Schizophrenia
Conditions
Keywords
Schizophrenia
Brief summary
The purpose of this study is to compare retrospective hospitalization rates of schizophrenic patients treated with oral antipsychotics to prospective hospitalization rates of these patients treated with IM depot aripiprazole.
Detailed description
Nonadherence to antipsychotic medications remains a frequent cause of relapse among patients with schizophrenia, increasing hospitalization rates, hospitalization days, and hospitalization costs. Among hospitalized adults, schizophrenia is the fourth most commonly diagnosed illness and has the seventh longest mean duration of hospital stay in the US. Frequent relapses and hospitalization can affect quality of life in these patients. Long-acting injections (intramuscular depot) antipsychotic medication is a means to treatment adherence and increased quality of life for patients with schizophrenia.
Interventions
400 mg IM depot injection every 26-30 days. Dosage may be adjusted at the investigator's discretion to 300 mg. Number of injections: 6. Subjects have the option of entering the extension phase of the study and continuing with injections every 26-30 days until the drug is either commercially available, or December 2013.
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Subjects who are able to provide written informed consent. If the IRB requires consent by a legally acceptable representative in addition to the subject, all required consents must be obtained prior to any protocol-required procedure. * Male and female subjects 18 to 65 years of age, inclusive. * Current diagnosis of schizophrenia as defined by DSM-IV-TR criteria and a history of the illness for at least 1 year (12 months). * Subjects who in the investigator's judgment would benefit from extended treatment with a long-acting injectable formulation. * Subjects who have at least 1 inpatient psychiatric hospitalization in the 4 years (48 months) prior to screening, but have been managed as outpatients for the 4 weeks prior entering the study. * Subjects must have been on oral antipsychotic treatment for the full 7 months prior to the screening phase. * Subjects who have shown response to previous antipsychotic treatment. * Subjects who understand the nature of the trial and are able to follow the protocol requirements.
Exclusion criteria
* Prisoners or subjects who are compulsorily detained (involuntarily incarcerated), or have been incarcerated in the past 7 months for any reason must not be enrolled into this trial. * Subjects who may require potent CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers during the trial. * Any subject who requires or may need any other antipsychotic medications during the course of the trial, other than allowed rescue medication. * Subjects who are known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other quinolinones. * Subjects with a history of hypersensitivity to antipsychotic agents. * Subjects deemed intolerant of receiving injectable treatment. * Subjects who have received electroconvulsive therapy within the last 7 months prior to screening. * Subjects with a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia as assessed by the investigator. * 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 requiring hospitalization for any psychiatric reason during the 4 weeks prior to signing the ICF or during the screening period. * Subjects without at least 1 inpatient psychiatric hospitalization in the last 4 years (48 months) prior to screening. * Subjects who have met DSM-IV-TR criteria for any significant substance use disorder within 3 months prior to screening. * Subjects who are considered treatment-resistant to antipsychotic medication other than clozapine. * Treatment with long-acting injectable antipsychotics in which the last dose was within 7 months prior to screening. * Subjects who have not been treated with oral antipsychotics for 7 months prior to screening. * Subjects who have a significant risk of committing suicide * Subjects who have a history or evidence of a medical condition that would expose them to an undue risk of a significant adverse event or interfere with assessments of safety or efficacy during the course of the trial. * Females who are pregnant or lactating, sexually active males and females who will not commit to utilizing birth control during the trial and for up to 180 days following the trial. * Abnormal laboratory or physical examination results indicating a condition which may interfere with the results of the study or pose a safety risk to the subject. * Subjects who have previously enrolled in an aripiprazole IM depot clinical study, except for subjects entering this trial from the Canadian 31-11-284 trial. * Subjects who have participated in any clinical trial with an investigational agent within the past 30 