| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A mood disorder that is characterized by at least one manic or mixed episode. |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10004939 |
| E.1.2 | Term | Bipolar I disorder |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.4 | Principal 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.5.1 | Primary 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.5.1.1 | Timepoint(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.5.2 | Secondary 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.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline and end of treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Japan |
| Romania |
| Hungary |
| Korea, Republic of |
| Malaysia |
| Poland |
| Taiwan |
| United States |
|
| E.8.7 | Trial 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. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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