| 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 | PT |
| E.1.2 | Classification code | 10039626 |
| E.1.2 | Term | Schizophrenia |
| 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 |
1) To evaluate the efficacy and safety of cariprazine at a target dose of 4.5 mg/d compared with placebo in prevention of relapse in patients with schizophrenia;
2) 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
schizophrenia who were initially stabilized on a target dose of 4.5 mg/d
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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 |
1. Written informed consent has been obtained.
2. Patients are male or female, 18 to 64 years of age, inclusive.
3. Patient meets DSM-5 criteria for schizophrenia as determined by SCID-5.
4. Diagnosis of schizophrenia for a minimum of 1 year before Visit 1.
5. Current psychotic episode < 4 weeks duration at Visit 1.
6. PANSS total score ≥ 70 and ≤ 120 at Visit 1 and Visit 2.
7. Rating of at least 4 (moderate) on at least 2 of the following 4 PANSS positive symptoms; P1: delusions; P2: conceptual disorganization; P3: hallucinatory behavior; P6: suspiciousness/persecution at Visit 1 and Visit 2.
8. 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.
9. 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]).
10. 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.
11. Continue to meet all Visit 1 (Screening) inclusion criteria at Visit 2 (Baseline); to be assessed at Visit 2.
12. 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.
13. 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.
14. Negative qualitative serum β-human chorionic gonadotropin (β-hCG) pregnancy test (women of childbearing potential only). |
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| E.4 | Principal exclusion criteria |
Psychiatric Criteria
1.Currently meeting DSM-5 criteria for any of the following:Schizoaffective disorder, schizophreniform disorder, and other psychotic disorders, Bipolar I and II disorder, Autism spectrum disorder, intellectual development disorder, delirium, major/minor neurocognitive disorder
2.History of meeting DSM-5 criteria for substance-related disorders (ie,use disorders except caffeine-and tobacco-related) within the prior 3 months before Visit 1 3.Positive result at Visit 1 from the urine drug screen (UDS). Patients with a positive UDS at Visit 1 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 (except for benzodiazepines which may be continued if the patient has been taking a stable dose; and c)A repeat UDS must be performed prior to Visit 2 and must be negative, except benzodiazepine use as described 3(b)
4.History of intolerance or hypersensitivity to cariprazine or allowed rescue medications 5.The patient is at imminent risk of injuring self or others or causing significant damage to property, as judged by the investigator 6.The patient represents a suicide risk, as determined by meeting any of the following criteria: a)Patient made a suicide attempt within the past one year before Visit 1 b)Significant risk, as judged by the investigator, based on the psychiatric interview or information collected in the C-SSRS at Visit 1 (Screening) or Visit 2 (Baseline)
Treatment-Related Criteria: 7.Patient received treatment with depot antipsychotic within 2 cycles prior to Visit 18.Patient received treatment with clozapine doses > 50 mg/d in the past 2 years9.Patients requiring concomitant treatment with a moderate or strong cytochrome P450(CYP) 3A4 inhibitors or CYP3A4 inducers10.Patient 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 component11.At Visit 2, patient requires pharmacologic treatment for the control of EPS12.Prior participation in any clinical trials involving experimental or investigational drugs within 6 months before Visit 1 or planned during the study
Other Medical Criteria:
13.Female patients who are pregnant, planning to become pregnant during the course of the study, or are currently lactating14. Any concurrent medical condition including psychiatric symptoms possibly secondary to any other general medical condition (eg, Vitamin B-12/folate deficiency, Cushing syndrome, etc) that, in the judgment of the investigator, might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the patient’s well-being15.Any cardiovascular disease (eg, hypertension) or endocrinological disease (eg, thyroid disease/disorders) that is clinically unstable, or decompensated, based on the investigator’s judgment16.Gastric bypass or any condition that would be expected to affect drug absorption (lap band procedures and gastric sleeve are acceptable if there is no problem with absorption)17.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 seizure18.Patients who meet any of the following ophthalmological criteria:
a.A clinically significant finding of lens opacifications at the screening ophthalmological examination that meets:
1.Opacification ≥AREDS standard photo #2 OR 2.Best-corrected visual acuity worse than LogMar 0.1 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 (with the exception of cataract surgery to remove or replace lenses bilaterally) or laser treatment
c.History or current findings of ocular disease (eg, open-or narrow-angle glaucoma, retinopathies, corneal diseases)
d.History of amiodarone or systemic corticosteroid use for ≥ 3 consecutive months in the past year
e.Intraocular pressure of >21 mm Hg in either eye
f.Unable to dilate pupil to at least 5mm in either eye
All exclusion criteria are listed in Protocol section 4.4 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Is the time to first relapse during the DB treatment period.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Number of days from the randomization date to the relapse date.
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 |
| Korea, Democratic People's Republic of |
| Malaysia |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Taiwan |
| Thailand |
| 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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The end of the trial is defined as last patient last visit.
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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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 7 |
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