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] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10037175 |
E.1.2 | Term | Psychiatric disorders |
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 |
The objective of this study is to evaluate the efficacy, safety, and tolerability of cariprazine 1.5 mg/day and 3.0 mg/day relative to placebo in patients with bipolar I depression. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria to be assessed at Visit 1 (Screening)
1. Written informed consent, signed, obtained from the patient before the initiation of any study-specific procedures
2. Male or female patients 18 to 65 years of age, inclusive
3. Currently meet the DSM-5 criteria for bipolar I disorder without psychotic features confirmed by the administration of the Mini International Neuropsychiatric Interview (MINI), with a current major depressive episode of at least 4 weeks and not
exceeding 12 months in duration
4. Currently treated as an outpatient at the time of enrolment
5. A verified previous manic or mixed episode. Verification must include one of the following sources:
a. Treatment of mania with an anti-manic agent (eg, lithium or divalproate) or antipsychotic medication with an approved indication for mania
b. Hospital records/Medical records
c. Patient report corroborated by caretaker or previous or current treating clinician
6. 17-item Hamilton Depression Rating Scale (HAMD-17) total score ≥ 20
7. HAMD-17 item 1 score ≥ 2
8. CGI-S score ≥ 4
9. Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test (women of childbearing potential only)
10. Normal physical examination, clinical laboratory test results, and electrocardiogram (ECG) results or abnormal findings that are judged not clinically significant by the PI
Inclusion criteria to be assessed at Visit 2 (Baseline)
11. Continue to meet Visit 1 inclusion criteria |
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E.4 | Principal exclusion criteria |
Exclusion criteria to be assessed at Visit 1 (Screening)
Psychiatric Criteria
1. Young Mania Rating Scale (YMRS) total score > 12
2. Four or more episodes of a mood disturbance (depression, mania, hypomania, or mixed state) within the 12 months before Visit 1
3. Any current axis 1 psychiatric diagnosis other than bipolar disorder with the exception of specific phobias
4. History of meeting DSM-5 criteria for Dementia, amnesic, or other cognitive disorder, Schizophrenia, schizoaffective, or other psychotic disorder or Mental retardation
5. DSM-5–based diagnosis of borderline or antisocial personality disorder or other axis II disorder of sufficient severity to interfere with participation in this study
6. History of meeting DSM-5 criteria for substance-related disorders (excluding caffeine-related and tobacco-related disorders) within the 6 months before Visit 1
7. Positive result on blood alcohol test or urine drug screen for any prohibited medication.
8. History of intolerance or hypersensitivity to cariprazine or to rescue medications
9. History of nonresponse in the current depressive episode to 2 or more antidepressant trials of adequate dose and treatment duration (at least 6 weeks at an adequate dose based on package insert recommendations) with or without mood stabilizers
10. Treatment failure of quetiapine, lurasidone, or Symbyax (fluoxetine and olanzapine) in the treatment of bipolar depression during the current depressive episode
11. At imminent risk of injuring self or others or causing significant damage to property, as judged by the PI
12. A patient who, in the PI’s judgment, cannot be safely treated as an outpatient
13. Suicide risk as determined by meeting the criteria listed in the protocol
Treatment-Related Criteria:
14. Electroconvulsive therapy in the 3 months before Visit 1
15. Previous lack of response to electroconvulsive therapy
16. Treatment with a depot antipsychotic drug within 6 months prior to Visit 1
17. Treatment with clozapine in a dose of > 50 mg/day in the past 2 years
18. Requiring concomitant treatment as per the protocol
19. Previous treatment with vagus nerve stimulation or transcranial magnetic stimulation within 6 months before Visit 1
20. Prior participation with any clinical trials, involving experimental or investigational drugs, within 6 months before Visit 1 or during the study
21. Initiation or termination of psychotherapy for depression within the 3 months preceding Visit 1, or plans to initiate, terminate, or change such therapy during the course of the study.
22. Initiation or termination of phototherapy within the 2 weeks before screening, or plans to initiate same during the course of the study
Other Medical Criteria:
23/24. Male/female patients who do not follow the contraception requirements of the study.
25. Any concurrent medical condition that, in the judgment of the PI, might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the patient’s well-being
26. Any cardiovascular disease that is clinically significant, unstable, or decompensated and other CV conditions as listed in the protocol
27. Hypothyroidism or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no change in dosage for at least 1 month before Visit 1
28. Hemoglobin A1c ≥ 6.5% on screening
29. Psychiatric symptoms possibly secondary to any other general medical condition
30. Gastric bypass or any condition that would be expected to affect drug absorption
31. History of seizure disorder, with the exception of febrile seizure, stroke, significant head injury, tumor of the central nervous system, or any other condition that predisposes toward a risk of seizure
32. Known history of cataracts or retinal detachment
33. Known human immunodeficiency virus infection
34. Positive hepatitis C antibody on screening
35. Positive test for hepatitis B surface antigen and/or hepatitis B core antibody immunoglobulin M
36. Screening liver enzyme test results > 2 x ULN or total bilirubin > 1 x ULN
37. History of tardive dyskinesia (except for mild cases attributed to use of conventional agents), or neuroleptic malignant syndrome
Other Criteria:
38. Employee, or immediate relative of an employee, of the Sponsor, any of its affiliates or partners, or the study center
39. Inability to speak, read, or understand the local language sufficiently to understand the nature of the study, to provide signed written informed consent, or to allow the completion of all study assessments
40. Unable or unlikely to comply with the study protocol or unsuitable for any other reason, as judged by the PI
Exclusion criteria to be assessed at Visit 2 (Baseline)
41. YMRS total score > 12
42. Suicide risk, as determined by meeting the criteria listed in the protocol
43. Any other Visit 1 exclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy will primarily be measured via the use of the clinician rated scales; Montgomery-Åsberg Depression Rating Scale (MADRS)
Safety will be measured via adverse event recording, clinical laboratory parameters (hematology, chemistry, urinalysis, prolactin), vital sign parameters, electrocardiograms, physical examinations, Young Mania Rating Scale (YMRS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Scale (SAS), and Columbia–Suicide Severity Rating Scale (C-SSRS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Various points throughout the study. |
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E.5.2 | Secondary end point(s) |
Clinical Global Impression-Severity |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Various points throughout the study. |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
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 | 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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Croatia |
Poland |
Romania |
Serbia |
Slovakia |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |