Schizophrenia
Conditions
Keywords
Aripiprazole, Intramuscular (IM) depot, Schizophrenia
Brief summary
The purpose of the this trial is to evaluate the efficacy, safety, and tolerability of an intramuscular (IM) depot formulation of aripiprazole as maintenance treatment in patients with schizophrenia The trial is designed into three treatment phases. Phase 1 is designed to allow for a subject to be converted from the current anti-psychotic treatment to oral non-generic aripiprazole monotherapy (oral conversion phase from 4 to 6 weeks). During Phase 2 the subject will be stabilized on oral non-generic aripiprazole monotherapy. Once the subject is stabilized in Phase 2 (oral stabilization phase from minimum 8 weeks to maximum 28 weeks), they are eligible to be randomized into the double-blind IM depot maintenance phase, Phase 3. During Phase 3, the subject will be assessed for exacerbation of psychotic symptoms and impending relapse for up to 38 weeks.
Detailed description
This will be a randomized, double-blind, active-controlled study consisting of a screening phase and 3 treatment phases. Eligibility will be determined during a screening phase of 2 to 42 days. Subjects currently receiving oral treatment with an anti-psychotic other than non-generic aripiprazole will enter Phase 1, and subjects with a lapse in aripiprazole or other anti-psychotic treatment at the time of study entry ("lapse" defined as \> 3 consecutive days without medication) will enter directly into Phase 2. During Phase 1 (oral conversion), subjects will be cross-titrated during weekly visits from other anti-psychotics to oral non-generic aripiprazole monotherapy over a minimum of 4 weeks and a maximum of 6 weeks. During Phase 2 (that will be a minimum of 8 weeks and a maximum of 28 weeks in duration), subjects will be assessed bi-weekly and stabilized on an oral dose of aripiprazole ranging from 10 mg to 30 mg daily. After stability criteria are met at Phase 2, subjects are eligible to be randomized into the double-blind IM depot maintenance phase, Phase 3. Subjects will be randomized with a 2:2:1 (aripiprazole IM depot 300-400 mg monthly, oral aripiprazole 10-30 mg daily, aripiprazole IM depot 25-50 mg monthly). During Phase 3 subjects will be assessed for impending relapse/exacerbation of psychotic symptoms. If a subject is identified with impending relapse/exacerbation of psychotic symptoms, they will be withdrawn from the trial and given the opportunity to enroll into an open-label aripiprazole IM depot trial, 31-08-248 (NCT00731549). Alternatively, any subject that discontinues in Phase 3 (up to and including Week 38) will have the option to enroll into an open-label aripiprazole IM depot trial, 31-08-248 (NCT00731549). The enrollment figure includes re-screened patients.
Interventions
DRUGAripiprazole depot 300 or 400 mg
Aripiprazole depot was supplied in 400 mg lyophilized vials. Patients received aripiprazole 300 mg if they were unable to tolerate aripiprazole 400 mg.
DRUGAripiprazole 10-30 mg orally
Aripiprazole was supplied as 10, 15, and 20 mg tablets. The dose that the patient received was based on the investigator's judgment and the subject's clinical need.
DRUGAripiprazole depot 25 or 50 mg
Aripiprazole depot was supplied in 200 mg lyophilized vials. Patients received aripiprazole 25 mg if they were unable to tolerate aripiprazole 50 mg.
DRUGPlacebo depot
Placebo depot was supplied in lyophilized vials.
DRUGPlacebo tablets
Placebo tablets were identical in appearance to the aripiprazole tablets.
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Subjects who are able to provide written informed consent and/or consent obtained from a legally acceptable representative (as required by Institutional Review Board/Independent Ethics Committee \[IRB/IEC\]), prior to the initiation of any protocol-required procedures. * Male and female subjects 18 to 60 years of age, inclusive, at time of informed consent. * Subjects with a current diagnosis of schizophrenia as defined by Diagnostic and Statistical Manual of Mental Disorders, version 4, Text Revision (DSM-IV-TR) criteria and a history of the illness for at least 3 years prior to screening. * Subjects who, in the investigator's judgment, require chronic treatment with an anti-psychotic medication. * Subjects able to understand the nature of the study and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, IM depot injection, discontinuation of prohibited concomitant medications, who can read and understand the written word in order to complete patient-reported outcome measures, and who can be reliably rated on assessment scales.
