A Multiple Dose Safety, Tolerability and Pharmacokinetics Study in Adult Patients With Schizophrenia Following Administration of Aripiprazole IM Depot

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability, efficacy and pharmacokinetics of aripiprazole intramuscular (IM) depot multiple doses every 4 weeks in adult patients with schizophrenia.

Official Title
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An Open-label Parallel Arm Multiple Dose Tolerability, Pharmacokinetics and Safety Study in Adult Patients With Schizophrenia Following Administration of Aripiprazole IM Depot Formulation Once Every Four Weeks

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: aripiprazole IM depot
* Drug: aripiprazole tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosis of schizophrenia as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria good physical health as determined by normal medical history, clinical laboratory results, electrocardiograms (ECGs) and physical examinations ability to provide informed consent and/or consent from a legally acceptable representation body mass index (BMI) of 18 to 35 kg/m^2 Exclusion Criteria: sexually active males and females of child-bearing potential who are not practicing double barrier birth control or are not abstinent during the study plus 30 days for female or 90 days for males following the last dose of medication history of drug or alcohol abuse within 6 months and/or positive urine drug screen participants who consume alcohol beverages routinely participants who consume alcohol beverages during the screening period use of any antipsychotic medication, other prohibited psychotropic medication, and any cytochrome P450 2D6 (CYP2D6) and cytochrome P450 3A4 (CYP3A4) inhibitors or CYP3A4 inducers within 14 days use of any prescription medication unless approved by Medical Monitor or Study Director history of current hepatitis or carrier of HBsAg (Hepatitis B surface antigen) and/or Hepatitis C Virus antibodies (anti-HCV) females who are pregnant or lactating participants who have participated in any clinical trial involving a psychotropic medication within one month prior to enrollment; participants who have participated in a previous IM Depot study within the last 1 year; patients who have previously enrolled and received study medication in an aripiprazole IM Depot clinical trial donation of blood or plasma to a blood bank or in a clinical study (except a screening visit)within 30 days prior to enrollment any major surgery within 30 days prior to enrollment blood transfusion within 30 days prior to enrollment evidence of organ dysfunction or any clinically significant deviation from normal in the physical, electrocardiographic, or clinical laboratory examinations patient represents a significant risk of committing suicide based on history patients currently in an acute relapse patients with Axis I (DSM-IV) diagnosis of schizoaffective or bipolar disorder patients who are considered treatment-resistant to antipsychotic medication patients with a history of neuroleptic malignant syndrome any other sound medical reason as determined by the clinical investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 400 mg Aripiprazole IM Depot<br>400 mg aripiprazole IM (intramuscular) depot intramuscular injection once every 4 weeks for 5 months. All participants were on a stable dose of 10 mg aripiprazole tablets once daily in the morning for at least 14 days prior to randomization and continued 10 mg aripiprazole tablets once daily on days 1 to 14. | Drug: aripiprazole IM depot<br>* Aripiprazole IM depot supplied as 200 mg or 400 mg vials of lyophilized aripiprazole powder to prepare for IM injection.<br>Drug: aripiprazole tablets<br>* Aripiprazole tablets 10 mg once daily in the morning for 14 days.<br>|
| Experimental: 300 mg Aripiprazole IM Depot<br>300 mg aripiprazole IM depot intramuscular injection once every 4 weeks for 5 months. All participants were on a stable dose of 10 mg aripiprazole tablets once daily in the morning for at least 14 days prior to randomization and continued 10 mg aripiprazole tablets once daily on days 1 to 14. | Drug: aripiprazole IM depot<br>* Aripiprazole IM depot supplied as 200 mg or 400 mg vials of lyophilized aripiprazole powder to prepare for IM injection.<br>Drug: aripiprazole tablets<br>* Aripiprazole tablets 10 mg once daily in the morning for 14 days.<br>|
| Experimental: 200 mg Aripiprazole IM depot<br>200 mg aripiprazole IM depot intramuscular injection once every 4 weeks for 5 months. All participants were on a stable dose of 10 mg aripiprazole tablets once daily in the morning for at least 14 days prior to randomization and continued 10 mg aripiprazole tablets once daily on days 1 to 14. | Drug: aripiprazole IM depot<br>* Aripiprazole IM depot supplied as 200 mg or 400 mg vials of lyophilized aripiprazole powder to prepare for IM injection.<br>Drug: aripiprazole tablets<br>* Aripiprazole tablets 10 mg once daily in the morning for 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety | Safety and tolerability was assessed by the number of participants with adverse events (AE). An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a subject while enrolled in the study, whether or not it was considered drug-related by the investigator. Abnormal laboratory test findings were considered AEs if, in the opinion of the investigator, they represented an abnormal (ie, clinically significant) change from baseline for that individual participant. | 7 Months | 
| Aripiprazole Maximum Steady State Plasma Concentration (Css,Max) | Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values for Css,max were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection. | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 
| Aripiprazole Minimum Steady State Plasma Concentration (Css,Min) | Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values for Css,min were determined directly from the observed data at 672 hours after the fifth monthly injection. | 672 hours post-dose at Month 5 | 
| Aripiprazole Area Under the Concentration-time Curve at Steady-state (AUCτ) | Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values of AUCτ were estimated using the linear trapezoidal rule during each dosing interval from 0 to 1344 hours post-dose. | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aripiprazole Maximum (Peak) Plasma Concentration (Tmax) | Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values for tmax were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection. | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 
| Aripiprazole Steady-state Plasma Concentration (Css,Avg) | Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values for Css,avg were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection. | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 
| Aripiprazole Terminal-phase Elimination Half-life (t1/2,z) | Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values for t1/2,z were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection. | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 
| Dehydro-aripiprazole Maximum Steady State Plasma Concentration (Css,Max) | Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for dehydro-aripiprazole. Values for Css,max were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection. | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 
| Dehydro-aripiprazole Minimum Steady State Plasma Concentration (Css,Min) | Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for dehydro-aripiprazole. Values for Css,min were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection. | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 
| Dehydro-aripiprazole Area Under the Concentration-Time Curve at Steady-State (AUCτ) | Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for dehydro-aripiprazole. Values of AUCτ were estimated using the linear trapezoidal rule during each dosing interval from 0 to 1344 hours post-dose. | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 
| Dehydro-aripiprazole Maximum (Peak) Plasma Concentration (Tmax) | Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for dehydro-aripiprazole. Values for tmax were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection. | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12 and Week 24 | The PANSS consisted of 3 subscales with a total of 30 symptom constructs each rated on a 7-point scale where 1=absence of symptoms to 7=extremely severe symptoms. The Positive Subscale consisted of 7 positive symptom constructs with a possible subscale score of 7 to 49, the Negative Subscale consisted of 7 negative symptom constructs with a possible subscale score of 7 to 49 and the General Psychopathology Subscale consisted of 16 symptom constructs for a possible subscale score of 16 to 112. The PANSS Total Score ranged from 30 (best) to 210 (worst; indicating more severe symptoms). A Negative change from Baseline indicated improvement. | Baseline, Week 12, Week 24 | 
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Subscale Scores at Week 12 and Week 24 | The PANSS Positive Subscale consisted of 7 symptom constructs: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. Severity was rated on a 7-point scale where 1=absence of symptoms to 7=extremely severe symptoms. The total score on the Positive Subscale ranged from 7 to 49 with a higher score indicating more severe symptoms. A Negative change from Baseline indicated improvement. | Baseline, Week 12, Week 24 | 
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Negative Subscale Scores at Week 12 and Week 24 | The PANSS Negative Subscale consisted of 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. Severity was rated on a 7-point scale where 1=absence of symptoms to 7=extremely severe symptoms. The total score on the Negative Subscale ranged from 7 to 49 with a higher score indicating more severe symptoms. A negative change from Baseline indicated improvement. | Baseline, Week 12, Week 24 | 
| Change From Baseline in the Clinical Global Impression- Severity of Illness Score (CGI-S) at Week 12 and Week 24 | The severity of illness for each participant was rated using the CGI-S scale. The investigator answered the following question: Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? using an 8-point scale where 0=not assessed to 7=among the most extremely ill patients. A negative change from Baseline indicated improvement. | Baseline, Week 12, Week 24 | 
| Clinical Global Impression-Improvement Scale (CGI-I) at Week 12 and Week 24 | The participant's overall improvement was rated for each participant using the CGI-I scale. The investigator rated the participant's total improvement by answering the following question: Compared to his/her condition at baseline (prior to randomization), how much has the patient changed? using an 8-point scale where 0=not assessed, 1=very much improved to 7=very much worse. Lower scores indicated improvement. | Baseline, Week 12, Week 24 | 
| Number of Participants Hospitalized for Adverse Event Worsening Schizophrenia | The number of participants hospitalized for the Adverse Event Worsening Schizophrenia included all participants who were hospitalized for any Adverse Event pertaining to the exacerbation of schizophrenic symptoms. | 7 Months |