Schizophrenia
Conditions
Keywords
Schizophrenia, long-acting injectable antipsychotic medication
Brief summary
The purpose of this study is to demonstrate the effectiveness of paliperidone palmitate in patients with Schizophrenia.
Detailed description
This is a randomized (patients assigned to treatment groups by chance), double-blind (patient and study staff will not know the treatment assignment) study of paliperidone palmitate compared with RISPERDAL CONSTA (Risperidone Long-Acting Intramuscular Injection) in adult patients with schizophrenia. The total duration of the study will be approximately 14 weeks. For those patients without source documentation of tolerability to oral (by mouth) risperidone or paliperidone Extended Release (ER) tablets, injectable RISPERDAL CONSTA or paliperidone palmitate, or those patients who were not currently taking another antipsychotic, a minimum of 4 days and a maximum of 6 days of oral paliperidone ER treatment at a dosage of 6 mg/day will be administered for tolerability testing before the first injection of double-blind (DB) study drug (paliperidone palmitate or RISPERDAL CONSTA). During the DB period, study drug will be administered to patients as an intramuscular (i.m.) injection. Paliperidone palmitate (PP) 150mg equivalent (eq) (and RISPERDAL CONSTA placebo) at Baseline (BL) (Day 1), 100mg eq at Visit (V) 4 (Day 8), 50 or 100mg eq at V7 (Day 36), and 50,100,or 150mg eq at V9 (Day 64) or RISPERDAL CONSTA (RC) 25mg at V4 and V6 (Day 22), 25 or 37.5mg at V7, and 25, 37.5, or 50mg at V9 will be given as i.m. injections. Patients in the RC group will also take risperidone tablets (1-6 mg/day) at BL for 28 days and be given an injection of PP placebo at BL, V1, V7, and V9.
Interventions
DRUGRISPERDAL CONSTA
RISPERDAL CONSTA: Type=exact number, unit=mg, number=25, 37.5, or 50, form=suspension for injection, route=Intramuscular use. One i.m. injection of RISPERDAL CONSTA 25-50 mg eq every 2 weeks at V4, V6, V7, V8, V9, and V10. PALIPERIDONE PALMITATE PLACEBO: Form=suspension for injection, route=Intramuscular use. One i.m. injection every 2 weeks at Baseline and at V4, V7, and V9. RISPERIDONE: Type=up to, unit=mg, number=1 to 6, form=Tablet, route=Oral Use. One tablet for the first 4 weeks (28 days) of the DB treatment period.
DRUGPaliperidone palmitate
PALIPERIDONE PALMITATE: Type=exact number, unit=mg, number=50, 100, or 150, form=suspension for injection, route=Intramuscular use. One i.m. injection of Paliperidone palmitate 50-150 mg eq every 4 wks at Baseline, V4, V7, and V9. RISPERDAL CONSTA PLACEBO: Form=suspension for injection, route=Intramuscular use. One i.m. injection every 4 weeks at Baseline, V4, V7, and V9.
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Meet diagnostic criteria for schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria as specified by the protocol for at least 1 year before screening * Prior medical records, written documentation or verbal information obtained from previous psychiatric providers obtained by the investigator must be consistent with the diagnosis of schizophrenia * A total PANSS score between 60 and 120, inclusive, at screening and baseline; Body mass index (BMI) at the screening visit BMI at least 17 kg/m2 * Female patients must be postmenopausal for at least 2 years, surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control before study entry and throughout the study as specified by the protocol. Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (b hCG) pregnancy test result at screening.
