| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behaviours [F01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| 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 |
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| 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 determine the efficacy and safety of asenapine compared with placebo in preventing the recurrence of any mood episodes. |
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| E.2.2 | Secondary objectives of the trial |
To compare asenapine and placebo in the treatment of subjects with bipolar I disorder with respect to:
1. Manic symptoms severity, as measured by the Young Mania Rating Scale (Y-MRS);
2. Depressive symptoms severity, as measured by the Montgomery Asberg Depression Rating Scale(MADRS);
3. Overall clinical impression of severity and improvement, as measured by the Clinical Global Impressions of improvement and Severity, Bipolar version (CGI-BP I and S);
4. Psychotic symptoms severity (including positive and negative symptoms) and symptoms of general psychopathology, as measured by the Positive and Negative Symptoms Scale (PANSS);
5. Suicidality, as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Open-Label Treatment Period
1. Each subject must be at least 18 years of age and of legal minimum age for signing the consent form;
2. Each subject must be a male or a female who is not of child-bearing potential (ie, surgically sterile, postmenopausal for at least 1 year) or who is non-pregnant, non-lactating and is using a medically accepted method of contraception.
Acceptable methods of contraception include condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed intrauterine device (IUD), and hormonal contraceptives. A female of child-bearing potential who is not currently sexually active must agree to use a medically accepted method of contraception should she become sexually active while participating in the trial;
Note: Each sexually active female of child-bearing potential must agree to use a medically accepted method of contraception while receiving protocol-specified medication and for 1 month after stopping the medication.
3. Each subject must have a current diagnosis of bipolar I disorder, and a current manic (DSM-IV296.4x) or mixed (DSM-IV 296.6x) episode, as determined by a structured clinical interview (MINI version 6.0.0) at Screening;
4. Each subject must have a Young Mania Rating Scale (Y-MRS) score ≥18 at Screening and at Baseline;
5. Each subject must have a Clinical Global Impression Scale for Bipolar Disorder (CGI-BP) Severity score of moderately ill or greater (4 or greater) in both the Mania and Overall Bipolar Illness subscales at Screening and Baseline;
6. Each subject must be confirmed (documented in the Psychiatric Intake Evaluation Form by the investigator and reviewed by the sponsor designated medical expert [SDME] prior to Enrollment into the Open-Label Treatment Period) to be experiencing an acute manic or mixed bipolar I episode, as evidenced by ALL of the following:
a. The subject has not shown a response (50% improvement) since the start of the current episode;
b. The subject’s current symptoms represent a marked and substantial change compared to the subject’s symptomatic state prior to the emergence of the current episode;
c. The subject is in need of increased medical attention to treat his/her worsening current manic or mixed episode;
d. The subject has a diagnosis of bipolar disorder for at least two years.
7. Each subject must have documented history of at least two previous moderate-to-severe manic or mixed episodes with or without psychotic features (with at least one of these episode being adequately treated with psychotropic medication).
Double-Blind Treatment Period
8. Each subject must have completed a minimum of 12 weeks and up to 16 weeks of the Open-Label Treatment Period;
9. Each subject must have met one of the following stabilization criteria:
a. A Y-MRS and MADRS scores of <=12 at either the last 5 consecutive visits of the Open-Label Treatment Period (ie, visits at Weeks 4, 6, 8, 10, and 12 or visits at Weeks 6, 8, 10, 12, and 14 or Weeks 8, 10, 12, 14, and 16); or
b. A Y-MRS and MADRS scores of <=12 at 5 out of 6 consecutive visits, with only one excursion event prior to the last visit in the series (the subject met the Y-MRS and MADRS scores at Weeks 6 and 16, and also 3 out of 4 times at Weeks 8, 10, 12, or 14;
Note: Subjects must be on asenapine as a monotherapy (ie, previous psychotropic medications already discontinued) for 4 weeks before a stabilization period of 8 weeks can be evaluated. During the 8 week stabilization period an excursion event of Y-MRS and/or MADRS score of less than 16 at a single visit is permitted; excursions of >=16 require the subject to be discontinued from the trial.
