Schizophrenia
Conditions
Keywords
Schizophrenia, Schizophrenic, Schizophrenias, Risperidone
Brief summary
The purpose of this study is to evaluate the efficacy and safety of RBP-7000 compared with placebo in the treatment of patients with schizophrenia. This will be a double-blind, placebo-controlled, Phase III study with 90 mg and 120 mg doses of RBP-7000 compared with placebo over an 8-week treatment period.
Interventions
DRUGRBP-7000
RBP-7000 90 mg and 120 mg were a mixture of the ATRIGEL Delivery System and 90 mg and 120 mg risperidone, respectively. The ATRIGEL Delivery System allows for sustained-release of risperidone in a controlled manner. Subcutaneous RBP-7000 injections on Days 1 and 29 in the lower quadrant of the abdomen rotating right and left on day 1 and 29.
DRUGPlacebo
Subcutaneous injection of placebo using the ATRIGEL Delivery System on Days 1 and 29 in the lower quadrant of the abdomen rotating right and left on day 1 and 29.
DRUGRisperidone
Oral risperidone 0.25 mg tablets daily for the first two days of the screening period. The two 0.25 mg tablets confirmed whether study participants had any negative reaction to risperidone prior to receiving a long-acting injection of risperidone (RBP-7000).
Sponsors
Indivior Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Males and females between the ages of 18 to 55 years, inclusive * Diagnosis of schizophrenia as defined by Diagnostic and Statistical Manual, Edition 4, text revision (DSM-IV-TR) criteria * Subjects who are deemed valid by the State, Assessability, Face, Ecological, and Rule (SAFER) interview * Subjects who are otherwise healthy on the basis of their physical examination
Exclusion criteria
* Subjects who have an improvement in their total Positive and Negative Syndrome Scale (PANSS) score of 20% or greater between the initial screening visit and the first day of treatment. * Subjects taking daily oral risperidone at a dose ≥ 6 mg/day * Subjects who have received a depot antipsychotic within 120 days of screen * Subjects with treatment resistant schizophrenia, as judged by the investigator, who have been treated with antipsychotics for adequate durations and with adequate dosages.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mixed Model for Repeated Measures (MMRM) Analysis of Change From Baseline to End of Treatment in the Positive and Negative Syndrome Scale (PANSS) Total Score | Day 1 prior to treatment (Baseline), Days 15, 29, 43 and 57 or early discontinuation | The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia including delusions, grandiosity, blunted affect, poor judgement, poor attention, and poor impulse control. The 30 symptoms are rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). The PANSS total score is the sum of all 30 PANSS items and ranges from 30 to 210, with 30 indicating absence of symptoms of schizophrenia and 210 indicating extreme ratings of all 30 symptoms. Negative change from baseline scores indicate improvements in symptoms. Estimates (least square means and standard errors), 2-sided confidence intervals, and -1-sided P values are based on a repeated-measures linear regression model of the change from baseline score, with fixed effects for visit as a categorical variable, baseline score, treatment and treatment by visit interaction, assuming an unstructured covariance matrix. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mixed Model for Repeated Measures (MMRM) Analysis of Change From Baseline to End of Treatment in Clinical Global Impression - Severity Scale (CGI-S) | Day 1 prior to treatment (Baseline), Days 15, 29, 43 and 57 or early discontinuation | The CGI-S rating scale is a 7-point global assessment that measures the clinician's impression of the severity of illness exhibited by a participant. A rating of 1 is equivalent to Normal, not at all ill and a rating of 7 is equivalent to Among the most extremely ill participants. Negative change from baseline scores indicate improvement in the severity of illness. Estimates (least square means and standard errors), 2-sided confidence intervals, and -1-sided P values are based on a repeated-measures linear regression model of the change from baseline score, with fixed effects for visit as a categorical variable, baseline score, treatment and treatment by visit interaction, assuming an unstructured covariance matrix. |
| Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Day 1 to Week 8 | An adverse event (AE) is defined as any study-related event that represents a change (positive or negative) in frequency or severity from a baseline (prestudy) event (if any), regardless of the presence of causal relationship or medical significance. Treatment-emergent adverse events are defined as any adverse event with a start date on or after the first study dose date. AEs are determined by the Investigator to be related or not related to the study drug. A serious AE (SAE) is defined by federal regulation as any AE occurring at any dose that results in any of the following outcomes: death, life-threatening AE, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Although a subject may have had 2 or more adverse experiences the subject is counted only once in a category. The same subject may appear in different categories. |
Countries
United States
Participant flow
Pre-assignment details
A total of 538 subjects were screened for study participation at 33 sites in the US, including 354 subjects randomly assigned to treatment. Four subjects were found to be randomized incorrectly; therefore, they were withdrawn from the study and did not receive study drug (counted as 'Physician Decision' for reason d/c below).
