An Efficacy Study of Paliperidone for the Prevention of Relapse in Participants With Schizophrenia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, tolerability and safety of paliperidone extended release (ER) tablets (between 3 to 12 milligram (mg), once a day) in the prevention of relapse in schizophrenia participants.

Detailed Description
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This is a double-blind (neither physician nor participant knows the name of the assigned drug), randomized (participants are assigned to treatment by a chance), placebo-controlled, and parallel-group study of paliperidone ER tablets. The study will consist of 6 phases: 14 days of screening phase, 8 weeks of open-label run-in phase (participants will be flexibly dosed with paliperidone ER once daily in a dose range of 3 mg to 12 mg), 6 weeks of stabilization phase (participants will continue to receive the fixed dose of paliperidone ER), double-blind (DB) phase of various length (participants will be randomly assigned in a 1:1 ratio to receive either paliperidone ER or placebo and this phase will be completed after 86 relapse events are observed or if the study is positive at the interim analysis), 6 months of open-label extension (participants who experience a relapse event or who remain relapse free for the entire duration of the double-blind phase and participants who are enrolled at the time the study is terminated, will be eligible for this phase. All participants will be treated with paliperidone ER and safety and tolerability information will be collected during this phase) phase and 6 months of follow-up phase (participants who withdraw during the DB phase for any reason other than relapse will be followed for 6 months or until they experience a relapse). Participants' safety will be monitored throughout the study.

Official Title
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Paliperidone Extended Release Tablets for the Prevention of Relapse in Subjects With Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Paliperidone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) Have experienced an acute episode, with a Positive and Negative Syndrome Scale (PANSS) total score between 70 and 120 inclusive, at Screening and Baseline Women must be postmenopausal (for at least 1 year), surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), practicing a highly effective method of birth control, if sexually active Men must be using a highly effective method of birth control and must not donate sperm during the study and for 3 months after receiving the last dose of study drug Be willing and capable to complete the questionnaires and able to take oral medications independently Exclusion Criteria: Has drug dependence diagnosis according to DSM-IV (excluding nicotine and caffeine dependence) within 6 months before screening Participants with Crohn's disease and hepatic or renal diseases Has had relevant history of any significant and/or unstable cardiovascular, respiratory, neurologic (including seizures or significant cerebrovascular dysfunction), renal, hepatic, endocrine, or immunologic diseases Has had history of neuroleptic malignant syndrome (the disorder caused by antipsychotic drugs with symptoms of fever, muscle rigidity and delirium) Has had known or suspected Stevens Johnson Syndrome (an immune disease with symptoms of fever, sore throat, ulcers and conjunctivitis) after exposure to phenytoin, carbamazepine, barbiturates, or lamotrigine Had been treated with clozapine for treatment refractory or treatment resistant schizophrenia Has significant risk of suicide or homicidal behavior, or significant risk of deliberate self harm or harm to others Has taken isocarboxazid, phenelzine, selegiline and tranylcypromine within 4 weeks before screening Has received electroconvulsive therapy within 60 days before screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paliperidone: Run-in or Stabilization phase<br>Paliperidone extended-release (ER) oral tablet will be administered at a starting dose of 3 milligram (mg) once daily for 8 weeks. Dose will be increased from milligram per day (3 mg/day) after 5 days based on Investigator's discretion, up to maximum of 12 mg/day. | Drug: Paliperidone<br>* Paliperidone extended-release (ER) oral tablet will be administered at a starting dose of 3 milligram (mg) up to 12 mg once daily for 8 weeks in Run-in or Stabilization phase, and 3-12 mg fixed dose oral tablet will be administered in DB phase. Participants who will enter open-label extension phase will receive paliperidone as 3-12 mg per day.<br>* Other names: R076477;|
| Experimental: Paliperidone: Double blind (DB) phase<br>Participants who transitioned from run-in or stabilization phase received 3 to 12 mg fixed dose of paliperidone ER oral tablet once daily during DB phase of the study. Participants who will experience a relapse event during the DB phase or who will remain relapse free for the entire duration of the DB phase and participants, who will be enrolled at the time the study termination will enter in open label extension phase, wherein paliperidone ER oral tablet will be administered once daily as 3 to 12 mg. | Drug: Paliperidone<br>* Paliperidone extended-release (ER) oral tablet will be administered at a starting dose of 3 milligram (mg) up to 12 mg once daily for 8 weeks in Run-in or Stabilization phase, and 3-12 mg fixed dose oral tablet will be administered in DB phase. Participants who will enter open-label extension phase will receive paliperidone as 3-12 mg per day.<br>* Other names: R076477;|
