| 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 |
|
| 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 | 10039626 |
| E.1.2 | Term | Schizophrenia |
| 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 of brexpiprazole compared
with placebo as maintenance treatment in adults with
schizophrenia. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of brexpiprazole as maintenance treatment in adults with schizophrenia. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects who are able to provide written informed consent
2. Ability, in the opinion of the principal investigator, to understand the nature of the trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, and discontinuation of prohibited concomitant medication, and to be reliably rated on assessment scales.
3. Subjects with a stable living environment, as demonstrated by the ability to provide contact information for themselves and/or family/friend(s)/caregiver(s).
4. Male and female subjects 18 to 65 years of age
5. Subjects with a current diagnosis of schizophrenia, as defined by DSM-IV-TR criteria and a history of the illness for at least three years prior to screening
6. Subjects who showed previous response to antipsychotic treatment (other than clozapine) in the past year, according to the investigator’s opinion.
7. Subjects who are currently being treated with oral or depot antipsychotics other than clozapine or who have had a recent lapse in antipsychotic treatment and who, in the opinion of the investigator, require chronic treatment with antipsychotic medication and could potentially benefit from monotherapy treatment with oral brexpiprazole for schizophrenia.
8. Subjects who are experiencing a current exacerbation of psychotic symptoms as demonstrated by a PANSS Total Score > 80 at screening.
9. Subjects with a history of relapse and/or exacerbation of symptoms when they are not receiving antipsychotic treatment.
10. Subjects willing to discontinue all prohibited psychotropic medications to meet protocol-required washouts at screening and during the trial period.
Inclusion Criteria Assessed Prior to Entry into Phase A
- Subject has completed washout of specific prohibited medications required for Phase A
Inclusion Criteria Assessed Prior to Entry into Phase B
- Subject has completed washout of all prohibited medications required for Phase B
- Subject is ready to receive oral brexpiprazole as monotherapy for treatment of schizophrenia at the
final dose achieved in Phase A
OR
- Subject is ready to receive oral brexpiprazole as monotherapy for treatment of schizophrenia at a
starting dose of 1 mg/day for subjects entering Phase B directly after screening.
Inclusion Criteria Assessed Prior to Entry into Phase C
- Subject is receiving monotherapy with single-blind brexpiprazole (1 to 4 mg/day) and the dose has
been stable for at least the last 4 weeks prior to randomization into Phase C.
Subject meets ALL of the following criteria for 12 weeks
- Outpatient status
- PANSS Total Score ≤ 70
- A score of ≤ 4 (moderate) on each of the following PANSS items
• Conceptual disorganization
• Suspiciousness
• Hallucinatory behavior
• Unusual thought content
- CGI-S score ≤ 4
- No current suicidal behavior as assessed by the C-SSRS
- No evidence of aggressive or violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. |
|
| E.4 | Principal exclusion criteria |
1. Sexually active females of childbearing potential and male subjects who are not practicing two different methods of birth control with their partner during the trial and for 30 days after the last dose of trial medication or who will not remain abstinent during the trial and for 30 days after the last dose
2. Females who are breast-feeding and/or who have a positive pregnancy test result
3. Subjects presenting with a first episode of schizophrenia based on the clinical judgment of the investigator.
4. Subjects with a current DSM-IV-TR Axis I diagnosis other than schizophrenia including, but not limited to schizoaffective disorder, MDD, bipolar disorder, posttraumatic stress disorder, anxiety disorders, delirium, dementia, amnestic or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder or mental retardation.
5. Subjects experiencing acute depressive symptoms within the past 30 days, according to the investigator’s opinion, that require treatment with an antidepressant.
6. Subjects with schizophrenia who are considered resistant/refractory to antipsychotic treatment by history or who have a history of failure to respond to clozapine or response to clozapine treatment only.
7. Subjects with a significant risk of violent behavior; who represent a risk of committing suicide as indicated by any suicidal ideation within the last 6 months or any suicidal behaviors within the last two years; or who in the clinical judgment of the investigator present a serious risk of suicide.