Participants by arm
| Arm | Count |
|---|---|
| RBP-7000 90 mg Risperidone tablets given during the screening period to check for sensitivity. RBP-7000 administered as a 90 mg subcutaneous injection on Days 1 and 29 for a total of two injections. | 115 |
| RBP-7000 120 mg Risperidone tablets given during the screening period to check for sensitivity. RBP-7000 administered as a 120 mg subcutaneous injection on Days 1 and 29 for a total of two injections. | 117 |
| Placebo Risperidone tablets given during the screening period to check for sensitivity. Placebo administered by subcutaneous injection on Days 1 and 29 for a total of two injections. | 118 |
| Total | 350 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 3 |
| Overall Study | Insufficient clinical response | 2 | 0 | 4 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 |
| Overall Study | Physician Decision | 3 | 4 | 5 |
| Overall Study | Protocol Violation | 0 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 20 | 25 | 21 |
Baseline characteristics
| Characteristic | Total | RBP-7000 90 mg | RBP-7000 120 mg | Placebo |
|---|---|---|---|---|
| Age at First Schizophrenia Diagnosis | 26.3 years STANDARD_DEVIATION 8.66 | 25.5 years STANDARD_DEVIATION 8.21 | 26.9 years STANDARD_DEVIATION 8.48 | 26.6 years STANDARD_DEVIATION 9.25 |
| Age, Continuous | 41.1 years STANDARD_DEVIATION 9.33 | 40.5 years STANDARD_DEVIATION 9.41 | 40.6 years STANDARD_DEVIATION 9.45 | 42.4 years STANDARD_DEVIATION 9.07 |
| Age, Customized 20 years and under | 4 Participants | 1 Participants | 2 Participants | 1 Participants |
| Age, Customized 21 to 30 years | 52 Participants | 16 Participants | 20 Participants | 16 Participants |
| Age, Customized 31 to 40 years | 98 Participants | 38 Participants | 32 Participants | 28 Participants |
| Age, Customized 41 to 50 years | 133 Participants | 41 Participants | 43 Participants | 49 Participants |
| Age, Customized 51 to 55 years | 63 Participants | 19 Participants | 20 Participants | 24 Participants |
| Body Mass Index | 29.890 kg/m^2 STANDARD_DEVIATION 6.667 | 29.576 kg/m^2 STANDARD_DEVIATION 5.938 | 29.376 kg/m^2 STANDARD_DEVIATION 6.664 | 30.706 kg/m^2 STANDARD_DEVIATION 7.293 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 7 Participants | 9 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 322 Participants | 108 Participants | 107 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Height | 174.1 cm STANDARD_DEVIATION 10.02 | 175.1 cm STANDARD_DEVIATION 9.09 | 174.3 cm STANDARD_DEVIATION 9.95 | 173.1 cm STANDARD_DEVIATION 10.91 |
| Previous Antipsychotic Treatment No | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Previous Antipsychotic Treatment Yes | 348 Participants | 114 Participants | 116 Participants | 118 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 1 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 254 Participants | 83 Participants | 83 Participants | 88 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 85 Participants | 28 Participants | 30 Participants | 27 Participants |
| Sex: Female, Male Female | 82 Participants | 20 Participants | 31 Participants | 31 Participants |
| Sex: Female, Male Male | 268 Participants | 95 Participants | 86 Participants | 87 Participants |
| Waist-to-Hip Ratio | 0.942 ratio STANDARD_DEVIATION 0.08 | 0.947 ratio STANDARD_DEVIATION 0.078 | 0.936 ratio STANDARD_DEVIATION 0.072 | 0.944 ratio STANDARD_DEVIATION 0.09 |
| Weight | 90.49 kg STANDARD_DEVIATION 20.802 | 90.60 kg STANDARD_DEVIATION 18.895 | 89.01 kg STANDARD_DEVIATION 20.462 | 91.84 kg STANDARD_DEVIATION 22.885 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 115 | 0 / 117 | 0 / 118 |
| other Total, other adverse events | 65 / 115 | 70 / 117 | 64 / 118 |