Exclusion criteria
* Patient unable to provide consent or involuntarily committed to psychiatric hospitalization; A primary, active DSM-IV diagnosis on Axis I other than schizophrenia * A DSM-IV diagnosis of active substance dependence within 3 months before screening (nicotine and caffeine are not exclusionary) * History of treatment resistance as defined by failure to respond to 2 adequate treatments with different antipsychotic medications (an adequate treatment is defined as a minimum of 6 weeks at maximum tolerated dosage) * Relevant history or current presence of any significant or unstable cardiovascular, respiratory, neurologic (including seizures or significant cerebrovascular disease), renal, hepatic, hematologic, endocrine, immunologic, or other systemic disease including history of neuroleptic malignant syndrome; History of any severe pre-existing gastrointestinal narrowing or inability to swallow oral study drug whole with the aid of water (applies to those patients requiring oral tolerability only) * Significant risk of suicidal or violent behavior, as clinically assessed by the investigator ; History of life-threatening allergic reaction to any drug; Known or suspected hypersensitivity or intolerance to risperidone, paliperidone, 20% Intralipid, or any of their excipients (e.g., soybean oil, egg yolks, phospholipids, and glycerol) * Have received an experimental drug or experimental biologic, or used an experimental medical device within 6 months before screening; History of any active malignancy within the previous 5 years, with the exception of basal cell carcinomas * Women who are pregnant or breast-feeding or are planning to become pregnant uring the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Positive and Negative Syndrome Scale (PANSS) Total Score for Schizophrenia | Baseline to the last postrandomization assessment in the double-blind treatment period (approximately 13 weeks) | The PANSS scale is used to assess the neuropsychiatric symptoms of schizophrenia. The 30-item PANSS scale provides a total score (sum of the scores of all 30 items) and scores for 3 subscales, the positive subscale (7 items), the negative subscale (7 items),and the general psychopathology subscale (16 items), each item rated on a scale of 1 (absent) to 7 (extreme). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Change From Baseline for the CGI-S Score | Baseline to the last postrandomization assessment in the double-blind treatment period (approximately 13 weeks)] | The CGI-S rating scale is used to rate the severity of a patient'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 patient's condition at a given time. A qualified rater administered the CGI-S. |
| The Change From Baseline in the PSP Score | Baseline to the last postrandomization assessment in the double-blind treatment period (approximately 13 weeks) | The PSP scale is used to assess the degree of dysfunction a patient exhibits over a 7-day period within 4 domains of behavior: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behavior. The results of the assessment are converted to a numeric score. A score between 71 and 100 indicates a mild degree of difficulty; a score between 31 and 70 indicates a moderate degree of dysfunction, and a patient with a score of 30 or less has functioning so poor he or she requires intensive supervision. |
Countries
Austria, Bulgaria, Czechia, Estonia, France, Germany, Hungary, India, Lithuania, Poland, Russia, Spain, Ukraine, United States
Participant flow
Recruitment details
This is a 13 week double-blind study to assess safety and efficacy of flexible dose of Paliperidone Palmitate (50, 100 or 150 mg equivalent) in patients aged 18 years or older with schizophrenia.
Pre-assignment details
In this study 1221 patients were enrolled of which 1220 patients were randomized as 1 patient was enrolled twice. Only the first patient number was included in the all randomized patients, safety, and intent to treat analysis sets. Out of 1220 patients 1214 patients received at least 1 dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| R092670 Double-blind period. Flexible dose of 50, 100 or 150 mg equivalent administered by i.m. injection every 4 weeks up to Week 9 (Day 64). | 606 |
| RISPERDAL CONSTA Double-blind period. Flexible dose of 25, 37.5 or 50 mg administered by i.m. injection every 2 weeks up to Week 11 (Day 78). | 608 |
| Total | 1,214 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 19 | 10 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Lack of Efficacy | 40 | 43 |
| Overall Study | Lost to Follow-up | 11 | 18 |
| Overall Study | Other | 22 | 17 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 55 | 49 |
Baseline characteristics
| Characteristic | Total | RISPERDAL CONSTA | R092670 |
|---|---|---|---|
| AgeCategorical 18-25 years | 195 participants | 92 participants | 103 participants |
| AgeCategorical <18 years | 0 participants | 0 participants | 0 participants |
| AgeCategorical 26-50 years | 778 participants | 397 participants | 381 participants |
| AgeCategorical 51-65 years | 228 participants | 113 participants | 115 participants |
| AgeCategorical >65 years | 13 participants | 6 participants | 7 participants |
| Age, Categorical <=18 years | 5 Participants | 2 Participants | 3 Participants |
| Age, Categorical >=65 years | 14 Participants | 7 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 1195 Participants | 599 Participants | 596 Participants |
| Age, Continuous | 38.9 years STANDARD_DEVIATION 11.98 | 38.7 years STANDARD_DEVIATION 11.83 | 39 years STANDARD_DEVIATION 12.13 |
| Region of Enrollment Austria | 6 participants | 3 participants | 3 participants |
| Region of Enrollment Bulgaria | 29 participants | 14 participants | 15 participants |
| Region of Enrollment Czech Republic | 98 participants | 48 participants | 50 participants |
| Region of Enrollment Estonia | 66 participants | 34 participants | 32 participants |
| Region of Enrollment France | 10 participants | 3 participants | 7 participants |
| Region of Enrollment Germany | 8 participants | 4 participants | 4 participants |
| Region of Enrollment Hungary | 65 participants | 34 participants | 31 participants |
| Region of Enrollment India | 62 participants | 31 participants | 31 participants |
| Region of Enrollment Lithuania | 37 participants | 20 participants | 17 participants |
| Region of Enrollment Poland | 44 participants | 20 participants | 24 participants |
| Region of Enrollment Russia | 318 participants | 159 participants | 159 participants |
| Region of Enrollment Spain | 34 participants | 17 participants | 17 participants |
| Region of Enrollment Ukraine | 168 participants | 84 participants | 84 participants |
| Region of Enrollment United States of America | 269 participants | 137 participants | 132 participants |
| Sex: Female, Male Female | 513 Participants | 268 Participants | 245 Participants |
| Sex: Female, Male Male | 701 Participants | 340 Participants | 361 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 147 / 606 | 108 / 608 |
| serious Total, serious adverse events | 41 / 606 | 29 / 608 |
Outcome results
Primary
Change in the Positive and Negative Syndrome Scale (PANSS) Total Score for Schizophrenia
The PANSS scale is used to assess the neuropsychiatric symptoms of schizophrenia. The 30-item PANSS scale provides a total score (sum of the scores of all 30 items) and scores for 3 subscales, the positive subscale (7 items), the negative subscale (7 items),and the general psychopathology subscale (16 items), each item rated on a scale of 1 (absent) to 7 (extreme).