| Active Comparator: Placebo: DB phase<br>Participants who transitioned from run-in or stabilization phase received matching placebo to paliperidone ER once daily during DB phase of the study. Participants who will experience a relapse event during the DB phase or who will remain relapse free for the entire duration of the DB phase and participants, who will be enrolled at the time the study termination will enter in open label extension phase, wherein paliperidone ER oral tablet will be administered once daily as 3 to 12 mg. | Drug: Placebo<br>* Participants who transitioned from run-in or stabilization phase will receive matching placebo to paliperidone ER once daily during DB phase of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double Blind (DB) Phase: Median Time to Relapse | A relapse is defined as any one of the following: 1. involuntary or voluntary psychiatric hospitalization 2. deliberate self-injury or violent behavior; 3. Suicidal or homicidal ideation and clinically significant aggressive behavior; 4. 25 percent (%) increase in Positive and Negative Syndrome Scale (PANSS) total score for 2 consecutive assessments for participants whose score was greater than 40 at randomization, or a 10-point increase for participants who scored less than or equal to (≤) 40 at randomization; 5. increase for 2 consecutive assessments in PANSS items (delusions, conceptual disorganization, hallucinatory behavior, suspiciousness, hostility or uncooperativeness) to greater than or equal to (≥) 5 for participants who scored ≤3 at randomization, or to ≥6 for participants with initial score of 4. Independent Data Monitoring Committee performed ongoing safety monitoring during double-blind treatment and conducted the interim analysis after 61 relapse events had taken place. | DB Baseline (Day 1 of Week 15) up to interim analysis data cut-off (24 August 2012) (Approximately 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Run-In and Stabilization Phase: Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 14 | The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia including delusions, grandiosity, blunted affect, 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 consists of the sum of all 30 PANSS items and ranges from 30 to 210. Higher scores indicate worsening. | Baseline and Week 14 | 
| Double Blind (DB) Phase: Change From DB Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at DB Endpoint | The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia including delusions, grandiosity, blunted affect, 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 consists of the sum of all 30 PANSS items and ranges from 30 to 210. Higher scores indicate worsening. Change at DB endpoint was calculated as value at interim analysis data cut-off (09 November 2012) minus value at DB Baseline (Day 1 of week 15). | DB Baseline (Day 1 of Week 15) up to DB endpoint (study completion [09 November 2012] [Approximately 1 year]) | 
| Run-In and Stabilization Phase: Number of Participants Assessed With Categorical Scores Based on Clinical Global Impression-Severity Scale (CGI-S) | The CGI-S is a 7-point clinician-rated scale to assess severity of participant's current illness state, ranging from (1)Normal, not ill at all, (2)Borderline mentally ill, (3)Mildly ill, (4)Moderately ill, (5)Markedly ill, (6)Severely ill, (7)Among the most severely ill. | Baseline and Week 14 | 
| Double Blind (DB) Phase: Change From DB Baseline in Clinical Global Impression-Severity Scale (CGI-S) Total Score at DB Endpoint | CGI-S is a 7-point clinician-rated scale to assess severity of participant's current illness state, ranging from (1)Normal, not ill at all, (2)Borderline mentally ill, (3)Mildly ill, (4)Moderately ill, (5)Markedly ill, (6)Severely ill, (7)Among the most severely ill. Change at DB endpoint was calculated as value at interim analysis data cut-off (09 November 2012) minus value at DB Baseline (Day 1 of week 15). | DB Baseline (Day 1 of Week 15) up to DB endpoint (study completion [09 November 2012] [Approximately 1 year]) | 
| Run-In and Stabilization Phase: Change From Baseline in Personal and Social Performance (PSP) Scale Total Score at Week 14 | The PSP is 100-point validated clinician-rated scale that assesses degree of difficulty in 4 areas of functioning: socially useful activities, personal and social relationships, self-care, disturbing and aggressive behaviors rated on 6-point scale (1=absent to 6=very severe).Total transformed score from 1 to 100 is generated from raw score based on clinical interpretation of scores generated in 4 areas of functioning, with higher transformed score indicating better function. Total score is divided into 3 levels: 71-100 (mild difficulty); 31-70 (marked difficulty) and 1-30 (severe difficulty). Percentage of participants achieving improvement in PSP score by at least one category was reported. | Baseline and Week 14 | 
| Double Blind (DB) Phase: Change From DB Baseline in Personal and Social Performance (PSP) Scale Total Score at DB Endpoint | The PSP is 100-point validated clinician-rated scale that assesses degree of difficulty in 4 areas of functioning: socially useful activities, personal and social relationships, self-care, disturbing and aggressive behaviors rated on 6-point scale (1=absent to 6=very severe).Total transformed score from 1 to 100 is generated from raw score based on clinical interpretation of scores generated in 4 areas of functioning, with higher transformed score indicating better function. Total score is divided into 3 levels: 71-100 (mild difficulty); 31-70 (marked difficulty) and 1-30 (severe difficulty). Percentage of participants achieving improvement in PSP score by at least one category was reported. Change at DB endpoint was calculated as value at interim analysis data cut-off (09 November 2012) minus value at DB Baseline (Day 1 of week 15). | DB Baseline (Day 1 of Week 15) up to DB endpoint (study completion [09 November 2012] [Approximately 1 year]) | 