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Inpatient Psychiatric Hospitalization for Retrospective Period (Months 4-6) and Prospective Period (Months 4-6). | Retrospective period Months 4-6; Prospective period Months 4-6 | The comparison of inpatient psychiatric hospitalization rates (proportion of patients with ≥ inpatient psychiatric hospitalizations) between the retrospective period months 4-6 (Weeks-12 to -24) while on oral standard of care antipsychotic treatment and the prospective period Phase B months 4-6 (Weeks 12 to 24) after the switch to aripiprazole IM depot. Open-label Aripiprazole IM Depot Treatment Phase 3-month Completer sample comprised of all participants who entered open-label aripiprazole IM depot treatment Phase and completed at least 3 months of treatment. This sample was used for the primary endpoint analysis (N=336). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in PANSS (Positive and Negative Syndrome Scale) Total Score. | Baseline to Week 24 | The PANSS consists of three subscales with a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicates (absence of symptoms) and a score of 7 indicates (extremely severe symptoms). The symptom constructs for each subscale are as follows: 7 Positive subscale symptom constructs, 7 Negative subscale symptom constructs and 16 General Psychopathology subscale symptom constructs. The PANSS total score ranges from 30 to 210. |
| Change From Baseline in PANSS Positive Subscale Score. | Baseline to Week 24 | The PANSS consists of three subscales with a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicates (absence of symptoms) and a score of 7 indicates (extremely severe symptoms). The symptom constructs for each subscale are as follows: 7 Positive subscale symptom constructs, 7 Negative subscale symptom constructs and 16 General Psychopathology subscale symptom constructs. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity suspiciousness/ persecution, and hostility. The PANSS Positive Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms). |
| Change From Baseline in PANSS Negative Subscale Score. | Baseline to Week 24 | The PANSS consists of three subscales with a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicates (absence of symptoms) and a score of 7 indicates (extremely severe symptoms). The symptom constructs for each subscale are as follows: 7 Positive subscale symptom constructs, 7 Negative subscale symptom constructs and 16 General Psychopathology subscale symptom constructs. The 7 negative symptom constructs are blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms). |
| Change From Baseline in Clinical Global Impression-Severity Score (CGI-S). | Baseline to Week 24 | The severity of illness for each participant were rated using the CGI-S scale. To assess CGI-S, study physician were to answer the following question: Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? Response choices included: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. |
| Mean Clinical Global Impression-Improvement Score (CGI-I) by Week. | Week 4, 12 and 24 | The efficacy of trial medication was rated for each participant using the CGI-I scale. The study physician would rate the participants total improvement whether or not it was entirely due to drug treatment. All responses were compared to the participants condition at Baseline of the appropriate phase. The CGI-I during Phase B were assessed relative to the participants condition at the Phase B Baseline visit. Response choices included: 0 = not assessed; 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; and 7 = very much worse. |
Countries
Canada, United States
Participant flow
Recruitment details
This study assessed hospitalization rates in adults with schizophrenia treated prospectively for 6 months with aripiprazole intramuscular depot compared with 6 month retrospective treatment with oral antipsychotics. The study comprised 3 phases: Tolerability/Cross-titration (Phase A), Open-label Aripiprazole (Phase B), Extension (Phase C).
Pre-assignment details
493 participants were enrolled, 325 of which had no history of tolerating oral aripiprazole entered Phase A, all participants completed Phase A combined with remainder of participants to enter Phase B. All outcome measures were assessed in Phase B.
Participants by arm
| Arm | Count |
|---|---|
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) In Phase B, all participants received aripiprazole IM depot 400 mg and had received supplemental oral aripiprazole for the first 14 days of Phase B (open-label aripiprazole IM depot treatment phase) for more than or equal to 3 months. However, at the discretion of the study physician, the dose of aripiprazole IM depot was decreased to 300 mg only if needed for tolerability and subsequently increased the dose to 400 mg for efficacy as required. This dose adjustment was permitted as often as necessary to maintain symptomatic stability with acceptable tolerability. For purposes of this study, participants who completed Week 24 of Phase B were defined as trial completers. | 433 |
| Total | 433 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extension Phase | Adverse Event | 0 | 0 | 10 |
| Extension Phase | Lost to Follow-up | 0 | 0 | 17 |
| Extension Phase | Met Withdrawal Criteria | 0 | 0 | 144 |
| Extension Phase | Physician Decision | 0 | 0 | 1 |
| Extension Phase | Sponsor Discontinued Trial | 0 | 0 | 7 |
| Extension Phase | Withdrawal by Subject | 0 | 0 | 13 |
| Tolerability/Cross-titration Phase | Adverse Event | 16 | 0 | 0 |
| Tolerability/Cross-titration Phase | Lack of Efficacy | 5 | 0 | 0 |
| Tolerability/Cross-titration Phase | Lost to Follow-up | 10 | 0 | 0 |
| Tolerability/Cross-titration Phase | Met Withdrawal Criteria | 5 | 0 | 0 |
| Tolerability/Cross-titration Phase | Physician Decision | 8 | 0 | 0 |
| Tolerability/Cross-titration Phase | Protocol Deviation | 1 | 0 | 0 |
| Tolerability/Cross-titration Phase | Withdrawal by Subject | 15 | 0 | 0 |
| Treatment Phase | Adverse Event | 0 | 37 | 0 |
| Treatment Phase | Lack of Efficacy | 0 | 10 | 0 |
| Treatment Phase | Lost to Follow-up | 0 | 33 | 0 |
| Treatment Phase | Met Withdrawal Criteria | 0 | 11 | 0 |
| Treatment Phase | Physician Decision | 0 | 5 | 0 |
| Treatment Phase | Protocol Deviation | 0 | 3 | 0 |
| Treatment Phase | Withdrawal by Subject | 0 | 41 | 0 |
Baseline characteristics
| Characteristic | Open-label Aripiprazole IM Depot Treatment Phase (Phase B) |
|---|---|
| Age, Continuous | 42.1 Years STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 132 Participants |
| Sex: Female, Male Male | 301 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 60 / 431 | 24 / 192 |
| serious Total, serious adverse events | 61 / 431 | 19 / 192 |
Outcome results
Primary
Number of Inpatient Psychiatric Hospitalization for Retrospective Period (Months 4-6) and Prospective Period (Months 4-6).
The comparison of inpatient psychiatric hospitalization rates (proportion of patients with ≥ inpatient psychiatric hospitalizations) between the retrospective period months 4-6 (Weeks-12 to -24) while on oral standard of care antipsychotic treatment and the prospective period Phase B months 4-6 (Weeks 12 to 24) after the switch to aripiprazole IM depot. Open-label Aripiprazole IM Depot Treatment Phase 3-month Completer sample comprised of all participants who entered open-label aripiprazole IM depot treatment Phase and completed at least 3 months of treatment. This sample was used for the primary endpoint analysis (N=336).
Time frame: Retrospective period Months 4-6; Prospective period Months 4-6
Population: The core dataset for all efficacy analyses is the Intent-to-Treat (ITT) dataset which consisted of data from all participants who entered Phase B regardless of receiving a dose in the Open-label Aripiprazole IM Depot Treatment Phase.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Number of Inpatient Psychiatric Hospitalization for Retrospective Period (Months 4-6) and Prospective Period (Months 4-6). | Retrospective period | 91 participants | 0.6 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Number of Inpatient Psychiatric Hospitalization for Retrospective Period (Months 4-6) and Prospective Period (Months 4-6). | Prospective period | 9 participants | 0.2 |
Comparison: Inpatient hospitalization for retrospective period (Months 4-6) and prospective period (Months 4-6) for closed or open unit.p-value: <0.0001McNemar
Secondary
Change From Baseline in Clinical Global Impression-Severity Score (CGI-S).
The severity of illness for each participant were rated using the CGI-S scale. To assess CGI-S, study physician were to answer the following question: Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? Response choices included: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients.
Time frame: Baseline to Week 24
Population: The core dataset for all efficacy analyses is the ITT dataset which consisted of data from all participants who entered Phase B regardless of receiving a dose in the Open-label Aripiprazole IM Depot Treatment Phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in Clinical Global Impression-Severity Score (CGI-S). | Week 4 (N= 391) | -0.3 Units on a scale | Standard Deviation 0.8 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in Clinical Global Impression-Severity Score (CGI-S). | Week 12 (N= 410) | -0.4 Units on a scale | Standard Deviation 0.9 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in Clinical Global Impression-Severity Score (CGI-S). | Week 24 (N= 410) | -0.5 Units on a scale | Standard Deviation 1 |
Comparison: Statistical analysEs for Week 4, 12 and 24.p-value: <0.0001t-test
Secondary
Change From Baseline in PANSS Negative Subscale Score.