10. Each subject must not have taken or required disallowed medication during the Open-Label Treatment Period;
11. Each subject must not have required or received hospitalization for his/her psychiatric symptoms during the Open-Label Treatment Period (excluding the discretionary in-patient stay up to Day 7 or extended hospitalization stay);
12. Each subject must continue to meet all criteria in the Open-Label Treatment Period (except those pertaining to minimum Y-MRS and CGI-BP scores). |
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| E.4 | Principal exclusion criteria |
Key Open-Label Exclusion Criteria
1. A subject must not have an uncontrolled, unstable, clinically significant medical condition (eg, renal, endocrine, hepatic, respiratory, cardiovascular, hematologic, immunologic or cerebrovascular disease, known serological evidence of human immunodeficiency virus [HIV] antibody, or malignancy) that may interfere with the interpretation of safety and efficacy evaluations in the opinion of the investigator;
2. A subject must not have a body mass index (BMI) <18.5 or >40.0 kg/m2;
3. A subject must not have clinically significant abnormal laboratory, vital sign, physical examination, or electrocardiogram (ECG) findings at Screening that, in the investigator’s opinion, preclude the subject’s participation in the trial (potentially interferes with the ability to evaluate safety, tolerability, and efficacy of trial medication, or potentially impairs the subject’s ability to complete the trial);
4. A subject must not be at imminent risk of self-harm or harm to others in the investigator’s opinion, based on clinical interview and responses provided on the Columbia-Suicide Severity Rating Scale (C-SSRS). Note that subjects must be excluded if they report suicidal ideation meeting the description of C-SSRS Type 4 or 5 (ie, suicidal ideation with intent, with or without a plan) in the past 2 months or suicidal behavior (as described by the C-SSRS) in the past 6 months at Screening. Subjects must be excluded at Baseline if they report suicidal ideation of Type 4 or 5 or suicidal behavior, as measured by the C-SSRS between Screening and Baseline.
5. A subject must not have a history of imprisonment, parole, or assaultive behavior in the past 2 years prior to Screening;
6. A subject must not have a history of rapid cycling according to DSM-IV-TRTM criteria. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The Primary Efficacy Endpoint for the current trial is time to recurrence of any mood event during the Double-Blind Treatment Period, defined as any of the following:
• Requirement or initiation of any non-study medication to treat mixed, manic, or depressive symptoms, including an antipsychotic, antidepressant,or mood-stabilizing agent;
• Requirement or initiation of psychiatric hospitalization;
• Discontinuation from the study because of a mood event (as determined by the investigator); or
• Y-MRS or MADRS score >= 16. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time to recurrence of any mood event during the Double-Blind Treatment Period |
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| E.5.2 | Secondary end point(s) |
The continuous efficacy variables will be summarized by visit for the Open-Label and Double Blind Treatment Periods separately for the ITT population.The change scores during the Double-Blind Treatment Period for the ITT population will be analyzed by using an analysis of covariance (ANCOVA) with baseline score included in the model for both the observed case (OC) data and last observation carried forward (LOCF) data. No adjustment will be made for the multiple testing. The change scores are listed as follows:
For Open-Label Treatment Period:
• Change from Baseline in Y-MRS total score by visit;
• Change from Baseline on MADRS total scores by visit;
• Change from Baseline on total PANSS scores and subscale (positive, negative, general psychopathology) scores by visit;
• Change from Baseline on PANSS Marder factor (positive, negative, disorganized thought, hostility/excitement, and anxiety/depression symptom) scores by visit;
• Change from Baseline on each CGI-BP severity score by visit.
For Double-Blind Treatment Period:
• Change from double-blind baseline in Y-MRS total score by visit;
• Change from double-blind baseline in MADRS total score by visit;
• Change from double-blind baseline on total PANSS scores and subscale (positive, negative, general psychopathology) scores by visit;
• Change from double-blind baseline on PANSS Marder factor (positive, negative, disorganized thought, hostility/excitement, and anxiety/depression symptom) scores by visit;
• Change from double-blind baseline on CGI-BP severity scores by visit. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The continuous efficacy variables will be summarized by visit for the Open-Label and Double Blind Treatment Periods separately for the ITT population. |
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| 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 | Yes |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Bulgaria |
| Canada |
| Croatia |
| India |
| Philippines |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Turkey |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| Last contact with last subject |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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