Psychotic Disorders, Schizophrenia
Conditions
Keywords
Schizophrenia, relapse prevention, Antipsychotic agents, Long-acting risperidone, Quetiapine, Aripiprazole
Brief summary
The purpose of this study is to investigate whether a long-acting injectable formulation of risperidone provides better effectiveness over 2 years, as measured by the time to relapse, compared with quetiapine tablets in a routine psychiatric care setting. Aripiprazole will be investigated in a descriptive manner.
Detailed description
Although many schizophrenia patients currently take oral antipsychotic medications, it is estimated that up to 75% of them have difficulty adhering to the daily oral regimen. Long-acting injectable formulations may eliminate the need for daily medication and enhance patient compliance with the treatment regimen. This is an open-label (all people involved know the identity of the intervention), randomized (study drug assigned by chance) study of a formulation of risperidone (coated microspheres) injected into the muscle at 2 week intervals over 104 weeks in stable patients with schizophrenia or schizoaffective disorder, who are being treated with oral risperidone, olanzapine, or other conventional antipsychotic agents. A comparator group will receive tablets of quetiapine to be taken 2 or 3 times daily, depending on the optimal dosage. In countries where aripiprazole is available, aripiprazole was also included in a descriptive manner. Reasons for switching symptomatically stable patients from their current antipsychotic treatment include insufficient effectiveness of the medication on symptoms, adverse events, or a patient's request. The principal measure of effectiveness of the drug is the time to relapse. Assessments of effectiveness also include: Positive and Negative Syndrome Scale (PANSS), which measures the symptoms of schizophrenia; overall severity of illness measured by the Clinical Global Impression subscale (CGI-S); patient's condition measured by the Clinical Global Impression condition subscale (CGI-C); quality of life assessed by the SF-12 survey. Safety evaluations include incidence of adverse events, Extrapyramidal Symptoms Rating Scale (ESRS), clinical laboratory tests (biochemistry, haematology, and urinalysis), and vital signs (pulse, blood pressure). The study hypothesis is that treatment with long-acting risperidone injected intramuscularly every 2 weeks provides better effectiveness than quetiapine, as measured by time to relapse, in patients with schizophrenia or schizoaffective disorder. Risperidone injections 25mg biweekly for 104 weeks, increasing or decreasing (increments of 12.5mg) at investigator's discretion. Risperidone tablets (2mg daily for 2 days) for patients starting on risperidone. Quetiapine and Aripiprazole used according to package insert.
Interventions
DRUGAripiprazole
10-30 mg oral once daily for 104 weeks
25 mg injection every 2 weeks until week 104. Dosage may be increased or decreased in steps of 12.5 mg. Additional oral risperidone can be administered as required until a dose increase becomes effective.
DRUGQuetiapine
Oral tablets are titrated from 50 mg daily to 300-400 mg daily in first 4 days. Subsequently treatment is maintained for 104 weeks and dosage can be adjusted with increments or decrements of 25 to 50 mg.
Sponsors
Janssen-Cilag International NV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Diseases, 4th edition (DSM-IV) * Patients currently treated with oral risperidone, olanzapine or a conventional neuroleptic monotherapy at doses not exceeding 6 mg risperdal, 20 mg olanzapine, or a conversion dose of 10 mg haloperidol for oral conventional agents * Patients who are stable (judged clinically stable by the investigator and on a stable dose of medication for 4 weeks or longer) but not optimally treated (non-satisfactory treatment regarding symptoms or adverse events)
Exclusion criteria
* Diagnosis other than schizophrenia or schizoaffective disorder by DSM-IV Axis I criteria * Patients being treated with antipsychotic agents other than oral risperidone, olanzapine or conventional oral neuroleptic agents * Patients with known hypersensitivity to oral risperidone, quetiapine, aripiprazole, or who are known non-responders to oral risperidone, quetiapine, aripiprazole or to previous treatment with at least 2 antipsychotic agents * Patients treated with mood stabilizers or antidepressants who are not on stable dose for at least 3 months before study initiation * Pregnant or nursing females, or those lacking adequate contraception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Relapse Free Period(Risperidone LAI Versus Quetiapine) | Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier) | Relapse was defined as meeting any of the predefined criteria (adapted from Csernansky et al., 2002) on 2 consecutive evaluations during treatment, 3 to 5 days apart. The relapse rate in each treatment arm was estimated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Relapse Free Period (Exploratory/Aripiprazole) | Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier) | As for risperidone and quetiapine, relapse was defined as meeting any of the predefined criteria (adapted from Csernansky et al., 2002) on 2 consecutive evaluations during treatment, 3 to 5 days apart. Since aripiprazole was new on the market at the time the study was conducted, this aripiprazole analysis was exploratory. |
