Trial of Aripiprazole Intramuscular Depot (OPC-14597, Lu AF41155) in the Acute Treatment of Adults With Schizophrenia

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the overall efficacy of aripiprazole intramuscular (IM) depot as acute treatment in subjects with schizophrenia. The secondary purpose is to evaluate the safety and tolerability of aripiprazole IM depot administered every 4 weeks for 12 weeks to adult subjects with schizophrenia.

Official Title
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A 12-week, Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Aripiprazole Intramuscular Depot (OPC-14597, Lu AF41155) in the Acute Treatment of Adults With Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Aripiprazole IM Depot
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects 18 to 65 years of age, inclusive, at time of informed consent. Subjects with a diagnosis of schizophrenia for at least 1 year as defined by DSM-IV-TR criteria and confirmed by the MINI for Schizophrenia and Psychotic Disorders Studies. Subjects with a stable living environment when not in hospital. Subjects who would benefit from hospitalization or continued hospitalization for treatment of a current acute relapse of schizophrenia at trial entry. Subjects who are experiencing an acute exacerbation of psychotic symptoms and marked deterioration of usual function as demonstrated by meeting BOTH of the following at screening and baseline: Currently experiencing an acute exacerbation of psychotic symptoms accompanied by significant deterioration in the subject's clinical and/or functional status from their baseline clinical presentation with a Positive and Negative Syndrome Scale (PANSS) Total Score ≥ 80 AND Specific psychotic symptoms on the PANSS as measured by a score of > 4 on each of the following items (possible scores of 1 to 7 for each item) Conceptual disorganization (P2) Hallucinatory behavior (P3) Suspiciousness/persecution (P6) Unusual thought content (G9) Subjects who have received previous outpatient antipsychotic treatment at an adequate dose for an adequate duration and who showed a previous good response to such antipsychotic treatment (other than clozapine) in last 12 months. Subjects with a history of relapse and/or exacerbation of symptoms when not receiving antipsychotic treatment, excluding current episode. Subjects willing to discontinue all prohibited psychotropic medications to meet protocol required washouts prior to and during trial period. BMI less ≤ 40 kg/m2 (morbid obesity) at screening. Subjects who are able to provide written informed consent. Ability to understand the nature of trial and follow protocol requirements. Exclusion Criteria: Sexually active males of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 180 days after last dose of trial medication. Sexually active females of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 150 days after last dose of trial medication. Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving IMP in this trial. Subjects with improvement of ≥ 30% in total PANSS score between the screening and baseline assessments. - Subjects presenting with a first episode of schizophrenia - Subjects hospitalized for ≥ 30 days out of the last 90 days prior to screening visit. Subjects who have been hospitalized > 5 days for current acute episode at the time of screening visit Subjects with schizophrenia who are considered resistant/refractory to antipsychotic treatment Subjects who have a history of response to clozapine treatment only. Subjects with a current DSM-IV-TR Axis I diagnosis other than schizophrenia Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder or mental retardation. Subjects experiencing acute depressive symptoms within past 30 days that require treatment with an antidepressant. Subjects with a significant risk of violent behavior; who represent a risk of committing suicide as indicated by any suicidal ideation within the last 1 month or any suicidal behaviors within the last year; or who present a serious risk of suicide. Subjects with clinically significant tardive dyskinesia,. Subjects with severe akathisia. Subjects who have met DSM-IV-TR criteria for substance abuse with past 3 months prior to screening or dependence within past 6 months; including alcohol and benzodiazepines, but excluding caffeine and nicotine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aripiprazole IM Depot<br>Aripiprazole IM Depot 400 mg, with allowed decrease to 300 mg for safety and return to 400 mg for efficacy if needed, every four weeks for 12 weeks | Drug: Aripiprazole IM Depot<br> <br> * Other names: Lu AF41155;|
| Placebo Comparator: Placebo<br>Matching placebo | Drug: Placebo<br>* Matching Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to Endpoint in Positive and Negative Syndrome Scale (PANSS) Total Score. | The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 that indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. The PANSS total score was the sum of the rating scores for 7 positive subscale items, 7 negative subscale items, and 16 general psychopathology subscale items from the PANSS panel. PANSS Total Score ranged from 30 (best possible outcome) to 210 (worst possible outcome). The primary statistical comparison was performed using the Mixed Model Repeated Measure (MMRM) approach. | Baseline to Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to Endpoint in Clinical Global Impression-Severity Scale (CGI-S) Score. | The severity of illness for each participants were rated using the CGI-S scale. The study physician were to answer the following question: Considering your total experience with this particular population, how mentally ill is the patient at this time? Response choices included were: 0= not assessed; 1= normal; not at all ill; 2= borderline mentally ill; 3= mildly ill; 4= moderately ill; 5= markedly ill; 6= severely ill; and 7= among the most extremely ill participants. | Baseline to Week 10 | 
| Mean Change From Baseline to Endpoint in PANSS Positive Subscale Score. | The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity is rated on a 7-point scale, with a score of 1 indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. In positive subscale, the 7 positive symptom constructs were: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. PANSS Positive Subscale Score ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms). | Baseline to Week 10 | 
| Mean Change From Baseline to Endpoint in PANSS Negative Subscale Score. | The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicated- absence of symptoms and a score of 7 indicated- extremely severe symptoms. The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs were: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation and stereotyped thinking. PANSS Negative Subscale Score ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms). | Baseline to Week 10 | 
| Mean Change From Baseline to Endpoint in Personal and Social Performance Scale (PSP) Score. | The PSP was a validated clinician scale that measured personal and social functionining in 4 domains: socially useful activities eg, work and study), personal and social relationships, self-care, disturbing and aggressive behaviours. Impairement in each of these domains was rated as absent, mild, manifest, marked, severe, or very severe. These ratings were then converted to a total score based on a 100-point scale using algorithms to identify the appropriate 10-point interval and the study physician's judgement to determine the total score within the 10-point interval. Participants with a PSP total score of 71 to 100 were considered to have mild functional difficulty. Scores of 31 to 70 represented varying degrees of disability (31 to 70) and ratings of 1 to 30 indicated minimal functioning that required intense support and/or supervision. | Week 10 | 
| Mean Clinical Global Impression-Improvement Scale (CGI-I) Score at Endpoint. | The severity of illness for each participants were rated using the CGI-S scale. The study physician were to answer the following question: Considering your total experience with this particular population, how mentally ill is the patient at this time? Response choices included were: 0= not assessed; 1= normal; not at all ill; 2= borderline mentally ill; 3= mildly ill; 4= moderately ill; 5= markedly ill; 6= severely ill; and 7= among the most extremely ill participants. | Week 10 | 
| Responder Rate Based on PANSS Total Score. | Responder rate was defined as ≥30% reduction from Baseline in PANSS Total Score. PANSS Total Score ranged from 30 (best possible outcome) to 210 (worst possible outcome). | Week 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia