Schizophrenia
Conditions
Brief summary
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.
Interventions
Aripiprazole IM depot supplied as 200 mg or 400 mg vials of lyophilized aripiprazole powder to prepare for IM injection.
Aripiprazole tablets 10 mg once daily in the morning for 14 days.
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events as a Measure of Safety | 7 Months | 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. |
| Aripiprazole Maximum Steady State Plasma Concentration (Css,Max) | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 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. |
| Aripiprazole Minimum Steady State Plasma Concentration (Css,Min) | 672 hours post-dose at Month 5 | 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. |
| Aripiprazole Area Under the Concentration-time Curve at Steady-state (AUCτ) | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dehydro-aripiprazole Minimum Steady State Plasma Concentration (Css,Min) | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 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. |
| Dehydro-aripiprazole Area Under the Concentration-Time Curve at Steady-State (AUCτ) | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 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. |
| Dehydro-aripiprazole Maximum (Peak) Plasma Concentration (Tmax) | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 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. |
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12 and Week 24 | Baseline, Week 12, 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. |
| Aripiprazole Maximum (Peak) Plasma Concentration (Tmax) | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 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. |
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Negative Subscale Scores at Week 12 and Week 24 | Baseline, Week 12, 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. |
| Change From Baseline in the Clinical Global Impression- Severity of Illness Score (CGI-S) at Week 12 and Week 24 | Baseline, Week 12, 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. |
| Clinical Global Impression-Improvement Scale (CGI-I) at Week 12 and Week 24 | Baseline, Week 12, 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. |
| Number of Participants Hospitalized for Adverse Event Worsening Schizophrenia | 7 Months | 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. |
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Subscale Scores at Week 12 and Week 24 | Baseline, Week 12, 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. |
| Aripiprazole Steady-state Plasma Concentration (Css,Avg) | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 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. |
| Aripiprazole Terminal-phase Elimination Half-life (t1/2,z) | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 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. |
| Dehydro-aripiprazole Maximum Steady State Plasma Concentration (Css,Max) | Pre-dose and 1 to 1344 hours post-dose at Month 5 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 400 mg Aripiprazole IM Depot 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. | 14 |
| 300 mg Aripiprazole IM Depot 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. | 16 |
| 200 mg Aripiprazole IM Depot 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. | 11 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Subject met withdrawal criteria | 3 | 2 | 0 |
| Overall Study | Subject withdrawn by Investigator | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 5 |
Baseline characteristics
| Characteristic | 400 mg Aripiprazole IM Depot | 300 mg Aripiprazole IM Depot | 200 mg Aripiprazole IM Depot | Total |
|---|---|---|---|---|
| Age, Continuous | 46.8 years STANDARD_DEVIATION 9.2 | 43.3 years STANDARD_DEVIATION 9.6 | 46.0 years STANDARD_DEVIATION 12.7 | 45.2 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 1 Participants | 12 Participants |
| Sex: Female, Male Male | 7 Participants | 12 Participants | 10 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 14 | 10 / 15 | 6 / 10 |
| serious Total, serious adverse events | 0 / 14 | 3 / 15 | 0 / 10 |
Outcome results
Primary
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.
Time frame: Pre-dose and 1 to 1344 hours post-dose at Month 5
Population: Participants who received at least 3 doses of study medication and had pharmacokinetic (pK) samples collected through at least 672 hours following the 3rd or 4th dose are included in the efficacy pK analysis set. Data was missing for 1 patient in the 300 mg Aripiprazole IM Depot arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Aripiprazole Area Under the Concentration-time Curve at Steady-state (AUCτ) | 163 μg*h/mL | Standard Deviation 88.8 |
| 300 mg Aripiprazole IM Depot | Aripiprazole Area Under the Concentration-time Curve at Steady-state (AUCτ) | 140 μg*h/mL | Standard Deviation 58.4 |
| 200 mg Aripiprazole IM Depot | Aripiprazole Area Under the Concentration-time Curve at Steady-state (AUCτ) | 54.5 μg*h/mL | Standard Deviation 39.4 |
Primary
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.
Time frame: Pre-dose and 1 to 1344 hours post-dose at Month 5
Population: Participants who received at least 3 doses of study medication and had pharmacokinetic (pK) samples collected through at least 672 hours following the 5th dose are included in the efficacy pK analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Aripiprazole Maximum Steady State Plasma Concentration (Css,Max) | 316 ng/mL | Standard Deviation 160 |
| 300 mg Aripiprazole IM Depot | Aripiprazole Maximum Steady State Plasma Concentration (Css,Max) | 269 ng/mL | Standard Deviation 128 |
| 200 mg Aripiprazole IM Depot | Aripiprazole Maximum Steady State Plasma Concentration (Css,Max) | 100 ng/mL | Standard Deviation 68.4 |
Primary
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.
Time frame: 672 hours post-dose at Month 5
Population: Participants who received at least 3 doses of study medication and had pharmacokinetic (pK) samples collected through at least 672 hours following the 5th dose are included in the efficacy pK analysis set. Data was missing for 1 patient in the 200 mg Aripiprazole IM Depot arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Aripiprazole Minimum Steady State Plasma Concentration (Css,Min) | 212 ng/mL | Standard Deviation 113 |
| 300 mg Aripiprazole IM Depot | Aripiprazole Minimum Steady State Plasma Concentration (Css,Min) | 156 ng/mL | Standard Deviation 67.7 |
| 200 mg Aripiprazole IM Depot | Aripiprazole Minimum Steady State Plasma Concentration (Css,Min) | 95.0 ng/mL | Standard Deviation 86.2 |
Primary
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.
Time frame: 7 Months
Population: Participants who received at least one dose of study medication are included in the safety analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 400 mg Aripiprazole IM Depot | Number of Participants With Adverse Events as a Measure of Safety | 11 Participants |
| 300 mg Aripiprazole IM Depot | Number of Participants With Adverse Events as a Measure of Safety | 11 Participants |
| 200 mg Aripiprazole IM Depot | Number of Participants With Adverse Events as a Measure of Safety | 6 Participants |
Secondary
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.
Time frame: Pre-dose and 1 to 1344 hours post-dose at Month 5
Population: Participants who received study medication and had pharmacokinetic (pK) samples collected through at least 672 hours following the 5th dose are included in the efficacy pK analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 400 mg Aripiprazole IM Depot | Aripiprazole Maximum (Peak) Plasma Concentration (Tmax) | 7.1 Day |
| 300 mg Aripiprazole IM Depot | Aripiprazole Maximum (Peak) Plasma Concentration (Tmax) | 6.5 Day |
| 200 mg Aripiprazole IM Depot | Aripiprazole Maximum (Peak) Plasma Concentration (Tmax) | 5.0 Day |
Secondary
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.
Time frame: Pre-dose and 1 to 1344 hours post-dose at Month 5
Population: Participants who received study medication and had pharmacokinetic (pK) samples collected through at least 672 hours following the 5th dose are included in the efficacy pK analysis set. Data was missing for 1 patient in the 300 mg Aripiprazole IM Depot arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Aripiprazole Steady-state Plasma Concentration (Css,Avg) | 242 ng/mL | Standard Deviation 132 |
| 300 mg Aripiprazole IM Depot | Aripiprazole Steady-state Plasma Concentration (Css,Avg) | 208 ng/mL | Standard Deviation 87 |
| 200 mg Aripiprazole IM Depot | Aripiprazole Steady-state Plasma Concentration (Css,Avg) | 81.1 ng/mL | Standard Deviation 58.7 |
Secondary
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.
Time frame: Pre-dose and 1 to 1344 hours post-dose at Month 5
Population: Participants who received at least 3 doses of study medication and had pharmacokinetic (pK) samples collected through at least 672 hours following the 3rd or 4th dose are included in the efficacy pK analysis set. The analysis population for this outcome measure represents a sub-set who were evaluable for this measure at month 5.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Aripiprazole Terminal-phase Elimination Half-life (t1/2,z) | 46.5 Day | Standard Deviation 10.8 |
| 300 mg Aripiprazole IM Depot | Aripiprazole Terminal-phase Elimination Half-life (t1/2,z) | 29.9 Day | Standard Deviation 8 |
Secondary
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.