| Change From Baseline to Endpoint in Total Positive and Negative Syndrome Scale (PANSS) Score | Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier) | The neuropsychiatric symptoms of schizophrenia were assessed by means of the 30-item PANSS scale. The PANSS scale provides a total score (sum of the scores of all 30 items) and scores for 3 subscales, i.e., the positive subscale (7 items), the negative subscale (7 items), and the general psychopathology subscale (16 items). Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme). |
| Change From Baseline to Endpoint in Clinical Global Impression Scale (CGI) Score | Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Month 24 or earlier) | The 7-point CGI scale of Severity (CGI-S) was used to assess the severity of a subject's psychotic condition (0= normal, not at all ill, 1= borderline, etc. and 6= among the most extremely ill subjects). |
| Change From Baseline to Endpoint in Short-Form Health Survey 12 (SF-12) Scores | Assessed at the moment the subject was randomized to a treatment arm (baseline visit) and after 1, 3, 6, 12, 18, and 24 months of treatment | Quality of life was assessed by means of the 12-item SF-12® survey. Two parameters, i.e., PCS (physical component summary) and MCS (mental component summary) were calculated. Both components scores range from 0 to 100 with higher scores indicating better QOL. |
Countries
Austria, Bulgaria, Croatia, Czechia, Denmark, Estonia, France, Germany, Greece, Hungary, Ireland, Israel, Latvia, Lithuania, Poland, Portugal, Romania, Saudi Arabia, Slovakia, Slovenia, Spain, Sweden, Turkey (Türkiye), United Kingdom
Participant flow
Recruitment details
Subjects had a diagnosis of schizophrenia or schizoaffective disorder (according to the Diagnostic and Statistical Manual of Mental Disorders - 4th edition \[DSM-IV\]) and were treated with oral risperidone, olanzapine, or conventional oral neuroleptic monotherapy at screening. They were to be symptomatically stable but not optimally treated.
Participants by arm
| Arm | Count |
|---|---|
| Risperidone LAI intramuscular injection, dose of 25, 37.5, or 50 mg every 2 weeks | 329 |
| Quetiapine oral, target dose of 300-400 mg b.i.d. or t.i.d. | 337 |
| Total | 666 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative Reasons | 1 | 1 | 0 |
| Overall Study | Adverse Event | 6 | 10 | 1 |
| Overall Study | Death | 2 | 0 | 0 |
| Overall Study | Higher dose/Extra Medication Required | 2 | 0 | 2 |
| Overall Study | Lack of Efficacy | 4 | 3 | 0 |
| Overall Study | Lost to Follow-up | 10 | 9 | 1 |
| Overall Study | No Further Need for Treatment | 3 | 4 | 1 |
| Overall Study | Non-compliance | 0 | 4 | 1 |
| Overall Study | Other | 0 | 0 | 1 |
| Overall Study | Patient Moved | 2 | 2 | 0 |
| Overall Study | Pregnancy | 0 | 1 | 1 |
| Overall Study | Protocol Deviation | 5 | 1 | 0 |
| Overall Study | Refuses Injection | 11 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 59 | 72 | 9 |
Baseline characteristics
| Characteristic | Risperidone LAI | Quetiapine | Total |
|---|---|---|---|
| Age, Continuous | 40.6 years STANDARD_DEVIATION 12.48 | 42.6 years STANDARD_DEVIATION 13.14 | 41.6 years STANDARD_DEVIATION 12.85 |
| Body Mass Index (BMI) | 27.6 kg/m2 STANDARD_DEVIATION 5.23 | 27.0 kg/m2 STANDARD_DEVIATION 5.32 | 27.3 kg/m2 STANDARD_DEVIATION 5.28 |
| Race/Ethnicity, Customized Arab | 5 participants | 4 participants | 9 participants |
| Race/Ethnicity, Customized Black | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 320 participants | 330 participants | 650 participants |
| Race/Ethnicity, Customized Hispanic | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Oriental | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Pakistani | 0 participants | 1 participants | 1 participants |
| Sex: Female, Male Female | 134 Participants | 146 Participants | 280 Participants |
| Sex: Female, Male Male | 195 Participants | 191 Participants | 386 Participants |
| Weight | 80.4 kg STANDARD_DEVIATION 16.93 | 79.0 kg STANDARD_DEVIATION 17.75 | 79.7 kg STANDARD_DEVIATION 17.35 |
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 | 201 / 329 | 213 / 337 | 28 / 45 |
| serious Total, serious adverse events | 63 / 329 | 77 / 337 | 7 / 45 |
Outcome results
Primary
Mean Relapse Free Period(Risperidone LAI Versus Quetiapine)
Relapse was defined as meeting any of the predefined criteria (adapted from Csernansky et al., 2002) on 2 consecutive evaluations during treatment, 3 to 5 days apart. The relapse rate in each treatment arm was estimated using the Kaplan-Meier method.
Time frame: Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier)
Population: Efficacy analysis set, defined as all subjects who received at least 1 dose of study medication and who had at least 1 efficacy assessment after baseline. This excluded 2 subjects of the risperidone LAI arm and 11 of the quetiapine arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Risperidone LAI | Mean Relapse Free Period(Risperidone LAI Versus Quetiapine) | 607 days | Standard Deviation 11.4 |
| Quetiapine | Mean Relapse Free Period(Risperidone LAI Versus Quetiapine) | 533 days | Standard Deviation 15.6 |
Comparison: Null hypothesis was that there is no difference in treatment effect between risperidone LAI and quetiapine by mean relapse free period; given a estimated relapse rate of 30% for risperidone LAI and 42% for quetiapine, with 80% power and 5% 2-tailed significance level, 251 subjects were needed per treatment arm. To adjust for an estimated 20% discontinuations for reasons other than relapse, 628 subjects in total were needed. Actual relapse rates were 17% (risperidone LAI) and 31% (quetiapine).p-value: <0.0001Log Rank
Secondary
Change From Baseline to Endpoint in Clinical Global Impression Scale (CGI) Score
The 7-point CGI scale of Severity (CGI-S) was used to assess the severity of a subject's psychotic condition (0= normal, not at all ill, 1= borderline, etc. and 6= among the most extremely ill subjects).
Time frame: Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Month 24 or earlier)
Population: Efficacy analysis set, defined as all subjects who received at least 1 dose of study medication and had at least 1 efficacy assessment after baseline. This excluded 2 subjects of the risperidone LAI arm, 11 of the quetipaine arm, and 1 of the aripiprazole arm. One additional subject in the risperidone LAI arm did not have CGI data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Risperidone LAI | Change From Baseline to Endpoint in Clinical Global Impression Scale (CGI) Score | -0.3 units on a scale | Standard Deviation 1.25 |
| Quetiapine | Change From Baseline to Endpoint in Clinical Global Impression Scale (CGI) Score | 0.1 units on a scale | Standard Deviation 1.24 |
| Aripiprazole | Change From Baseline to Endpoint in Clinical Global Impression Scale (CGI) Score | -0.1 units on a scale | Standard Deviation 1.32 |
Comparison: Between-group comparison of the change from baseline to endpoint in CGI-S score. The endpoint of the study was based on the LOCF principle.p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: Within-group comparison of the change from baseline to endpoint in CGI-S score. The endpoint of the study was based on the LOCF principle.p-value: <0.0001Wilcoxon signed-rank test
Comparison: Within-group comparison of the change from baseline to endpoint in CGI-S score. The endpoint of the study was based on the LOCF principle.p-value: 0.0446Wilcoxon signed-rank test
Secondary
Change From Baseline to Endpoint in Short-Form Health Survey 12 (SF-12) Scores
Quality of life was assessed by means of the 12-item SF-12® survey. Two parameters, i.e., PCS (physical component summary) and MCS (mental component summary) were calculated. Both components scores range from 0 to 100 with higher scores indicating better QOL.