| serious Total, serious adverse events | 0 / 115 | 1 / 117 | 1 / 118 |
Outcome results
Primary
Mixed Model for Repeated Measures (MMRM) Analysis of Change From Baseline to End of Treatment in the Positive and Negative Syndrome Scale (PANSS) Total Score
The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia including delusions, grandiosity, blunted affect, poor judgement, poor attention, and poor impulse control. The 30 symptoms are rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). The PANSS total score is the sum of all 30 PANSS items and ranges from 30 to 210, with 30 indicating absence of symptoms of schizophrenia and 210 indicating extreme ratings of all 30 symptoms. Negative change from baseline scores indicate improvements in symptoms. Estimates (least square means and standard errors), 2-sided confidence intervals, and -1-sided P values are based on a repeated-measures linear regression model of the change from baseline score, with fixed effects for visit as a categorical variable, baseline score, treatment and treatment by visit interaction, assuming an unstructured covariance matrix.
Time frame: Day 1 prior to treatment (Baseline), Days 15, 29, 43 and 57 or early discontinuation
Population: Intent to treat (ITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RBP-7000 90 mg | Mixed Model for Repeated Measures (MMRM) Analysis of Change From Baseline to End of Treatment in the Positive and Negative Syndrome Scale (PANSS) Total Score | -15.367 units on a scale | Standard Error 1.223 |
| RBP-7000 120 mg | Mixed Model for Repeated Measures (MMRM) Analysis of Change From Baseline to End of Treatment in the Positive and Negative Syndrome Scale (PANSS) Total Score | -16.456 units on a scale | Standard Error 1.2073 |
| Placebo | Mixed Model for Repeated Measures (MMRM) Analysis of Change From Baseline to End of Treatment in the Positive and Negative Syndrome Scale (PANSS) Total Score | -9.219 units on a scale | Standard Error 1.2162 |
Comparison: Estimates, standard errors (SE), 2-sided confidence intervals (CIs), and -1-sided P values are based on a repeated-measures linear regression model of the change from baseline score, with fixed effects for visit as a categorical variable, baseline score, treatment and treatment by visit interaction, assuming an unstructured covariance matrix.p-value: 0.000495% CI: [-9.982, -2.314]repeated measure linear regression model
Comparison: Estimates, standard errors (SE), 2-sided confidence intervals (CIs), and -1-sided P values are based on a repeated-measures linear regression model of the change from baseline score, with fixed effects for visit as a categorical variable, baseline score, treatment and treatment by visit interaction, assuming an unstructured covariance matrix.p-value: <0.000195% CI: [-11.045, -3.429]repeated measure linear regression model
Secondary
Mixed Model for Repeated Measures (MMRM) Analysis of Change From Baseline to End of Treatment in Clinical Global Impression - Severity Scale (CGI-S)
The CGI-S rating scale is a 7-point global assessment that measures the clinician's impression of the severity of illness exhibited by a participant. A rating of 1 is equivalent to Normal, not at all ill and a rating of 7 is equivalent to Among the most extremely ill participants. Negative change from baseline scores indicate improvement in the severity of illness. Estimates (least square means and standard errors), 2-sided confidence intervals, and -1-sided P values are based on a repeated-measures linear regression model of the change from baseline score, with fixed effects for visit as a categorical variable, baseline score, treatment and treatment by visit interaction, assuming an unstructured covariance matrix.
