| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Manic or Mixed Episodes Associated with Bipolar I Disorder |
|
| E.1.1.1 | Medical condition in easily understood language |
| Bipolar disorder is a psychiatric diagnosis where patients have one or more episodes of abnormally elevated energy levels, cognition and mood (mania) with or without one or more depressive episodes. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068455 |
| E.1.2 | Term | Bipolar I disorder, hypomanic |
| 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 demonstrate clinical and statistical superiority of at least one dose of asenapine to placebo in pediatric subjects (12 to 17 years) with a manic or mixed episode associated with bipolar I disorder, measured by the change from Baseline in Young-Mania Rating Scale (YMRS) total score at Day 21. |
|
| E.2.2 | Secondary objectives of the trial |
To demonstrate superiority of at least one dose of asenapine to placebo in pediatric subjects with a manic or mixed episode associated with bipolar I disorder, measured by CGI-BP at Day 21.
To evaluate the effect of asenapine with respect to:
- The proportion of Y-MRS responders & remitters
- Severity of bipolar mania and bipolar depression as measured by the CGI-BP
- Depressive symptoms as measured by the CDRS-R
To investigate the dose response relationship of 2.5 mg, 5 mg, and 10 mg asenapine BID, evaluate the safety & tolerability of asenapine compared with placebo by:
- (S)AE reporting
- Clinical laboratory values
- Vital signs
- ECG, Extrapyramidal symptoms using the ESRS
- Suicidality using the C-SSRS
- Anthropometry
- Sexual development (Tanner staging)
- Menstrual cycle regularity assessment in female subjects
To evaluate the population PK of asenapine and to obtain data on the PK of asenapine in pediatric subjects with bipolar I disorder |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Each subject’s parent(s) or legal representative must be willing and able to provide written informed consent for the trial. Each subject must indicate assent/consent before study participation.
Each subject’s parent(s) or legal representative must provide separate written informed consent for pharmacogentic testing and each subject must indicate assent/consent.
2. Each subject must be ≥12 years of age when indicating assent/consent to participate in the trial and ≤17 years of age when randomly assigned to treatment. A subject may be of either sex, and of any race/ethnicity.
3. Each subject must have a diagnosis of primary bipolar I disorder, current episode manic (296.4x), or mixed (296.6x) with or without psychotic features as confirmed by a structured clinical interview (K-SADS-PL) at screening.;
4. Each subject must have a YMRS total score ≥ 20 at Screening and Baseline;
Each subject must have a severity of bipolar illness ≥ 4 as measured on the CGI-BPoverall at Screening and Baseline;
6. Each subject must be a male, or a female who is not of childbearing potential (eg, surgically sterile) or who is non-pregnant, non-lactating, and is using a medically accepted method of contraception. If a female subject of childbearing potential, must agree to use a medically
accepted method of contraception while receiving protocol specified medication and for 1 month after stopping the medication.
7. Each subject must understand the nature of the study;
8. Each subject must have tapered off all prohibited psychotropic medications prior to Baseline;
9. Each subject must be fluent in the language of the investigator, trial staff (including raters), and the informed consent;
10. Each subject must have a caregiver, or an identified responsible person, living with the subject, who is considered reliable by the investigator and who has agreed to provide support to the subject to ensure compliance with trial treatment, outpatient visits, and protocol procedures;
Refer to protocol for complete list
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| E.4 | Principal exclusion criteria |
1. The subject has a diagnosis of bipolar II disorder, bipolar disorder not otherwise specified, a pervasive developmental disorder, schizophrenia, schizoaffective disorder, post traumatic stress disorder (PTSD), or obsessive compulsive disorder (OCD);
2. The subject has a primary Axis I diagnosis other than bipolar I disorder and has a comorbid Axis I diagnosis that is primarily responsible for current symptoms and functional impairment;
3. The subject has a diagnosis of psychotic disorder or psychosis due to another medical condition or concomitant medication;
4. The subject has a known or suspected diagnosis of mental retardation, organic brain disorder, or an IQ <70;
5. The subject meets the DSM IV TR™ criteria for substance abuse or dependence (excluding nicotine and caffeine) within the past 6 months;
6. The subject has a diagnosis of psychotic disorder or a behavioral disturbance thought to be substance induced or due to substance abuse;
7. The subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion based on clinical interview or on responses provided on the C-SSRS. Subjects must be excluded at Screening if they report suicidal ideation of Type 4 or 5 (ie, suicidal ideation with intent, with or without a plan) in the past 2 months or suicidal behavior in the past 6 months as measured by the C-SSRS; subjects must be excluded at Baseline if they report suicidal ideation of Type 4 or
5 or suicidal behavior between Screening and Baseline as measured by the C-SSRS;
8. The subject has a history of tardive dyskinesia or tardive dystonia;
9. The subject has or had catatonic features;
10. The subject has uncontrolled or unstable diabetes or had a clinically significant abnormal blood glucose level at Screening that was confirmed by repeat testing;