The PANSS consists of three subscales with a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicates (absence of symptoms) and a score of 7 indicates (extremely severe symptoms). The symptom constructs for each subscale are as follows: 7 Positive subscale symptom constructs, 7 Negative subscale symptom constructs and 16 General Psychopathology subscale symptom constructs. The 7 negative symptom constructs are blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
Time frame: Baseline to Week 24
Population: The core dataset for all efficacy analyses is the ITT dataset which consisted of data from all participants who entered Phase B regardless of receiving a dose in the Open-label Aripiprazole IM Depot Treatment Phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in PANSS Negative Subscale Score. | Week 4 | -1.7 Units on a scale | Standard Deviation 4.6 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in PANSS Negative Subscale Score. | Week 12 | -1.6 Units on a scale | Standard Deviation 5.1 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in PANSS Negative Subscale Score. | Week 24 | -1.6 Units on a scale | Standard Deviation 5.8 |
Comparison: Statistical analysis for Week 4, 12 and 24.p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline in PANSS (Positive and Negative Syndrome Scale) Total Score.
The PANSS consists of three subscales with a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicates (absence of symptoms) and a score of 7 indicates (extremely severe symptoms). The symptom constructs for each subscale are as follows: 7 Positive subscale symptom constructs, 7 Negative subscale symptom constructs and 16 General Psychopathology subscale symptom constructs. The PANSS total score ranges from 30 to 210.
Time frame: Baseline to Week 24
Population: The core dataset for all efficacy analyses is the ITT dataset which consisted of data from all participants who entered Phase B regardless of receiving a dose in the Open-label Aripiprazole IM Depot Treatment Phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in PANSS (Positive and Negative Syndrome Scale) Total Score. | Week 4 (N= 390) | -7.9 Units on a scale | Standard Deviation 14 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in PANSS (Positive and Negative Syndrome Scale) Total Score. | Week 12 (N= 410) | -8.4 Units on a scale | Standard Deviation 15.6 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in PANSS (Positive and Negative Syndrome Scale) Total Score. | Week 24 (N= 410) | -8.4 Units on a scale | Standard Deviation 17.7 |
Comparison: Statistical analyses for Week 4, 12 and 24.p-value: <0.0001t-test
Secondary
Change From Baseline in PANSS Positive Subscale Score.
The PANSS consists of three subscales with a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicates (absence of symptoms) and a score of 7 indicates (extremely severe symptoms). The symptom constructs for each subscale are as follows: 7 Positive subscale symptom constructs, 7 Negative subscale symptom constructs and 16 General Psychopathology subscale symptom constructs. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity suspiciousness/ persecution, and hostility. The PANSS Positive Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
Time frame: Baseline to Week 24
Population: The core dataset for all efficacy analyses is the ITT dataset which consisted of data from all participants who entered Phase B regardless of receiving a dose in the Open-label Aripiprazole IM Depot Treatment Phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in PANSS Positive Subscale Score. | Week 4 (N= 390) | -2.7 Units on a scale | Standard Deviation 4.4 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in PANSS Positive Subscale Score. | Week 12 (N= 410) | -2.9 Units on a scale | Standard Deviation 4.9 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Change From Baseline in PANSS Positive Subscale Score. | Week 24 (N= 410) | -3.0 Units on a scale | Standard Deviation 5.4 |
Comparison: Statistical analyses for Week 4, Week 12 and Week 24.p-value: <0.0001t-test, 2 sided
Secondary
Mean Clinical Global Impression-Improvement Score (CGI-I) by Week.
The efficacy of trial medication was rated for each participant using the CGI-I scale. The study physician would rate the participants total improvement whether or not it was entirely due to drug treatment. All responses were compared to the participants condition at Baseline of the appropriate phase. The CGI-I during Phase B were assessed relative to the participants condition at the Phase B Baseline visit. Response choices included: 0 = not assessed; 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; and 7 = very much worse.
Time frame: Week 4, 12 and 24
Population: The core dataset for all efficacy analyses is the ITT dataset which consisted of data from all participants who entered Phase B regardless of receiving a dose in the Open-label Aripiprazole IM Depot Treatment Phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Mean Clinical Global Impression-Improvement Score (CGI-I) by Week. | Week 4 (N= 283) | 2.9 Units on a scale | Standard Deviation 0.9 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Mean Clinical Global Impression-Improvement Score (CGI-I) by Week. | Week 12 (N= 293) | 2.7 Units on a scale | Standard Deviation 1 |
| Open-label Aripiprazole IM Depot Treatment Phase (Phase B) | Mean Clinical Global Impression-Improvement Score (CGI-I) by Week. | Week 24 (N= 293) | 2.5 Units on a scale | Standard Deviation 1 |