open-label Study to Evaluate the Effectiveness of an Intramuscular Depot Formulation of Aripiprazole (OPC-14597) as Maintenance Treatment in Patients with Bipolar I Disorder
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effectiveness of an Intramuscular Formuation of Aripiprazole (OPC-14597) as Maintenance Treatment in Bipolar I Patients
    A.4.1Sponsor's protocol code number31-08-252
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01710709
    A.5.4Other Identifiers
    Name:IND No. Number:114,284
    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 & Commercialization, Inc.
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportH. Lundbeck A/S
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationINC Research
    B.5.2Functional name of contact pointRegulatory Project Manager
    B.5.3 Address:
    B.5.3.1Street AddressRiverview, the Meadows Business Park, Station Approach, Blackwater
    B.5.3.2Town/ cityCamberley, Surrey
    B.5.3.3Post codeGU17 9AB
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number441276481000
    B.5.5Fax number44127635743
    B.5.6E-mailSM_Regaffairs_eu_ap@incresearch.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 Yes
    D.2.1.1.1Trade name ABILIFY MAINTENA
    D.2.1.1.2Name of the Marketing Authorisation holderOtsuka Pharmaceutical Europe Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameIntramuscular (IM) Depot Aripiprazole
    D.3.2Product code OPC-14597
    D.3.4Pharmaceutical form Lyophilisate for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular 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.3.9.4EV Substance CodeSUB05564MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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
    Bipolar I disorder
    E.1.1.1Medical condition in easily understood language
    A mood disorder that is characterized by at least one manic or mixed episode.
    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 16.1
    E.1.2Level PT
    E.1.2Classification code 10004939
    E.1.2Term Bipolar I disorder
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and tolerability of aripiprazole IM depot administered every 4 weeks for 52 weeks to patients with bipolar I disorder.
    To evaluate the efficacy, as measured by the percentage of stable subjects at baseline who remain stable at the end of treatment in Phase C, of aripiprazole IM depot administered every 4 weeks for 52 weeks to patients with bipolar I disorder.
    E.2.2Secondary objectives of the trial
    Percentage of stable subjects at baseline of Phase C who remain stable at endpoint, where “stable” is defined as meeting ALL of the following criteria:
    1) Outpatient status
    2) YMRS total score ≤12
    3) MADRS total score ≤12
    4) No active suicidality; with active suicidality defined as
    a score of 4 or more on the MADRS item 10 OR an
    answer of “yes” on questions 4 and 5 on the C-SSRS
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria Assessed Prior to Entry into Phase C
    1. Subjects who are able to provide written informed consent. If the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requires consent by a legally acceptable representative (LAR) in addition to the subject, all required consents must be obtained prior to the initiation of any protocol-required procedure.
    2. Male and female subjects 18 years of age or older at time of informed consent.
    3. Subjects who have completed Trials 250 and did not meet the criteria for recurrence of mood episode at the End of Trial Visit.
    4. Subjects who, in the investigator’s judgment, require chronic treatment with an antipsychotic medication for their bipolar I disorder and would benefit from extended treatment with a longacting injectable formulation.
    5. In the investigator’s opinion, subjects who are able to understand the nature of this trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, aripiprazole IM depot injection, and discontinuation of prohibited concomitant medications; who can read and understand the written word in order to complete subject-reported outcomes measures; and who can be reliably rated on assessment scales.