Exclusion criteria
* Subjects with a current DSM-IV-TR diagnosis other than schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar disorder, delirium, dementia, amnestic, or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder. * Subjects with schizophrenia that are considered resistant/refractory to antipsychotic treatment by history or response only to clozapine. * Subjects with a significant risk of violent behavior or a significant risk of committing suicide based on history or investigator's judgment. * Subjects who currently meet DSM-IV-TR criteria for substance dependence; including alcohol and benzodiazepines, but excluding caffeine and nicotine, or 2 positive drug screens for cocaine. * Subjects who are known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other quinolinones, or hypersensitivity to anti-psychotic agents, including aripiprazole. * Subjects with a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia at screening. * Subjects with uncontrolled thyroid function abnormalities. * Subjects with a history of seizures, neuroleptic malignant syndrome, clinically significant tardive dyskinesia, or other medical condition that would expose the subject to undue risk or interfere with study assessments. * Subjects who are involuntarily incarcerated. * Subjects who have undergone electroconvulsive therapy within 180 days of entry into Phase 2. * Subjects who have used an investigational agent within 30 days of screening; and prior participation in a clinical study with aripiprazole IM depot. * Subjects with clinically significant abnormalities in laboratory test results, vital signs, or ECG results. * Subjects hospitalized for more than 30 days in the 90 days prior to Phase 1 (or Phase 2 for subjects bypassing Phase 1). * Subjects requiring more than 1 benzodiazepine beyond screening (eg, lorazepam and oxazepam). * Subjects who fail to wash-out from prohibited concomitant medications, including the use of CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers, antipsychotics, antidepressants (including monoamine oxidase inhibitors \[MAOI\]), and mood stabilizers, during screening and Phase 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria by the End of Week 26 | Baseline to Week 26 | A patient had exacerbation of psychotic symptoms/impending relapse if they met any of the following 4 criteria. 1) Clinical Global Impression of Improvement score ≥ 5 and either an increase on any of the following Positive and Negative Syndrome Scale (PANSS) items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score \> 4 with an increase of ≥ 2 on that item since randomization or an increase on any of the same PANSS items to a score \> 4 and an increase of ≥ 4 on the same combined PANSS items since randomization, 2) Hospitalization due to worsening of psychotic symptoms, 3) Clinical Global Impression of Severity of Suicide (CGI-SS) score of 4 or 5 on Part 1 and/or 6 or 7 on Part 2, or 4) Violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Exacerbation of Psychotic Symptoms/Impending Relapse | Baseline to the end of the study (Week 38) | — |
| Percentage of Responders up to Week 38 | Baseline to the end of the study (Week 38) | A patient was considered to be a responder if all of the following criteria were met. 1) Outpatient status, 2) PANSS total score ≤ 80, 3) Lack of 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, suspiciousness, hallucinatory behavior, unusual thought content, and 4) Clinical Global Impression of Severity of Illness (CGI-S) ≤ 4 (moderately ill) and 5) CGI-SS ≤ 2 (mildly suicidal) on Part 1 and ≤ 5 (minimally worsened) on Part 2. |
| Percentage of Patients Achieving Remission | Baseline to the end of the study (Week 38) | A patient was considered to have achieved remission if they had a score of ≤ 3 on each of the following PANSS items, maintained for a period of 6 months: Delusions (P1), unusual thought content (G9), hallucinatory behavior (P3), conceptual disorganization (P2), mannerisms/posturing (G5), blunted affect (N1), social withdrawal (N4), and lack of spontaneity (N6). |
Countries
Austria, Belgium, Bulgaria, Chile, Croatia, Estonia, France, Hungary, Italy, Poland, Puerto Rico, South Africa, South Korea, Thailand, United States
Participant flow
Pre-assignment details
There were 3 phases in this study. In phases 1 and 2 (Conversion Phase and Oral Stabilization Phase), there was 1 reporting group. In phase 3 (Depot Maintenance Phase), there were 3 reporting groups. All Outcome Measures were assessed in the Depot Maintenance Phase of the study.
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole Depot 300 or 400 mg - Depot Maintenance Phase Patients received aripiprazole 300 mg or 400 mg depot intramuscularly every 28 days for 38 weeks. | 265 |
| Aripiprazole 10-30 mg Orally - Depot Maintenance Phase Patients received aripiprazole 10-30 mg orally daily for 38 weeks. | 266 |
| Aripiprazole Depot 25 or 50 mg - Depot Maintenance Phase Patients received aripiprazole 25 mg or 50 mg depot intramuscularly every 28 days for 38 weeks. | 131 |
| Total | 662 |
Baseline characteristics
| Characteristic | Aripiprazole Depot 300 or 400 mg - Depot Maintenance Phase | Aripiprazole 10-30 mg Orally - Depot Maintenance Phase | Aripiprazole Depot 25 or 50 mg - Depot Maintenance Phase | Total |
|---|---|---|---|---|
| Age, Continuous | 41.7 years STANDARD_DEVIATION 10.4 | 41.2 years STANDARD_DEVIATION 10.8 | 40.2 years STANDARD_DEVIATION 9.6 | 40.7 years STANDARD_DEVIATION 10.4 |
| Sex/Gender, Customized Female | 105 Participants | 98 Participants | 53 Participants | 256 Participants |
| Sex/Gender, Customized Male | 160 Participants | 168 Participants | 78 Participants | 406 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| other Total, other adverse events | 140 / 709 | 177 / 842 | 161 / 265 | 142 / 266 | 74 / 131 |
| serious Total, serious adverse events | 21 / 709 | 39 / 842 | 15 / 265 | 15 / 266 | 11 / 131 |
Outcome results
Primary
Percentage of Patients Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria by the End of Week 26
A patient had exacerbation of psychotic symptoms/impending relapse if they met any of the following 4 criteria. 1) Clinical Global Impression of Improvement score ≥ 5 and either an increase on any of the following Positive and Negative Syndrome Scale (PANSS) items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score \> 4 with an increase of ≥ 2 on that item since randomization or an increase on any of the same PANSS items to a score \> 4 and an increase of ≥ 4 on the same combined PANSS items since randomization, 2) Hospitalization due to worsening of psychotic symptoms, 3) Clinical Global Impression of Severity of Suicide (CGI-SS) score of 4 or 5 on Part 1 and/or 6 or 7 on Part 2, or 4) Violent behavior resulting in clinically significant self-injury, injury to another person, or property damage.