Time frame: Assessed at the moment the subject was randomized to a treatment arm (baseline visit) and after 1, 3, 6, 12, 18, and 24 months of treatment
Population: Efficacy analysis set, defined as all subjects who received at least 1 dose of study medication and had at least 1 efficacy assessment after baseline. This excluded 2 subjects of the risperidone LAI, 11 of the quetipaine, and 1 of the aripiprazole arm. An additional 32, 32, and 2 subjects in the respective arms did not have SF-12 data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Risperidone LAI | Change From Baseline to Endpoint in Short-Form Health Survey 12 (SF-12) Scores | PCS score | 2.1 units on a scale | Standard Deviation 9.04 |
| Risperidone LAI | Change From Baseline to Endpoint in Short-Form Health Survey 12 (SF-12) Scores | MCS score | 3.2 units on a scale | Standard Deviation 10.43 |
| Quetiapine | Change From Baseline to Endpoint in Short-Form Health Survey 12 (SF-12) Scores | PCS score | 1.0 units on a scale | Standard Deviation 9.31 |
| Quetiapine | Change From Baseline to Endpoint in Short-Form Health Survey 12 (SF-12) Scores | MCS score | 2.7 units on a scale | Standard Deviation 10.88 |
| Aripiprazole | Change From Baseline to Endpoint in Short-Form Health Survey 12 (SF-12) Scores | PCS score | 2.4 units on a scale | Standard Deviation 10.36 |
| Aripiprazole | Change From Baseline to Endpoint in Short-Form Health Survey 12 (SF-12) Scores | MCS score | 4.9 units on a scale | Standard Deviation 12.1 |
Comparison: Within-group comparison of the change from baseline to endpoint in PCS score. The endpoint of the study was based on the LOCF principle.p-value: 0.1146Wilcoxon signed-rank test
Comparison: Between-group comparison of the change from baseline to endpoint in PCS score. The endpoint of the study was based on the LOCF principle.p-value: 0.0941Wilcoxon (Mann-Whitney)
Comparison: Within-group comparison of the change from baseline to endpoint in PCS score. The endpoint of the study was based on the LOCF principle.p-value: <0.0001Wilcoxon signed-rank test
Comparison: Between-group comparison of the change from baseline to endpoint in MCS score. The endpoint of the study was based on the LOCF principle.p-value: 0.5589Wilcoxon (Mann-Whitney)
Comparison: Within-group comparison of the change from baseline to endpoint in MCS score. The endpoint of the study was based on the LOCF principle.p-value: <0.0001Wilcoxon signed-rank test
Comparison: Within-group comparison of the change from baseline to endpoint in MCS score. The endpoint of the study was based on the LOCF principle.p-value: <0.0001Wilcoxon signed-rank test
Secondary
Change From Baseline to Endpoint in Total Positive and Negative Syndrome Scale (PANSS) Score
The neuropsychiatric symptoms of schizophrenia were assessed by means of the 30-item PANSS scale. The PANSS scale provides a total score (sum of the scores of all 30 items) and scores for 3 subscales, i.e., the positive subscale (7 items), the negative subscale (7 items), and the general psychopathology subscale (16 items). Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme).
Time frame: Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier)
Population: Efficacy analysis set, defined as all subjects who received at least 1 dose of study medication and had at least 1 efficacy assessment after baseline. This excluded 2 subjects of the risperidone LAI, 11 of the quetipaine, and 1 of the aripiprazole arm. One additional subject in each the risperidone LAI and quetiapine arm did not have PANSS data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Risperidone LAI | Change From Baseline to Endpoint in Total Positive and Negative Syndrome Scale (PANSS) Score | -9.3 units on a scale | Standard Deviation 25.65 |
| Quetiapine | Change From Baseline to Endpoint in Total Positive and Negative Syndrome Scale (PANSS) Score | -1.1 units on a scale | Standard Deviation 26.28 |
| Aripiprazole | Change From Baseline to Endpoint in Total Positive and Negative Syndrome Scale (PANSS) Score | -7.7 units on a scale | Standard Deviation 27.99 |
Comparison: Between-group comparison of the change from baseline to endpoint in total PANSS score. The endpoint of the study was based on the Last Observation Carried Forward (LOCF) principle, i.e., it was defined as the last available visit during the study with non-missing data for a parameter (excluding the baseline value).p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: Within-group comparison of the change from baseline to endpoint in total PANSS score. The endpoint of the study was based on the LOCF principle.p-value: <0.0001Wilcoxon signed-rank test
Comparison: Within-group comparison of the change from baseline to endpoint in total PANSS score. The endpoint of the study was based on the LOCF principle.p-value: 0.1026Wilcoxon signed-rank test
Secondary
Mean Relapse Free Period (Exploratory/Aripiprazole)
As for risperidone and quetiapine, relapse was defined as meeting any of the predefined criteria (adapted from Csernansky et al., 2002) on 2 consecutive evaluations during treatment, 3 to 5 days apart. Since aripiprazole was new on the market at the time the study was conducted, this aripiprazole analysis was exploratory.
Time frame: Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier)
Population: Efficacy analysis set, defined as all subjects who received at least 1 dose of study medication and who had at least 1 efficacy assessment after baseline. This excluded 1 subject of the aripiprazole arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Risperidone LAI | Mean Relapse Free Period (Exploratory/Aripiprazole) | 314 days | Standard Error 20.4 |