8. Subjects with clinically significant tardive dyskinesia at enrollment, as determined by a score of 3 on Item 8 of the AIMS at Screening.
9. Subjects with a score of 5 (severe akathisia) on the BARS global clinical assessment of akathisia at Screening, Baseline of Phase A, End of Phase A, or Baseline of Phase B.
10. Subjects who have met DSM-IV-TR criteria for substance abuse or dependence within the past 180 days; including alcohol and benzodiazepines, but excluding caffeine and nicotine.
11. Subjects with hypothyroidism or hyperthyroidism (unless condition has been stabilized with medications for at least the past 90 days) and/or an abnormal result for free T4 at Screening
12. Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders such as any history of myocardial infarction, congestive heart failure, HIV seropositive status/acquired immunodeficiency syndrome, or chronic hepatitis B or C
13. Subjects currently treated with insulin for diabetes. Subjects being treated for diabetes with medications other than insulin are eligible for the trial if their condition is stable
14. Subjects with uncontrolled hypertension, symptomatic hypotension, or orthostatic hypotension
15. Subjects with known ischemic heart disease or history of myocardial infarction, congestive heart failure, angioplasty, stenting or coronary artery bypass surgery.
16. Subjects with epilepsy or a history of seizures, except for a single seizure episode, for instance childhood febrile seizure, post traumatic, or alcohol withdrawal.
17. Subjects with a positive drug screen for cocaine or other drugs of abuse
18. Subjects who previously participated in any prior brexpiprazole clinical trial
19. Subjects with a history of neuroleptic malignant syndrome
20. Subjects who participated in a clinical trial within the last 180 days or who participated in more than two clinical trials within the past year.
21. Subjects with a history of neuroleptic malignant syndrome (NMS).
22. Subjects with a history of true allergic response (ie, not intolerance) to more than one class of medications.
23. Any subject who, in the opinion of the investigator or medical monitor, should not participate in the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this trial is the time from randomization to exacerbation of psychotic symptoms/impending relapse in Phase C, defined as meeting any of the following four criteria:
1) CGI-I score ≥ 5 (minimally worse) AND
• an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score of > 4 with an absolute increase of ≥ 2 on that specific item since randomization OR
• an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score of > 4 and an absolute increase of ≥ 4 on the combined four PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) since randomization
OR
2) Hospitalization due to worsening of psychotic symptoms (including partial hospitalization programs), but excluding hospitalization for psychosocial reasons (eg, homelessness or need for shelter that is unrelated to the subject’s underlying psychiatric condition) OR
3) Current suicidal behavior as assessed by the C-SSRS (ie, an answer of “yes” to any of the questions on the Suicidal Behavior section of the C-SSRS) OR
4) Violent or aggressive behavior resulting in clinically significant self-injury, injury to another person, or property damage.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time from randomization to exacerbation of psychotic symptoms |
|
| E.5.2 | Secondary end point(s) |
Percentage of subjects meeting exacerbation of psychotic symptoms/impending relapse criteria
Other secondary efficacy endpoints evaluated for Phase C will include:
• Proportion of subjects meeting stability criteria at endpoint in each treatment group
• Change from baseline to endpoint in PANSS Total Score
• Change from baseline to endpoint in CGI-S score
• Change from baseline to endpoint in PANSS positive subscale score
• Change from baseline to endpoint in PANSS negative subscale score
• Change from baseline to endpoint in CGI-S score
• CGI-I score at endpoint
• Change from baseline to endpoint in PSP score
• Change from baseline to endpoint in Global Assessment of Functioning scale (GAF) score
• Time to discontinuation due to all causes
• Change from baseline to endpoint in PANSS Excited Component (PEC) score
• Change from baseline to endpoint in PANSS Marder Factor Scores
|
|
| 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 | Yes |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 Trial Date is defined as the last Date of Contact or the Date of Final Contact Attempt from the Post-treatment Follow-up eCRF page for the last subject completing or withdrawing from the trial. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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