Time frame: Baseline to Week 26
Population: Intent-to-treat population: All randomized patients.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Aripiprazole Depot 300 or 400 mg - Depot Maintenance Phase | Percentage of Patients Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria by the End of Week 26 | 7.12 Percentage of patients | 1.62 |
| Aripiprazole 10-30 mg Orally - Depot Maintenance Phase | Percentage of Patients Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria by the End of Week 26 | 7.76 Percentage of patients | 1.72 |
| Aripiprazole Depot 25 or 50 mg - Depot Maintenance Phase | Percentage of Patients Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria by the End of Week 26 | 21.80 Percentage of patients | 3.97 |
Comparison: Sample sizes were estimated to achieve 93% power for the primary non-inferiority 2-sided comparison at 0.05 significance using large sample normal approximations for the distribution of the difference in binomial proportions. The assumed proportion of impending relapse at or before Week 26 for the oral aripiprazole 10-30 mg arm was 18% and the predefined non-inferiority margin was 11.5%. The sample size was projected to be 260 each for the IM depot 300 or 400 mg and oral 10-30 mg arms.p-value: 0.787195% CI: [-5.26, 3.99]z-statistics
Comparison: For the superiority comparison (assay sensitivity analysis) of IM depot 300 or 400 mg to IM depot 25 or 50 mg, on a 2:1 randomization, sample sizes of 260 and 130, respectively, were calculated to provide about 95% power at the 0.05 significance level (2-sided). A superiority margin of 17% was assumed.p-value: 0.000695% CI: [-23.09, -6.27]z-statistics
Secondary
Percentage of Patients Achieving Remission
A patient was considered to have achieved remission if they had a score of ≤ 3 on each of the following PANSS items, maintained for a period of 6 months: Delusions (P1), unusual thought content (G9), hallucinatory behavior (P3), conceptual disorganization (P2), mannerisms/posturing (G5), blunted affect (N1), social withdrawal (N4), and lack of spontaneity (N6).
Time frame: Baseline to the end of the study (Week 38)
Population: Intent-to-treat population: All randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aripiprazole Depot 300 or 400 mg - Depot Maintenance Phase | Percentage of Patients Achieving Remission | 48.8 Percentage of patients |
| Aripiprazole 10-30 mg Orally - Depot Maintenance Phase | Percentage of Patients Achieving Remission | 53.2 Percentage of patients |
| Aripiprazole Depot 25 or 50 mg - Depot Maintenance Phase | Percentage of Patients Achieving Remission | 59.7 Percentage of patients |
p-value: 0.37z-statistics
p-value: 0.1097z-statistics
Secondary
Percentage of Responders up to Week 38
A patient was considered to be a responder if all of the following criteria were met. 1) Outpatient status, 2) PANSS total score ≤ 80, 3) Lack of 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, suspiciousness, hallucinatory behavior, unusual thought content, and 4) Clinical Global Impression of Severity of Illness (CGI-S) ≤ 4 (moderately ill) and 5) CGI-SS ≤ 2 (mildly suicidal) on Part 1 and ≤ 5 (minimally worsened) on Part 2.
Time frame: Baseline to the end of the study (Week 38)
Population: Intent-to-treat population: All randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aripiprazole Depot 300 or 400 mg - Depot Maintenance Phase | Percentage of Responders up to Week 38 | 89.8 Percentage of patients |
| Aripiprazole 10-30 mg Orally - Depot Maintenance Phase | Percentage of Responders up to Week 38 | 89.4 Percentage of patients |
| Aripiprazole Depot 25 or 50 mg - Depot Maintenance Phase | Percentage of Responders up to Week 38 | 75.2 Percentage of patients |
p-value: 0.875z-statistics
p-value: 0.0001z-statistics
Secondary
Time to Exacerbation of Psychotic Symptoms/Impending Relapse
Time frame: Baseline to the end of the study (Week 38)
Population: Intent-to-treat population: All randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aripiprazole Depot 300 or 400 mg - Depot Maintenance Phase | Time to Exacerbation of Psychotic Symptoms/Impending Relapse | NA Days |
| Aripiprazole 10-30 mg Orally - Depot Maintenance Phase | Time to Exacerbation of Psychotic Symptoms/Impending Relapse | NA Days |
| Aripiprazole Depot 25 or 50 mg - Depot Maintenance Phase | Time to Exacerbation of Psychotic Symptoms/Impending Relapse | NA Days |