Schizophrenia
Conditions
Keywords
Schizophrenia, intramuscular injection, antipsychotic agents, long-acting risperidone
Brief summary
The primary objective of this randomized trial was to investigate whether early initiation of treatment with Risperdal Consta after an acute episode was not inferior to the routine approach (oral treatment for 12 weeks followed by treatment with Risperdal Consta). .
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 regiment. Long-acting injectable formulations may eliminate the need for daily medication and enhance patient compliance with the treatment regimen. Traditionally, patients experiencing an episode of schizophrenia are first treated with oral medications until they are stabilized, and then injectable long-acting formulations are given. This is an open, multicenter, randomized Phase IV trial in patients after an acute episode of schizophrenia. Patients will be in the trial for 6 months. One treatment group will receive injections starting at baseline (early initiation); the other group will start with treatment as usual at baseline and begin injections at Week 12 (late initiation). Assessment of effectiveness include Positive And Negative Syndrome Scale (PANSS), in order to measure symptoms of schizophrenia; Clinical Global Impression - Severity (CGI-S), measuring overall severity of illness; Global Assessment of Functioning (GAF), assessesing overall psychological, social, and occupational functioning; and Quality of Life Questionnaire SF-12, measuring overall health status. Safety evaluations include the Extrapyramidal Symptoms Rating Scale (ESRS), incidence of adverse events throughout the study, and vital signs (pulse, blood pressure). The study hypothesis is that early initiation of long-acting risperidone injections is not inferior to late initiation as measured by changes in PANSS total score from baseline through endpoint (after 6 months). Risperidone, long-acting formulation for intramuscular injections (25 to 50 mg (maximum)), given every 14 days through 6 months, starting at baseline or Month 3. Treatment as usual for 3 months for late initiation group
Interventions
DRUGearly initiation of treatment with Risperdal Consta
25 mg to 50 mg Risperdal Consta intrmuscular injection every 14 days starting at baseline. Treatment with oral antipsychotics or risperidone will continue 21 days after the first injection of Risperdal Consta. This treatment will then be tapered off within the next 7 days.
DRUGroutine initiation of treatment with Risperdal Consta
25 mg to 50 mg Risperdal Consta intrmuscular injection every 14 days starting at week 12. Treatment with oral antipsychotics or risperidone will continue 21 days after the first injection of Risperdal Consta. This treatment will then be tapered off within the next 7 days.
Sponsors
Janssen Pharmaceutica N.V., Belgium
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of schizophrenia by criteria of Diagnostic and Statistical Manual of Mental Diseases, Fourth Edition (DSM-IV) * acute episode of schizophrenia within 2 weeks of study entry * o subjects currently not treated or treated with oral antipsychotics or short-acting injectable antipsychotics (zuclopenthixol acutard is allowed) at doses not exceeding the registered dose * Positive And Negative Syndrome Scale (PANSS) score \>=80 * Clinical Global Impression - Severity (CGI-S) score \>=5
Exclusion criteria
* DSM-IV axis I diagnosis other than schizophrenia * known hypersensitivity or lack of response to risperidone * pregnant or nursing females, or those without adequate contraception * alcohol or drug abuse or dependence diagnosed in the last month prior to entry,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Positive And Negative Syndrome Scale (PANSS) Total Score From Baseline to Endpoint | at baseline and Week 26 or at premature discontinuation | The PANSS is a specific scale for the measurement of the symptoms of schizophrenia. Symptoms of schizophrenia will be assessed using the 30-item PANSS scale. Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme).The total score can range from 30 to 210. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in PANSS Total Score at Week 6 | at baseline and Week 6. | The PANSS is a specific scale for the measurement of the symptoms of schizophrenia. Symptoms of schizophrenia will be assessed using the 30-item PANSS scale. Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme). The total score can range from 30 to 210. |