    Inclusion Criteria - Entry For De novo Subjects
    Screening
    1. Subjects who are able to provide written informed consent. If the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requires consent by a legally acceptable representative (LAR) in addition to the subject, all required consents must be obtained prior to the initiation of any protocol-required procedure.
    2. Male and female subjects 18 to 65 years of age, inclusive, at time of informed consent.
    3. Subjects with a current diagnosis of bipolar I disorder, as defined by DSM-IV-TR criteria and confirmed by the MINI and a history of at least one previous manic or mixed episode with manic symptoms of sufficient severity to require one of the following interventions: hospitalization and/or treatment with a mood stabilizer and/or treatment with an antipsychotic agent. “Require” is defined as an intervention that occurred rather than one that was recommended. Rapid cyclers with 8 or fewer episodes in the previous year will be included.
    5. Subjects who, in the investigator’s judgment, require treatment with an antipsychotic medication for their bipolar I disorder and would benefit from treatment with a long-acting injectable formulation.
    6. Subjects who have had a recurrence of mood episode or exacerbations of mood symptoms when they are not receiving treatment for their bipolar I disorder or are noncompliant with treatment for their bipolar I disorder.
    7. In the investigator’s opinion, subjects who are able to understand the nature of this trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, aripiprazole IM depot injection, and discontinuation of prohibited concomitant medications; who can read and understand the written word in order to complete subject-reported outcomes measures; and who can be reliably rated on assessment scales.

    Inclusion Criteria Assessed Prior to Entry into Phase A
    8. Subjects with an adequate washout of prohibited/restricted concomitant medication.
    9. Subjects who have an outpatient status.

    Inclusion Criteria Assessed Prior to Entry into Phase B
    10. Subjects with an adequate washout of prohibited/restricted concomitant medication.
    11. Phase A subjects receiving treatment with oral aripiprazole monotherapy 15 to 30 mg/day (12 to 30 mg/day in Japan).
    12. Subjects who have an outpatient status.