Time frame: Baseline, Week 12, Week 24
Population: All randomized participants with data available were included in this analysis population (LOCF).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Change From Baseline in the Clinical Global Impression- Severity of Illness Score (CGI-S) at Week 12 and Week 24 | Week 12 | -0.1 units on a scale | Standard Deviation 0.5 |
| 400 mg Aripiprazole IM Depot | Change From Baseline in the Clinical Global Impression- Severity of Illness Score (CGI-S) at Week 12 and Week 24 | Week 24 | -0.1 units on a scale | Standard Deviation 0.5 |
| 300 mg Aripiprazole IM Depot | Change From Baseline in the Clinical Global Impression- Severity of Illness Score (CGI-S) at Week 12 and Week 24 | Week 12 | 0.0 units on a scale | Standard Deviation 0.6 |
| 300 mg Aripiprazole IM Depot | Change From Baseline in the Clinical Global Impression- Severity of Illness Score (CGI-S) at Week 12 and Week 24 | Week 24 | -0.1 units on a scale | Standard Deviation 0.7 |
| 200 mg Aripiprazole IM Depot | Change From Baseline in the Clinical Global Impression- Severity of Illness Score (CGI-S) at Week 12 and Week 24 | Week 12 | -0.2 units on a scale | Standard Deviation 0.4 |
| 200 mg Aripiprazole IM Depot | Change From Baseline in the Clinical Global Impression- Severity of Illness Score (CGI-S) at Week 12 and Week 24 | Week 24 | -0.2 units on a scale | Standard Deviation 0.4 |
Secondary
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.
Time frame: Baseline, Week 12, Week 24
Population: All randomized participants with data available were included in this analysis population (LOCF).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Negative Subscale Scores at Week 12 and Week 24 | Week 12 | 1.1 units on a scale | Standard Deviation 4.4 |
| 400 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Negative Subscale Scores at Week 12 and Week 24 | Week 24 | 0.5 units on a scale | Standard Deviation 4.2 |
| 300 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Negative Subscale Scores at Week 12 and Week 24 | Week 12 | 0.1 units on a scale | Standard Deviation 3.2 |
| 300 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Negative Subscale Scores at Week 12 and Week 24 | Week 24 | -0.1 units on a scale | Standard Deviation 3.7 |
| 200 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Negative Subscale Scores at Week 12 and Week 24 | Week 12 | 0.0 units on a scale | Standard Deviation 2 |
| 200 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Negative Subscale Scores at Week 12 and Week 24 | Week 24 | -0.6 units on a scale | Standard Deviation 2 |
Secondary
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.
Time frame: Baseline, Week 12, Week 24
Population: All randomized participants with data available were included in this analysis population (LOCF).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Subscale Scores at Week 12 and Week 24 | Week 12 | -1.2 units on a scale | Standard Deviation 6.1 |
| 400 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Subscale Scores at Week 12 and Week 24 | Week 24 | -1.6 units on a scale | Standard Deviation 6.1 |
| 300 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Subscale Scores at Week 12 and Week 24 | Week 12 | 1.3 units on a scale | Standard Deviation 4 |
| 300 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Subscale Scores at Week 12 and Week 24 | Week 24 | 0.4 units on a scale | Standard Deviation 4.5 |
| 200 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Subscale Scores at Week 12 and Week 24 | Week 12 | -1.0 units on a scale | Standard Deviation 1.2 |
| 200 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Subscale Scores at Week 12 and Week 24 | Week 24 | -1.0 units on a scale | Standard Deviation 1.6 |
Secondary
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.
Time frame: Baseline, Week 12, Week 24
Population: All randomized participants with data available were included in this analysis population-last observation carried forward (LOCF).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12 and Week 24 | Week 12 | 0.0 units on a scale | Standard Deviation 20.2 |
| 400 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12 and Week 24 | Week 24 | -0.8 units on a scale | Standard Deviation 20.9 |
| 300 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12 and Week 24 | Week 12 | 1.1 units on a scale | Standard Deviation 12.1 |
| 300 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12 and Week 24 | Week 24 | -1.6 units on a scale | Standard Deviation 14.1 |
| 200 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12 and Week 24 | Week 12 | -1.3 units on a scale | Standard Deviation 4.8 |
| 200 mg Aripiprazole IM Depot | Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12 and Week 24 | Week 24 | -1.3 units on a scale | Standard Deviation 5.3 |
Secondary
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.
Time frame: Baseline, Week 12, Week 24
Population: All randomized participants with data available at the given time-point were included in this analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Clinical Global Impression-Improvement Scale (CGI-I) at Week 12 and Week 24 | Week 12 (n=12, 13, 9) | 3.3 units on a scale | Standard Deviation 0.9 |
| 400 mg Aripiprazole IM Depot | Clinical Global Impression-Improvement Scale (CGI-I) at Week 12 and Week 24 | Week 24 | 3.7 units on a scale | Standard Deviation 1 |
| 300 mg Aripiprazole IM Depot | Clinical Global Impression-Improvement Scale (CGI-I) at Week 12 and Week 24 | Week 12 (n=12, 13, 9) | 3.6 units on a scale | Standard Deviation 0.8 |
| 300 mg Aripiprazole IM Depot | Clinical Global Impression-Improvement Scale (CGI-I) at Week 12 and Week 24 | Week 24 | 3.4 units on a scale | Standard Deviation 0.7 |
| 200 mg Aripiprazole IM Depot | Clinical Global Impression-Improvement Scale (CGI-I) at Week 12 and Week 24 | Week 12 (n=12, 13, 9) | 3.4 units on a scale | Standard Deviation 0.7 |
| 200 mg Aripiprazole IM Depot | Clinical Global Impression-Improvement Scale (CGI-I) at Week 12 and Week 24 | Week 24 | 3.7 units on a scale | Standard Deviation 0.7 |
Secondary
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.