| Change From Baseline in PANSS Total Score at Week 12 | at baseline and Week 12. | The PANSS is a specific scale for the measurement of the symptoms of schizophrenia. Symptoms of schizophrenia will be assessed using the 30-item PANSS scale. Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme). The total score can range from 30 to 210. |
| Change From Baseline to Endpoint in Clinical Global Impression - Severity (CGI-S) | at baseline and endpoint (week 26 or at premature discontinuation). | The CGI-S rating scale is used to rate the severity of a subject's psychotic condition on a 7-point scale ranging from 1 (not ill) to 7 (extremely severe). This scale permits a global evaluation of the subject's condition at a given time. |
| Change From Baseline to Endpoint in Global Assessment of Functioning (GAF) | at baseline and endpoint (week 26 or at premature discontinuation). | Overall psychological, social, and occupational functioning is rated on a scale of mental health-illness from 1 being the worst functioning to 100 being the best. Impairment in functioning due to physical (or environmental) limitations must not be included in the rating. |
| Change From Baseline to Endpoint in Quality of Life Questionnaire SF-12 | at baseline, Weeks 6, 12, and endpoint (week 26 or at premature discontinuation). | Short Form Health Survey: A generic dual-ie, mental and physical health-scale measure of quality of life. This is a 12-item subset of the SF-36 survey that measures the same 8 domains of health. As a brief, reliable measure of overall health status, the SF-12 is the instrument of choice in large population health surveys and has been used extensively as a screening tool. SF-12 will be filled in by the patient. The scores range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. |
Countries
Denmark, Finland, France, Greece, Israel, Norway, Slovenia, Sweden, Switzerland, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Early Initiation of Treatment 25 mg to 50 mg Risperdal Consta intramuscular (i.m.) injection every 14 days starting at baseline. Treatment with oral antipsychotics (APs) or risperidone will continue 21 days after the first injection of Risperdal Consta. This treatment will then be tapered off within the next 7 days. Two enrolled patients were excluded from the baseline analysis as these patients dropped out early and no safety or efficacy data were present. | 108 |
| Late Initiation of Treatment routine practice: The oral AP treatment started during the acute episode will be maintained until week 12. Starting at week 12, 25 mg to 50 mg Risperdal Consta i.m. injection every 14 days. Treatment with previous oral APs will continue 21 days after the first injection and then be tapered off within the next 7 days. Two enrolled patients were excluded from the baseline analysis as these patients dropped out early and no efficacy data were present. | 108 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 9 |
| Overall Study | Ineligible | 0 | 2 |
| Overall Study | Ineligible, no efficacy data | 2 | 2 |
| Overall Study | Insufficient Response | 9 | 4 |
| Overall Study | Insufficient Response Adverse Event | 2 | 1 |
| Overall Study | Investigator Illness | 0 | 1 |
| Overall Study | Lost to Follow-up | 3 | 5 |
| Overall Study | Non compliant | 2 | 2 |
| Overall Study | No Need to Continue Medication | 1 | 1 |
| Overall Study | Patient Moved | 0 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Protocol Violation | 3 | 5 |
| Overall Study | Refused Injections | 3 | 13 |
| Overall Study | Relapse | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 2 |
Baseline characteristics
| Characteristic | Early Initiation of Treatment | Late Initiation of Treatment | Total |
|---|---|---|---|
| Age Continuous | 38 years STANDARD_DEVIATION 11 | 38 years STANDARD_DEVIATION 11 | 38 years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 41 Participants | 43 Participants | 84 Participants |
| Sex: Female, Male Male | 67 Participants | 65 Participants | 132 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 58 / 110 | 66 / 110 |
| serious Total, serious adverse events | 18 / 110 | 22 / 110 |
Outcome results
Primary
Change in Positive And Negative Syndrome Scale (PANSS) Total Score From Baseline to Endpoint
The PANSS is a specific scale for the measurement of the symptoms of schizophrenia. Symptoms of schizophrenia will be assessed using the 30-item PANSS scale. Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme).The total score can range from 30 to 210.