11. The subject has an uncontrolled or unstable clinically significant medical condition (eg, renal, endocrine, respiratory, cardiovascular, hematological, immunologic, neurological or cerebrovascular disease, malignancy, or eating disorder) that may interfere with the interpretation of safety and efficacy evaluations in the opinion of the investigator;
12. The subject has clinically significant abnormal laboratory, vital sign, physical examination, or ECG findings at Screening that, in the investigator’s opinion, preclude the subject’s participation in the trial;
13. A subject has laboratory and/or clinical evidence of clinically significant hepatic conditions, such as:
• ALT or AST >3 x ULN and total bilirubin >2 x ULN; or
• ALT or AST >3 x ULN with the appearance of jaundice, worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia;
14. The subject is a female who is pregnant or breast-feeding;
15. The subject is a female with a positive pregnancy test at Screening, or with the intention to become pregnant during the course of the trial including the follow-up;
16. The subject has any known or suspected (non-febrile) seizure disorder;
17. The subject has known serological evidence of human immunodeficiency virus (HIV) antibody;
18. The subject has a history of neuroleptic malignant syndrome;
19. The subject has a positive drug/alcohol screen at the screening visit. (Subjects with positive psychotropic medication results may be included provided the finding can be accounted for by documented prescription use and the subject is able and willing to comply with protocol requirements regarding excluded medications. Subjects with positive alcohol or cannabis results may be included at the investigator’s discretion, provided the investigator does not feel the subject
is a compliance risk and the subject does not fulfill the criteria for substance abuse or dependence;
20. The subject is under involuntary inpatient commitment;
21. The subject has used an investigational drug within 6 months prior to Randomization;
22. The subject is participating in any other clinical trial;
23. The subject has been treated previously in an asenapine trial;
24. The subject, if previously exposed to marketed asenapine, has been included if the subject was previously non-responsive to asenapine, experienced an allergic reaction to asenapine, or if the subject was treated with asenapine for the subject’s current episode;
25. The subject is a member or a family member of the personnel of the investigational or sponsor staff directly involved with this trial;
26. The subject has been judged by the investigator to be medically non-compliant in the management of their disease;
27. The subject has been judged to be treatment resistant by the investigator or by the SDME;
28. The subject is unwilling to discontinue or, in the opinion of the investigator, is unable to safely taper off any prohibited treatment prior to the Baseline Visit without significant destabilization or increased suicidality.
Refer to protocol for complete list
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To demonstrate clinical and statistical superiority of at least one dose of asenapine to placebo in pediatric subjects (12 to 17 years) with a manic or mixed episode associated with bipolar I disorder, as measured by the change from Baseline in Young-Mania Rating Scale (Y-MRS) total score at Day 21. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
To demonstrate superiority of at least one dose of asenapine to placebo in pediatric subjects (12 to 17 years) with a manic or mixed episode associated with bipolar I disorder, as measured by the change from Baseline in severity of bipolar illness on the Clinical Global Impression Scale for use in Bipolar Illness (CGI-BPoverall) at Day 21.
• To evaluate the effect of asenapine compared with placebo with respect to:
- The proportion of Y-MRS responders (Y-MRS decrease from Baseline ≥50%);
- The proportion of Y-MRS remitters (Y-MRS ≤12);
- Severity of bipolar mania and bipolar depression as measured by the CGI-BP (CGI-BPmania, CGI-BPdepression);
- Depressive symptoms as measured by the Revised Children’s Depression Rating Scale (CDRS-R);
• To investigate the dose response relationship of the three asenapine doses (2.5 mg, 5 mg, and 10 mg twice daily [BID]) in order to study the minimum effective dose in pediatric subjects with a manic or mixed episode associated with bipolar I disorder;
• To evaluate the safety and tolerability of asenapine compared with placebo by means of:
- (Serious) Adverse Event reporting,
- Clinical laboratory values,
- Vital signs,
- Electrocardiogram (ECG),
- Extrapyramidal symptoms using the Extrapyramidal Symptom Rating Scale
(ESRS),
- Suicidality using the Columbia Suicide Severity Rating Scale (C-SSRS),
- Anthropometry,
- Sexual development (Tanner staging), and
- Menstrual cycle regularity assessment in female subjects.
• To evaluate change in subjects’ social functioning as measured by the Children’s Global Assessment Scale (CGAS) and subjects’ quality of life enjoyment and satisfaction as measured by the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaires (PQ-LES-Q); and
• To evaluate the population PK of asenapine (black cherry flavored formulation) and to obtain data on the PK of asenapine in pediatric subjects with bipolar I disorder by using sparse sampling methodology.
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | Yes |
| 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.8.3 |
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.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 18 |
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