Time frame: Pre-dose and 1 to 1344 hours post-dose at Month 5
Population: Participants who received at least 3 doses of study medication and had pharmacokinetic (pK) samples collected through at least 672 hours following the 3rd or 4th dose are included in the efficacy pK analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Dehydro-aripiprazole Area Under the Concentration-Time Curve at Steady-State (AUCτ) | 47.8 μg*h/mL | Standard Deviation 19.1 |
| 300 mg Aripiprazole IM Depot | Dehydro-aripiprazole Area Under the Concentration-Time Curve at Steady-State (AUCτ) | 38.9 μg*h/mL | Standard Deviation 13.2 |
| 200 mg Aripiprazole IM Depot | Dehydro-aripiprazole Area Under the Concentration-Time Curve at Steady-State (AUCτ) | 14.7 μg*h/mL | Standard Deviation 9.47 |
Secondary
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.
Time frame: Pre-dose and 1 to 1344 hours post-dose at Month 5
Population: Participants who received at least 3 doses of study medication and had pharmacokinetic (pK) samples collected through at least 672 hours following the 3rd or 4th dose are included in the efficacy pK analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 400 mg Aripiprazole IM Depot | Dehydro-aripiprazole Maximum (Peak) Plasma Concentration (Tmax) | 6.6 Day |
| 300 mg Aripiprazole IM Depot | Dehydro-aripiprazole Maximum (Peak) Plasma Concentration (Tmax) | 12.5 Day |
| 200 mg Aripiprazole IM Depot | Dehydro-aripiprazole Maximum (Peak) Plasma Concentration (Tmax) | 5.5 Day |
Secondary
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.
Time frame: Pre-dose and 1 to 1344 hours post-dose at Month 5
Population: Participants who received at least 3 doses of study medication and had pharmacokinetic (pK) samples collected through at least 672 hours following the 3rd or 4th dose are included in the efficacy pK analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Dehydro-aripiprazole Maximum Steady State Plasma Concentration (Css,Max) | 89.4 ng/mL | Standard Deviation 37.9 |
| 300 mg Aripiprazole IM Depot | Dehydro-aripiprazole Maximum Steady State Plasma Concentration (Css,Max) | 74.7 ng/mL | Standard Deviation 20.8 |
| 200 mg Aripiprazole IM Depot | Dehydro-aripiprazole Maximum Steady State Plasma Concentration (Css,Max) | 30.3 ng/mL | Standard Deviation 19.8 |
Secondary
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.
Time frame: Pre-dose and 1 to 1344 hours post-dose at Month 5
Population: Participants who received at least 3 doses of study medication and had pharmacokinetic (pK) samples collected through at least 672 hours following the 3rd or 4th dose are included in the efficacy pK analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 400 mg Aripiprazole IM Depot | Dehydro-aripiprazole Minimum Steady State Plasma Concentration (Css,Min) | 64.1 ng/mL | Standard Deviation 27 |
| 300 mg Aripiprazole IM Depot | Dehydro-aripiprazole Minimum Steady State Plasma Concentration (Css,Min) | 54.1 ng/mL | Standard Deviation 21.1 |
| 200 mg Aripiprazole IM Depot | Dehydro-aripiprazole Minimum Steady State Plasma Concentration (Css,Min) | 26.2 ng/mL | Standard Deviation 24.7 |
Secondary
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.
Time frame: 7 Months
Population: All randomized participants were included in the analysis population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 400 mg Aripiprazole IM Depot | Number of Participants Hospitalized for Adverse Event Worsening Schizophrenia | 0 Participants |
| 300 mg Aripiprazole IM Depot | Number of Participants Hospitalized for Adverse Event Worsening Schizophrenia | 1 Participants |
| 200 mg Aripiprazole IM Depot | Number of Participants Hospitalized for Adverse Event Worsening Schizophrenia | 0 Participants |