Time frame: at baseline and Week 26 or at premature discontinuation
Population: Per Protocol analysis: all randomized patients who had no violation on eligibility criteria or no major protocol violation. This excluded 42 patients in the early and 34 in the late initiation group. 1 patient in the early initiation group had no PANSS at endpoint. The endpoint is the last post-baseline value of the patient.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Initiation of Treatment | Change in Positive And Negative Syndrome Scale (PANSS) Total Score From Baseline to Endpoint | -38.37 scores on a scale | Standard Deviation 23.1 |
| Late Initiation of Treatment | Change in Positive And Negative Syndrome Scale (PANSS) Total Score From Baseline to Endpoint | -37.24 scores on a scale | Standard Deviation 25.02 |
Comparison: Assuming a difference of 3 points in favor of early initiation of treatment with Risperdal Consta, a sample size of 87 subjects per treatment arm has a power of 80% to demonstrate non-inferiority at the 0.025-level (1-sided). It was expected that about 20% of randomized subjects had to be excluded from the per-protocol (PP) analysis. Therefore, 220 subjects were to be included.p-value: 0.78495% CI: [-9.24, 6.99]ANCOVA
Secondary
Change From Baseline in PANSS Total Score at Week 12
The PANSS is a specific scale for the measurement of the symptoms of schizophrenia. Symptoms of schizophrenia will be assessed using the 30-item PANSS scale. Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme). The total score can range from 30 to 210.
Time frame: at baseline and Week 12.
Population: Per protocol population. This excluded 42 patients in the early start group and 34 patients in the late start group. An additional 9 and 23 patients in the respective groups had missing PANSS data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Initiation of Treatment | Change From Baseline in PANSS Total Score at Week 12 | -35.84 scores on a scale | Standard Deviation 22.83 |
| Late Initiation of Treatment | Change From Baseline in PANSS Total Score at Week 12 | -34.49 scores on a scale | Standard Deviation 19.12 |
Secondary
Change From Baseline in PANSS Total Score at Week 6
The PANSS is a specific scale for the measurement of the symptoms of schizophrenia. Symptoms of schizophrenia will be assessed using the 30-item PANSS scale. Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme). The total score can range from 30 to 210.
Time frame: at baseline and Week 6.
Population: Per protocol population. This excluded 42 patients in the early start group and 34 patients in the late start group. An additional 3 and 5 patients in the respective groups had missing PANSS data at week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Initiation of Treatment | Change From Baseline in PANSS Total Score at Week 6 | -27.48 scores on a scale | Standard Deviation 17.97 |
| Late Initiation of Treatment | Change From Baseline in PANSS Total Score at Week 6 | -27.96 scores on a scale | Standard Deviation 20.1 |
Secondary
Change From Baseline to Endpoint in Clinical Global Impression - Severity (CGI-S)
The CGI-S rating scale is used to rate the severity of a subject's psychotic condition on a 7-point scale ranging from 1 (not ill) to 7 (extremely severe). This scale permits a global evaluation of the subject's condition at a given time.
Time frame: at baseline and endpoint (week 26 or at premature discontinuation).
Population: Per protocol population. This excluded 42 patients in the early start group and 34 patients in the late start group.One additional patient in the Early Initiation group has missing CGI-S data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Initiation of Treatment | Change From Baseline to Endpoint in Clinical Global Impression - Severity (CGI-S) | -1.91 scores on a scale | Standard Deviation 1.35 |
| Late Initiation of Treatment | Change From Baseline to Endpoint in Clinical Global Impression - Severity (CGI-S) | -2.03 scores on a scale | Standard Deviation 1.27 |
Comparison: Between-group comparison of the change in CGI-S from baseline to endpoint was analyzed as is with no derived calculations. CGI-S scores were coded as follows: 0=normal, not at all ill, 1=borderline, etc. and 6=among the most extremely ill patients.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: 0.8Wilcoxon two sample test
Comparison: Within-group comparison of the change in CGI-S from baseline to endpoint was analyzed as is with no derived calculations. CGI-S scores were coded as follows: 0=normal, not at all ill, 1=borderline, etc. and 6=among the most extremely ill patients.p-value: <0.001Wilcoxon-signed-rank test
Comparison: Within-group comparison of the change in CGI-S from baseline to endpoint was analyzed as is with no derived calculations. CGI-S scores were coded as follows: 0=normal, not at all ill, 1=borderline, etc. and 6=among the most extremely ill patients.p-value: <0.001Wilcoxon-signed-rank test
Secondary
Change From Baseline to Endpoint in Global Assessment of Functioning (GAF)
Overall psychological, social, and occupational functioning is rated on a scale of mental health-illness from 1 being the worst functioning to 100 being the best. Impairment in functioning due to physical (or environmental) limitations must not be included in the rating.
