| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Bipolar I Disorder Major Depressive Episode |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 14.1 |
| 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 efficacy, safety, and tolerability of cariprazine relative to placebo in patients with bipolar depression |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent, signed or thumbprinted (only if allowed by local
regulations), 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-IV-TR criteria for bipolar I disorder without psychotic
features confirmed by the administration of the Structured Clinical Interview (SCID),
with a current major depressive episode of at least 4 weeks and not exceeding
12 months in duration
4. A verified previous manic or mixed episode. Verification must include one of the following sources;
○ Hospital records
○ Medical Records
○ Patient report corroborated by:
- family member, caretaker, or previous or current treating clinician with
confirmation of treatment with an anti-manic or antipsychotic medication
or
- confirmation of treatment with an anti-manic or antipsychotic medication
5. 17-item Hamilton Depression Rating Scale (HAMD-17) total score ≥ 20
6. HAMD-17 item 1 score ≥ 2
7. Clinical Global Impressions–Severity (CGI-S) score ≥ 4
8. Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test (women of
childbearing potential only)
9. Normal physical examination findings, clinical laboratory test results, and
electrocardiogram (ECG) results or abnormal results that are judged not clinically
significant by the PI and documented as such in the eCRF
10. Body mass index between 18 and 40, inclusive
Inclusion criteria to be assessed at Visit 2 (Baseline)
11. Continue to meet Visit 1 inclusion criteria
|
|
| E.4 | Principal exclusion criteria |
1. Young Mania Rating Scale (YMRS) total score > 10
2. Four or more episodes of a mood disturbance (depression, mania, hypomania, or
mixed state) within the 12 months before Visit 1
3. Principal DSM-IV-TR–based diagnosis of an axis I disorder other than bipolar
disorder or any axis I disorder other than bipolar disorder that was the primary focus
of treatment within 6 months before Visit 1 (secondary diagnoses of comorbid
generalized anxiety disorder, social anxiety disorder, or specific phobias are
acceptable)
4. History of meeting DSM-IV-TR criteria for:
a. Dementia, amnesic, or other cognitive disorder
b. Schizophrenia, schizoaffective, or other psychotic disorder
c. Mental retardation
5. DSM-IV-TR–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-IV-TR criteria for alcohol or substance abuse or dependence
(other than nicotine or caffeine) within the 6 months before Visit 1
7. Positive result on blood alcohol test or urine drug screen for methadone,
phencyclidine, amphetamines, or cocaine. (Patients with a positive urine drug screen
for cannabinoids, barbiturates, opiates, or benzodiazepines may be allowed in the
study provided that a discussion with the Medical Monitor has occurred and the use
of such products can be discontinued before participation in the study; medically
appropriate episodic use [up to 3 days] of narcotic analgesics for acute medical
indications is allowed during the study; discussion with Medical Monitor is
recommended).
8. History of intolerance or hypersensitivity to other drugs of the same class as
cariprazine or to rescue medications (see Section 9.4.7)
9. History of nonresponse in the current depressive episode to 2 or more adequate
treatment trials (at least 6 weeks at an adequate dose based on package insert
recommendations) with Symbyax (fluoxetine and olanzapine), quetiapine (including
monotherapy), lithium (including monotherapy) or a mood stabilizer (lithium,
valproate, lamotrigine, carbamazepine, or oxcarbazepine) in combination with an
antidepressant. Aripirazole was found ineffective for bipolar depression in 2 large
controlled trials. It should not be considered as a treatment failure for the history of
nonresponse exclusion criteria.
10. At imminent risk of injuring self or others or causing significant damage to property,
as judged by the PI
11. Suicide risk, as determined by meeting any of the following criteria:
○ A suicide attempt within the past year
○ Significant risk, as judged by the PI, based on the psychiatric interview or
information collected in the Columbia–Suicide Severity Rating Scale (C-SSRS)
○ HAMD-17 Item 3 score ≥ 3
○ MADRS Item 10 score ≥ 4
Treatment-Related Criteria:
12. Electroconvulsive therapy in the 3 months before Visit 1
13. Previous lack of response to electroconvulsive therapy
14. Treatment with a depot neuroleptic within 1 treatment cycle before Visit 1
15. Treatment with clozapine in the past 2 years (exceptions: episodic use of clozapine at
doses ≤ 150 mg/day for the treatment of insomnia)
16. Requiring concomitant treatment with any of the prohibited medications,
supplements, or herbal products listed in Appendix II, including any psychotropic
drug or any drug with psychotropic activity or with a potentially psychotropic
component, except for the following (refer to Section 9.4.7):
○ Eszopiclone, zolpidem, zolpidem extended-release, zopiclone, chloral hydrate or
zaleplon for insomnia
○ Lorazepam (or oxazepam or diazepam in countries where lorazepam is not readily
available)
○ Diphenhydramine, benztropine or equivalent (eg, trihexyphenidyl), or propranolol
for EPSs
17. Prior participation in any investigational study of RGH-188 or cariprazine
18. Previous treatment with vagus nerve stimulation, transcranial magnetic stimulation,
or any experimental central nervous system treatment within 6 months before Visit 1
19. 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. (Support meetings or counseling [eg, marital counseling] are
allowed provided they are no more frequent than weekly and do not have treatment of
depression as their objective)
20. Initiation or termination of phototherapy within the 2 weeks before screening, or
plans to initiate same during the course of the study
Other criteria;
Positive hepatitis C antibody on screening, unless:
○ The condition has been stable for ≥ 1 year,
○ The patient is not a candidate for antiviral therapy,
○ The hepatitis B core antibody total is nonreactive, and
○ The condition is judged by the PI not to interfere with the patient’s participation
in the study
Discussion with the medical monitor is required for these cases
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from Baseline to Week 6 in MADRS total score |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 4 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Argentina |
| Bulgaria |
| Canada |
| Colombia |
| Russian Federation |
| Ukraine |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
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