Time frame: Day 1 prior to treatment (Baseline), Days 15, 29, 43 and 57 or early discontinuation
Population: Intent to treat population (ITT)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RBP-7000 90 mg | Mixed Model for Repeated Measures (MMRM) Analysis of Change From Baseline to End of Treatment in Clinical Global Impression - Severity Scale (CGI-S) | -0.868 units on a scale | Standard Error 0.0662 |
| RBP-7000 120 mg | Mixed Model for Repeated Measures (MMRM) Analysis of Change From Baseline to End of Treatment in Clinical Global Impression - Severity Scale (CGI-S) | -0.914 units on a scale | Standard Error 0.0654 |
| Placebo | Mixed Model for Repeated Measures (MMRM) Analysis of Change From Baseline to End of Treatment in Clinical Global Impression - Severity Scale (CGI-S) | -0.518 units on a scale | Standard Error 0.0659 |
Comparison: Estimates, standard errors (SE), 2-sided confidence intervals (CIs), and -1-sided P values are based on a repeated-measures linear regression model of the change from baseline score, with fixed effects for visit as a categorical variable, baseline score, treatment and treatment by visit interaction, assuming an unstructured covariance matrix.p-value: 0.000295% CI: [-0.557, -0.143]repeated measure linear regression model
Comparison: Estimates, standard errors (SE), 2-sided confidence intervals (CIs), and -1-sided P values are based on a repeated-measures linear regression model of the change from baseline score, with fixed effects for visit as a categorical variable, baseline score, treatment and treatment by visit interaction, assuming an unstructured covariance matrix.p-value: <0.000195% CI: [-0.602, -0.19]repeated measure linear regression model
Secondary
Summary of Participants With Treatment-Emergent Adverse Events (TEAE)
An adverse event (AE) is defined as any study-related event that represents a change (positive or negative) in frequency or severity from a baseline (prestudy) event (if any), regardless of the presence of causal relationship or medical significance. Treatment-emergent adverse events are defined as any adverse event with a start date on or after the first study dose date. AEs are determined by the Investigator to be related or not related to the study drug. A serious AE (SAE) is defined by federal regulation as any AE occurring at any dose that results in any of the following outcomes: death, life-threatening AE, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Although a subject may have had 2 or more adverse experiences the subject is counted only once in a category. The same subject may appear in different categories.
Time frame: Day 1 to Week 8
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RBP-7000 90 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Death | 0 Participants |
| RBP-7000 90 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE | 0 Participants |
| RBP-7000 90 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Related TEAE | 58 Participants |
| RBP-7000 90 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE causing discontinuation | 0 Participants |
| RBP-7000 90 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | 1 or more TEAEs | 81 Participants |
| RBP-7000 90 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | No TEAEs | 34 Participants |
| RBP-7000 90 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Serious, related TEAE | 0 Participants |
| RBP-7000 120 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | 1 or more TEAEs | 91 Participants |
| RBP-7000 120 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE causing discontinuation | 2 Participants |
| RBP-7000 120 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Death | 0 Participants |
| RBP-7000 120 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | No TEAEs | 26 Participants |
| RBP-7000 120 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Related TEAE | 65 Participants |
| RBP-7000 120 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Serious, related TEAE | 0 Participants |
| RBP-7000 120 mg | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE | 1 Participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Death | 0 Participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | No TEAEs | 37 Participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | 1 or more TEAEs | 81 Participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Related TEAE | 50 Participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE | 1 Participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | Serious, related TEAE | 0 Participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE causing discontinuation | 3 Participants |