Time frame: at baseline and endpoint (week 26 or at premature discontinuation).
Population: Per protocol population. This excluded 42 patients in the early start group and 34 patients in the late start group.One additional patient in the Early Initation group has missing GAF data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Initiation of Treatment | Change From Baseline to Endpoint in Global Assessment of Functioning (GAF) | 19.65 scores on a scale | Standard Deviation 14.2 |
| Late Initiation of Treatment | Change From Baseline to Endpoint in Global Assessment of Functioning (GAF) | 18.72 scores on a scale | Standard Deviation 16.76 |
Comparison: Between-group comparison of the change in GAF from baseline to endpoint. 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: 0.798Wilcoxon two sample test
Comparison: Within-group comparison of the change in GAF from baseline to endpoint. 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: <0.001Wilcoxon-signed-rank test
Comparison: Within-group comparison of the change in GAF from baseline to endpoint. 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: <0.001Wilcoxon-signed-rank test
Secondary
Change From Baseline to Endpoint in Quality of Life Questionnaire SF-12
Short Form Health Survey: A generic dual-ie, mental and physical health-scale measure of quality of life. This is a 12-item subset of the SF-36 survey that measures the same 8 domains of health. As a brief, reliable measure of overall health status, the SF-12 is the instrument of choice in large population health surveys and has been used extensively as a screening tool. SF-12 will be filled in by the patient. The scores range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.
Time frame: at baseline, Weeks 6, 12, and endpoint (week 26 or at premature discontinuation).
Population: Per protocol population. This excluded 42 patients in the early start group and 34 patients in the late start group.An additional 9 and 11 patients in the respective groups had missing SF-12 data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Early Initiation of Treatment | Change From Baseline to Endpoint in Quality of Life Questionnaire SF-12 | Physical Component Summary (PCS) | 2.76 scores on a scale | Standard Deviation 10.73 |
| Early Initiation of Treatment | Change From Baseline to Endpoint in Quality of Life Questionnaire SF-12 | Mental Component Summary (MCS) | 3.25 scores on a scale | Standard Deviation 9.19 |
| Late Initiation of Treatment | Change From Baseline to Endpoint in Quality of Life Questionnaire SF-12 | Physical Component Summary (PCS) | 1.75 scores on a scale | Standard Deviation 7.93 |
| Late Initiation of Treatment | Change From Baseline to Endpoint in Quality of Life Questionnaire SF-12 | Mental Component Summary (MCS) | 2.96 scores on a scale | Standard Deviation 10.76 |
Comparison: Between-group comparison of the change in SF-12 PCS score from baseline to endpoint. 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: 0.519Wilcoxon two sample test
Comparison: Within-group comparison of the change in SF-12 PCS score from baseline to endpoint. 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: <0.001Wilcoxon-signed-rank test
Comparison: Within-group comparison of the change in SF-12 PCS score from baseline to endpoint. 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: <0.001Wilcoxon-signed-rank test
Comparison: Between-group comparison of the change in SF-12 MCS score from baseline to endpoint. 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: 0.721Wilcoxon two sample test
Comparison: Within-group comparison of the change in SF-12 MCS score from baseline to endpoint. 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: <0.001Wilcoxon-signed-rank test
Comparison: Within-group comparison of the change in SF-12 MCS score from baseline to endpoint. 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: <0.001Wilcoxon-signed-rank test