| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004939 |
|
| 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 |
| The primary objective of this trial is to demonstrate clinical and statistical superiority of asenapine compared to placebo in subjects who have not completely responded to continuing treatment with lithium or VPA to treat acute manic or mixed episodes associated with bipolar I disorder. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives include evaluating the adjunctive treatment effects of asenapine compared to placebo with respect to:
·Overall clinical impression of severity of, and improvement in, mania, depression, and overall bipolarstate
·Depression
·Psychotic symptoms
·Anxiety
·Readiness to discharge
·Quality of life
·Cognitive function
·Suicidal thinking
·Safety and tolerability [including extrapyramidal symptoms (EPS)]
The effect of lithium and of VPA on plasma levels of asenapine and desmethylasenapine, and vice versa, will be characterized in population pharmacokinetic analyses. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Demographic
1. Be at least 18 years of age and of legal minimum age for trial participation;
2. Be a male, or a female who is not of childbearing potential (ie, surgically sterile, postmenopausal for at least 1 year); or non-pregnant using a method of birth control that is acceptable to the investigator, and not breast-feeding;
Procedural
3. Sign written informed consent after the scope and nature of the investigation have been explained to them before screening evaluations. Subjects unable or incapable of signing may participate if a legal representative provides consent and the subject affirms their participation;
4. Be fluent in the language of the investigator, trial staff (including raters), and the informed consent;
5. Have a caregiver or an identified responsible person (eg, family member, social worker, case worker, or nurse) considered reliable by the investigator in providing support to the subject toensure compliance with trial treatment, outpatient visits, and protocol procedures;
Diagnoses
6. Have a primary diagnosis of bipolar I disorder, current episode manic (DSM-IV 296.4×), or mixed (DSM-IV 296.6×) as determined by a structured clinical interview (Mini International Neuropsychiatric Interview [MINI]) at screening;
7. Have a Y-MRS score ≥20 at Screening and at Baseline;
8. Have a current manic or mixed bipolar I episode that must have begun no more than 3 months prior to the screening visit;
9. Have a documented history of at least one previous moderate-to-severe mood episode with or without psychotic features in the previous 5 years (manic or mixed);
Pre-trial medication
10. Have been continuously treated with lithium or VPA at a fixed dose for at least 2 weeks immediately prior to screening, with at least 1 therapeutic trough blood level of lithium (0.6-1.2 mmol/L) or valproate (50-125 mcg/mL) at least 14 days prior to screening and at screening; and
11. Have discontinued depot neuroleptics prior to baseline (discontinuation must have occurred at least 1 dosing cycle prior to baseline); |
|
| E.4 | Principal exclusion criteria |
Medical Status
1. An uncontrolled, unstable, clinically significant medical condition (eg, renal, endocrine, hepatic, respiratory, cardiovascular, hematologic, immunologic or cerebrovascular disease, or malignancy), including extreme obesity (body mass index [BMI] >35 kg/m2) or anorexia (BMI <18.5 kg/m2), that, in the opinion of the investigator, may interfere with the interpretation of safety and efficacy;
2. Clinically significant abnormal laboratory, vital sign, physical examination, or ECG findings identified during the screening process and which, in the investigator’s opinion, preclude the subject’s participation in the trial (interfere with the ability to evaluate safety, tolerability and efficacy of trial medication or impair completion of the trial as a result of non-medication related medical complications);
3. A positive result of the serum pregnancy test at screening (prospective subject and investigator will be notified), or the intent to become pregnant during the course of the trial;
4. Narrow angle glaucoma;
5. A seizure disorder beyond childhood or are taking anticonvulsants to preventseizures;
6. A urine drug screen that is positive for heroin, cocaine, or amphetamines (at the discretion of the investigator and after discussion with Pfizer or a designated representative, subjects with urine drug screen positive for other drugs may be eligible for admission, provided the subject does not meet any other exclusion criteria);
7. Known serological evidence of HIV antibody;
Psychiatric
8. Schizophrenia, schizoaffective disorder, or other psychotic disordersd;
9. A primary diagnosis other than bipolar I disorderd;
10. Borderline personality disorder (DSM-IV 301.83), antisocial personality disorder (DSM-IV 301.7), or mental retardation (DMS-IV 317, 318.x, 319)d;
11. Current (past 3 months) substance abuse or dependence (excluding nicotine)d;
12. An imminent risk of self-harm or harm to others;
13. An organic brain syndrome/disorder;
14. Had 9 or more (including current episode) mood episodes during the previous 12 months that met both the duration and symptom criteria for a Major Depressive, Manic, Mixed, or Hypomanic Episode. Each previous episode must be demarcated by either a period of full remission or by a switch to an episode of the opposite polarity. Manic, Hypomanic, and Mixed Episodes are counted as being on the same pole (eg, a Manic Episode immediately followed by a Mixed Episode counts as only 1 episode). Mood episodes directly caused by a substance (eg, cocaine, corticosteroids) or a general medical condition are not counted as a previous episode.)
15. Been hospitalized for 3 weeks or longer for the index manic or mixed episode;
16. A substance-induced psychotic disorder or a behavioral disturbance thought to be due to substance abuse;
Medication
17. Previously participated in an asenapine trial;
18. Taken an investigational drug within 30 days prior to baseline;
19. Been judged by the investigator to be medically noncompliant in the management of his/her disease;
20. Been judged by the investigator to be unable to reduce his or her daily lorazepamequivalent intake (as specified in the protocol) to a maximum of 4 mg per day during screening/washout, to a maximum of 2 mg per day during the first 7 days of randomized therapy, and to complete prohibition after the first 7 days of randomized therapy;
21. A history of hypersensitivity to, or neuroleptic malignant syndrome developing from, the administration of antipsychotic compounds;
22. A history of tardive dyskinesia;
23. A known allergy or hypersensitivity to asenapine;
24. Received clozapine for the treatment of bipolar disorder within 12 weeks or a monoamine oxidase inhibitor within 2 weeks prior to screening; or
25. Been unable to discontinue any excluded medications. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change from baseline, last observation carriedforward (LOCF), to Week 3 on the Y-MRS. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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.8.5 | The trial involves multiple Member States | No |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
| 30 days after last subject, last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 14 |
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