Time frame: Baseline to the last postrandomization assessment in the double-blind treatment period (approximately 13 weeks)
Population: The per-protocol analysis set of patients included those randomized to treatment after IEC/ IRB approval of protocol Amendment INT-4 with both a baseline measurement and at least 1 postrandomization measurement on the primary efficacy variable, a minimum exposure of 36 days to the double-blind treatment regimen, and no major protocol violations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R092670 | Change in the Positive and Negative Syndrome Scale (PANSS) Total Score for Schizophrenia | -18.6 Scores on a scale | Standard Deviation 15.45 |
| RISPERDAL CONSTA | Change in the Positive and Negative Syndrome Scale (PANSS) Total Score for Schizophrenia | -17.9 Scores on a scale | Standard Deviation 14.24 |
Comparison: Null hypothesis: Difference between groups (RISPERDAL CONSTA minus paliperidone palmitate) for the mean change from baseline to endpoint in PANSS total score (LOCF) was less than or equal to -5 (prespecified non-inferiority margin). Sample size: SD of 20 for the change in PANSS total score, a true difference between treatment groups of 0.1 in favor of RISPERDAL CONSTA, 2-sided significance level of 5%, and 80% power. A sample size reestimation was performed when 60% of the data was available.95% CI: [-1.62, 2.38]ANCOVA
Secondary
The Change From Baseline for the CGI-S Score
The CGI-S rating scale is used to rate the severity of a patient'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 patient's condition at a given time. A qualified rater administered the CGI-S.
Time frame: Baseline to the last postrandomization assessment in the double-blind treatment period (approximately 13 weeks)]
Population: The intent-to-treat (ITT) analysis set of patients included those randomized to treatment after IEC/IRB approval of protocol Amendment INT-4 who received at least 1 injection of double-blind study drug and had at least 1 efficacy measurement during the double-blind treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R092670 | The Change From Baseline for the CGI-S Score | -0.9 Scores on a scale | Standard Deviation 0.97 |
| RISPERDAL CONSTA | The Change From Baseline for the CGI-S Score | -0.9 Scores on a scale | Standard Deviation 0.93 |
Comparison: The change from baseline was analyzed using an ANCOVA model with factors for treatment and country and baseline score as a covariate.95% CI: [-0.07, 0.17]ANCOVA
Secondary
The Change From Baseline in the PSP Score
The PSP scale is used to assess the degree of dysfunction a patient exhibits over a 7-day period within 4 domains of behavior: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behavior. The results of the assessment are converted to a numeric score. A score between 71 and 100 indicates a mild degree of difficulty; a score between 31 and 70 indicates a moderate degree of dysfunction, and a patient with a score of 30 or less has functioning so poor he or she requires intensive supervision.
Time frame: Baseline to the last postrandomization assessment in the double-blind treatment period (approximately 13 weeks)
Population: The intent-to-treat (ITT) analysis set of patients included those randomized to treatment after IEC/IRB approval of protocol Amendment INT-4 who received at least 1 injection of double-blind study drug and had at least 1 efficacy measurement during the double-blind treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R092670 | The Change From Baseline in the PSP Score | 8.5 Scores on a scale | Standard Deviation 11.82 |
| RISPERDAL CONSTA | The Change From Baseline in the PSP Score | 8.8 Scores on a scale | Standard Deviation 11.65 |
Comparison: The change from baseline was analyzed using an ANCOVA model with factors for treatment and country and baseline score as a covariate.95% CI: [-1.22, 1.69]ANCOVA