| Run-In and Stabilization Phase: Change From Baseline in Sleep Quality Based on Visual Analog Scale (VAS) at Week 14 | Sleep quality was assessed by an 11-point visual analog scale that rates how well participants slept. Participants indicated on the scale (from 0 to 100 millimeter) how well they slept in the previous 7 days (from 0: very badly to 100: very well). | Baseline and Week 14 | 
| Double Blind (DB) Phase: Change From DB Baseline in Sleep Quality Based on Visual Analog Scale (VAS) at DB Endpoint | Sleep quality was assessed by an 11-point visual analog scale that rates how well participants slept. Participants indicated on the scale (from 0 to 100 millimeter) how well they slept in the previous 7 days (from 0: very badly to 100: very well). Change at DB endpoint was calculated as value at interim analysis data cut-off (09 November 2012) minus value at DB Baseline (Day 1 of week 15). | DB Baseline (Day 1 of Week 15) up to DB endpoint (study completion [09 November 2012] [Approximately 1 year]) | 
| Run-In and Stabilization Phase: Change From Baseline in Daytime Drowsiness Based on Visual Analog Scale (VAS) at Week 14 | Daytime drowsiness was assessed by an 11-point visual analog scale that rates how well participants slept. Participants indicated on the scale (from 0 to 100 millimeter) how often they felt drowsy in the previous 7 days (from 0: very badly to 100: very well). | Baseline and Week 14 | 
| Double Blind (DB) Phase: Change From DB Baseline in Daytime Drowsiness Based on Visual Analog Scale (VAS) at DB Endpoint | Daytime drowsiness was assessed by an 11-point visual analog scale that rates how well participants slept. Participants indicated on the scale (from 0 to 100 millimeter) how often they felt drowsy in the previous 7 days (from 0: very badly to 100: very well). Change at DB endpoint was calculated as value at interim analysis data cut-off (09 November 2012) minus value at DB Baseline (Day 1 of week 15). | DB Baseline (Day 1 of Week 15) up to DB endpoint (study completion [09 November 2012] [Approximately 1 year]) | 
| Double Blind (DB) Phase: Median Time to Relapse (Final Analysis) | A relapse is defined as any one of the following: 1. involuntary or voluntary psychiatric hospitalization 2. deliberate self-injury or violent behavior; 3. Suicidal or homicidal ideation and clinically significant aggressive behavior; 4. 25 percent (%) increase in Positive and Negative Syndrome Scale (PANSS) total score for 2 consecutive assessments for participants whose score was greater than 40 at randomization, or a 10-point increase for participants who scored less than or equal to (≤) 40 at randomization; 5. increase for 2 consecutive assessments in PANSS items (delusions, conceptual disorganization, hallucinatory behavior, suspiciousness, hostility or uncooperativeness) to greater than or equal to (≥) 5 for participants who scored ≤3 at randomization, or to ≥6 for participants with initial score of 4. Independent Data Monitoring Committee performed final analysis at the end of double-blind treatment (09 November 2012). | DB Baseline (Day 1 of Week 15) up to study completion (09 November 2012) (Approximately 1 year) | 
| Open-label Extension (OLE) Phase: Change From OLE Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at OLE Endpoint | The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia including delusions, grandiosity, blunted affect, 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 consists of the sum of all 30 PANSS items and ranges from 30 to 210. Higher scores indicate worsening. Change at OLE endpoint was calculated as value at OLE endpoint (24 weeks after DB phase (26 April 2013) minus value at OLE Baseline (09 November 2012). | OLE Baseline (09 November 2012) up to OLE endpoint (that is, up to 24 Weeks [26 April 2013] from DB endpoint) | 
| Open-label Extension (OLE) Phase: Change From OLE Baseline in Clinical Global Impression-Severity Scale (CGI-S) Total Score at OLE Endpoint | CGI-S is a 7-point clinician-rated scale to assess severity of participant's current illness state, ranging from (1)Normal, not ill at all, (2)Borderline mentally ill, (3)Mildly ill, (4)Moderately ill, (5)Markedly ill, (6)Severely ill, (7)Among the most severely ill. Change at OLE endpoint was calculated as value at OLE endpoint (24 weeks after DB phase (26 April 2013) minus value at OLE Baseline (09 November 2012). | OLE Baseline (09 November 2012) up to OLE endpoint (that is, up to 24 Weeks [26 April 2013] from DB endpoint) | 
| Open-label Extension (OLE) Phase: Change From OLE Baseline in Personal and Social Performance (PSP) Scale Total Score at OLE Endpoint | The PSP is 100-point validated clinician-rated scale that assesses degree of difficulty in 4 areas of functioning: socially useful activities, personal and social relationships, self-care, disturbing and aggressive behaviors rated on 6-point scale (1=absent to 6=very severe).Total transformed score from 1 to 100 is generated from raw score based on clinical interpretation of scores generated in 4 areas of functioning, with higher transformed score indicating better function. Total score is divided into 3 levels: 71-100 (mild difficulty); 31-70 (marked difficulty) and 1-30 (severe difficulty). Percentage of participants achieving improvement in PSP score by at least one category was reported. Change at OLE endpoint was calculated as value at OLE endpoint (24 weeks after DB phase (26 April 2013) minus value at OLE Baseline (09 November 2012). | OLE Baseline (09 November 2012) up to OLE endpoint (that is, up to 24 Weeks [26 April 2013] from DB endpoint) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Paliperidone, Paliperidone Extended-Release