    Inclusion Criteria Assessed Prior to Entry into Phase C
    13. Subjects who have met criteria for stabilization for 4 consecutive weeks (2 consecutive biweekly visits).
    14. Subjects receiving treatment with oral aripiprazole monotherapy 15 to 30 mg/day (12 to 30 mg in Japan).
    15. Subjects who currently have an outpatient status.
    E.4Principal exclusion criteria
    1. Subjects with a current Axis I (DSM-IV-TR) diagnosis other than bipolar I disorder, including schizophrenia, schizoaffective disorder, major depressive disorder, attention-deficit/hyperactivity disorder, delirium, dementia, amnestic, or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder. All other current diagnoses must be discussed with the medical monitor.
    2. Subjects who have experienced 9 or more mood episodes within the past year.
    3. Subjects who have NOT experienced at least one previous manic or mixed episode with manic symptoms of sufficient severity to require one of the following interventions: hospitalization and/or treatment with a mood stabilizer and/or treatment with antipsychotic agent. “Require” is defined as an intervention that occurred rather than one that was recommended.
    4. Subjects with a current manic episode with a duration of > 2 years.
    5. Subjects who are currently experiencing a depressive episode (per DSM-IV-TR criteria).
    6. Subjects with bipolar I disorder who are considered resistant/refractory to treatment for manic symptoms by history.
    7. Subjects unresponsive to clozapine for treatment of mania.
    8. Subjects who only respond to clozapine for treatment of mania.
    9. Subjects with a significant risk of committing suicide based on history, mental status examination, investigator’s judgment, or C-SSRS answer of “yes” to questions 4 or 5 (current or within the last 90 days).
    10. Subjects who currently (within the past month)meet DSM-IV-TR criteria for substance abuse or substance dependence; this includes the abuse of alcohol and benzodiazepines, but excludes the use of caffeine and/or nicotine.
    11. Subjects with hypothyroidism or hyperthyroidism and/or other unstable thyroid pathology, unless condition has been stabilized with medications for at least the past 3 months.
    12. Subjects who have a history or evidence of a medical condition that would expose them to an undue risk of a significant AE or interfere with assessments of safety or efficacy during the course
    of the trial, including but not limited to hepatic, renal, respiratory, cardiovascular, endocrine, neurologic, hematologic, or immunologic disease as determined by the clinical judgment of the investigator.
    13. Subjects with epilepsy or a history of seizures (except for a single childhood febrile seizure, post traumatic, alcohol withdrawal, etc).
    14. Subjects with a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia as assessed by the investigator.
    15. Subjects likely to require prohibited concomitant therapy during this trial.
    16. Subjects who may require cytochrome P450 (CYP) 2D6 or CYP3A4 inhibitors, or CYP3A4 inducers during this trial (see Table 4.2.1-1).
    17. Subjects who are known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other quinolinones.
    18. Subjects with a history of hypersensitivity to antipsychotic agents.
    19. Subjects deemed intolerant of receiving injectable treatment.
    20. Sexually active women of childbearing potential (WOCBP) who will not commit to utilizing 2 of the approved birth control methods or who will not remain abstinent during this trial and for 150 days following the last dose of trial medication.
    - 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, condome with spermicide, intrauterine device, birth control pills, birth control depot injections,birth condom implant, birth control patch, bith control vaginal ring, or sponge with spermicide.
    21. Sexually active men (unless sterile, defined as having had an orchiectomy) who will not commit to utilizing 2 of the approved birth control methods or who will not remain abstinent during this trial and for 180 days following the last dose of trial medication.
    22. Female subjects who are breast-feeding and/or who have a positive serum pregnancy test result prior to receiving trial medications.
    E.5 End points
    E.5.1Primary end point(s)
    1. AEs will be examined by frequency, severity, seriousness, and discontinuation (all cause and due to AEs).
    2. Injection site pain will be evaluated by mean visual analog scale (VAS) scores as reported by the subject. The investigator rating of localized pain, redness, swelling, and induration. at the injection site will also be tabulated for postinjection site evaluations
    3. The incidence of clinically relevant values and mean changes from baseline will be calculated for vital signs, routine laboratory tests, and ECG parameters. In addition, body weight and serum prolactin concentrations will be monitored. A central ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety analysis. Extrapyramidal symptoms will be evaluated by calculating mean change from baseline in Simpson-Angus Scale (SAS; used in countries other than Japan), Druginduced Extrapyramidal Symptoms Scale (DIEPSS; used in Japan), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BARS).
    By-patient listings of physical examination findings will be reviewed as a further assessment of safety.
    The primary efficacy endpoint of this trial is the percentage of stable subjects at baseline who remain stable at the end of the treatment in Phase C, where “stable” is defined as meeting ALL of the following criteria:
    1) Outpatient status
    2) YMRS total score < or equals 12
    3) MADRS total score < or equals 12
    4) No active suicidality; with active suicidality defined as a score of or more on the MADRS item 10 OR an answer of “yes” on questions 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1.The C-SSRS will be completed at screening (for De Novo patients only), baseline, and all subsequent visits to assess the risk of suicide events and to classify reported suicide events.
    2. Each injection visit
    3. Mean changes from baseline

    E.5.2Secondary end point(s)
    Other endpoints evaluated in Phase C include the following:
    Mean change from baseline to endpoint (Week 52) in the
    following:
    - YMRS total score
    - MADRS total score
    -CGI-BP-S scores (overall, mania, depression)
    Mean CGI-BP Change from preceding phase scores
    (overall, mania, depression) at endpoint
    Time to discontinuation due to all causes
    Proportion of subjects meeting criteria for remission (at each specified trial visit, subjects with a YMRS and MADRS total scores < or equals 12 will be considered remitters for a given visit)
    Proportion of subjects meeting criteria for recovery (subjects meeting criteria for remission, which is maintained for 8 consecutive weeks)
    Quality of life will be assessed using the Brief Quality of Life in Bipolar Disorder (Brief QoL.BD) questionnaire.
    Functioning will be assessed using the Functioning Assessment Short Test (FAST).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline and end of treatment
    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 No
    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
    tolerability
    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) Yes
    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 trial1
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    France
    Hungary
    Japan
    Korea, Republic of
    Malaysia
    Poland
    Romania
    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 Trial Date is defined as the last Date of Contact or the Date of Final Contact Attempt from the Post-treatment Follow-up eCRF page for the last subject completing or
    withdrawing from this trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 925
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 75
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 1000
    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
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-02-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-02-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-11-18
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