| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Mood, behavior, mental disorder |
|
| 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 | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10026753 |
| E.1.2 | Term | Manic and bipolar mood disorders and disturbances |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| 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 |
1) To evaluate the efficacy and safety of cariprazine at a target dose of 3.0 mg/d compared with placebo in prevention of relapse in patients with bipolar I disorder whose current episode (ie, index episode) is manic or depressive, with or without mixed features;
2) To evaluate the efficacy and safety of cariprazine at a target dose of 1.5 mg/d compared with placebo in prevention of relapse in patients with bipolar I disorder whose current episode (ie, index episode) is manic or depressive, with or without mixed features, who were initially stabilized on a target dose of 3.0 mg/d |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The following are requirements for entry into the study:
1. Written informed consent has been obtained.
2. Patients are male or female, 18 to 65 years of age, inclusive.
3. Patients meet DSM-5 criteria at both screening and baseline for one of the following:
a. DSM-5 criteria for bipolar I disorder current episode manic with or without
psychotic features; with or without mixed features, or
b. DSM-5 criteria for bipolar I disorder current episode depressive with or
without psychotic features; with or without mixed features
4. Patients meet one of the following at both screening and baseline (note: the same criterion must be met at both visits):
a.YMRS total score ≥ 20 and a score of at least 4 on 2 of the following YMRS items: irritability, speech, content, and disruptive/aggressive behavior, or
b.MADRS total score ≥ 23 and a score of at least 3 on 2 of the following MADRS items: apparent sadness, reported sadness, inner tension or inability to feel
5. Normal physical examination results, vital signs, clinical laboratory test results, and electrocardiogram (ECG) results or abnormal results that are judged not clinically significant by the investigator.
6. Written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable (eg, written authorization for use and release of health and research study information [US sites] and written data protection consent [EU sites]).
7. Ability to follow study instructions, complete study assessment tools with minimal assistance and no alteration to the assessment tools, and likely to complete all required visits.
8. Continue to meet all Visit 1 (Screening) inclusion criteria at Visit 2 (Baseline); to be assessed at Visit 2.
9. Each patient must have an identified external contact person or an identified responsible person (eg, family member, friend, social worker, case worker, or nurse) who is considered reliable by the investigator and who will provide support to the patient and act as an external contact in the event the site is having difficulty reaching the patient during the trial and to ensure observation of patient’s well being.
10. Male and female patients must agree to use a medically acceptable and highly effective method of birth control during the course of the entire study and for 12 weeks after the last dose of investigational product, as defined in Section 4.8.1.
11. Women of childbearing potential only must have a negative qualitative serum β-human chorionic gonadotropin (β-hCG) pregnancy test prior to enrollment. |
|
| E.4 | Principal exclusion criteria |
Psychiatric Criteria
1.4 or more episodes of a mood disturbance within the 12months before Visit1
2.Another psychiatric disorder other than bipolar disorder with the exception of specific phobias
3.Currently meeting DSM-5 criteria for any of the following:
a.Major/minor neurocognitive disorder,amnestic,or other neurocognitive disorders
b.Schizophrenia,schizoaffective disorder,and other psychotic disorders
c.Intellectual development disability
4.Known or suspected borderline or antisocial personality disorder or other DSM-5 personality disorders of sufficient severity to interfere with participation in this study
5.History of meeting DSM-5 criteria for substance-related disorders within 3months prior to Visit1
6.Positive result at Visit1 from the urine drug screen.Patients with a positive UDS at Visit1 for opiates,cannabinoids,amphetamines,barbiturates,or benzodiazepines may be enrolled if all of the following are satisfied:
a.The drug was used for a legitimate medical purpose
b.The drug can be discontinued prior to participation in the study
c.A repeat UDS must be performed prior to Visit2 and must be negative, except benzodiazepine use as described in 6(b)
7.History of intolerance or hypersensitivity to cariprazine or rescue medications
8.The patient is at imminent risk of injuring self or others or causing significant damage to property, as judged by the investigator
9.The patient represents a suicide risk, as determined by meeting any of the following criteria:
a.made a suicide attempt within the past year before Visit1
b.had a score of 4 or> on Item10 of the MADRS at Visit1(Screening) or Visit2(Baseline)
c.Significant risk, as judged by the investigator, based on the psychiatric interview or information collected in the C-SSRS at Visits1 or 2
Treatment-Related Criteria:
10.Patient had electroconvulsive therapy in the 3months prior to Visit1
11.Patient received treatment with depot antipsychotic within 6months prior to Visit1
12.Patient received treatment with clozapine doses >50mg/d in the past 2years
13.Patients requiring concomitant treatment with moderate or strong cytochrome P450(CYP) 3A4 inhibitors or CYP3A4 inducers. If applicable, these drugs must be discontinued 7days prior to Visit2/Baseline
14.Requires concomitant treatment with any prohibited medication, supplement, or herbal product including any psychotropic drug or any drug with psychotropic activity or with a potentially psychotropic component
15.Previous treatment with vagus nerve stimulation or transcranial magnetic stimulation within 6months before Visit1
16.Initiation or termination of psychotherapy within the 3months preceding Visit1,or plans to initiate,terminate,or change such therapy during the course of the study
17.Initiation or termination of phototherapy within the 2weeks before Visit1, or plans to initiate same during the course of the study
18.Prior participation in any clinical trials involving experimental or investigational drugs within 6months before Visit1 or during the study
Other Medical Criteria
19.Female patients who are pregnant, planning to become pregnant during the course of the study,or are currently lactating
20.Any concurrent medical condition that, in the judgment of the investigator, might interfere with the conduct of the study, confounds the interpretation of the study results, or endangers the patient’s well-being
21.Any cardiovascular disease or endocrinological disease that is clinically unstable or decompensated based on the investigator's judgment
22.Gastric bypass or any condition that would be expected to affect drug absorption
23.History of seizure disorder, stroke, significant head injury, tumor of the central nervous system, or any other condition that predisposes toward a risk of seizure
24.Patients who meet any of the following ophthalmologic criteria
a.A clinically significant finding of lens opacifications at the screening ophthalmologic examination that meets:
1.Opacification≥AREDS standard photo#2 OR 2.Best-corrected visual acuity worse than LogMar0.1 OR 3.Cataract surgery is planned or expected at anytime during the trial
b.Any clinically significant ocular trauma or complications of ocular trauma, or history of retinal detachment, intraocular surgery or laser treatment
c.History or current findings of ocular disease
d.History of amiodarone or systemic corticosteroid use for ≥3 consecutive months in the past year
e.Intraocular pressure of >21mm Hg in either eye
f.Unable to dilate pupil to at least 5mm in either eye
25.Allergies to dilating drops, optic medications, or topical ocular anesthetics that are to be used in the ophthalmologic examination
26.Known human immunodeficiency virus infection
27.Positive hepatitisC antibody on screening
28.Positive test for hepatitisB surface antigen and/or hepatitis B core antibody immunoglobulin M on screening
29.Screening liver enzyme test results >2× the upper limit of normal or total bilirubin >1×ULN |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy parameter is the time to first relapse of any mood episode during the DB treatment period.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The time to first relapse is defined as the number of days from randomization to
the first relapse. |
|
| E.5.2 | Secondary end point(s) |
| The primary efficacy parameter is the time to first relapse of any mood episode during the DB treatment period. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The time to first relapse is defined as the number of days from randomization to
the first relapse. |
|
| 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 | Yes |
| 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 | 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Korea, Democratic People's Republic of |
| Malaysia |
| Taiwan |
| Thailand |
| United States |
| Poland |
| Bulgaria |
| Romania |
| Russian Federation |
| Serbia |
| Ukraine |
|
| 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
|
| The end of the trial is defined as last patient last visit. |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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