Long Term Study of RBP 7000 in the Treatment of Subjects With Schizophrenia

Study Overview
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Brief Summary
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This is a Phase 3, open label study administering RBP-7000 in the treatment of patients with schizophrenia. Study will assess the long-term safety and tolerability of RBP-7000 subcutaneous (SC) injections in subjects with schizophrenia and to continue collecting clinical outcome data with RBP-7000 SC injections in subjects with schizophrenia using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity Illness (CGI-S) scale.

Detailed Description
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Patients to be screened must be diagnosed with schizophrenia with a designated score based on the PANSS, as confirmed by a State, Assessability, Face, Ecological and Rule (SAFER) interview. De novo patients are patients who are already receiving 3- or 4-mg oral risperidone/day and will not have to complete the run-in or conversion phases (see below) and will be assigned to receive RBP-7000 after eligibility has been confirmed. Patients who completed the double-blind, placebo-controlled, efficacy study of RBP-7000 (RB-US-09-0010, NCT02109562), conducted in patients with acute schizophrenia (referred to as roll-over patients) will be screened. All patients will be assigned the 120 mg dose of RBP-7000, which is subject to a one-time down-titration to 90-mg RBP-7000 for tolerability, at the investigator's discretion. Patients receiving the 90-mg dose of RBP-7000 who exhibit a worsening in psychiatric symptoms, confirmed by a total PANSS score >70 or a 20% increase in the PANSS score from the previous assessment at the 120-mg dose level (before the dose was decreased to 90 mg), can receive a one-time, up-titration back to 120-mg RBP-7000 at the discretion of the investigator. De novo patients entering into the study are those patients who did not participate in study RB-US-09-0010 (NCT02109562) and are allocated into three groups with different pre-study procedures to prepare for the treatment period: Run-in patients are patients who are not already receiving oral risperidone (as no other antipsychotic medications are allowed during study participation) and will begin a 14-day run-in period by titrating up to a dose of 3 or 4 mg oral risperidone/day before the first injection of RBP-7000. Conversion patients are patients who are receiving oral risperidone doses other than 3 or 4mg/day and will begin a 7-day conversion period to achieve an oral risperidone dose level of 3 or 4-mg before the first injection of RBP-7000, only if clinically indicated. De novo patients taking an oral risperidone dose of 3 or 4 mg/day prestudy will (once screened/enrolled) receive the first injection of RBP-7000. Roll-over patients entering into the study are patients who completed 56 days of double-blind treatment in Study RB-US-09-0010. These patients will be eligible to enter the current study provided that continuation of treatment is clinically warranted, as judged by the investigator, and that there have been no significant protocol deviations or clinically relevant adverse events (AEs) that would preclude inclusion in this study. Roll-over patients will not undergo the complete screening process and will not require either a run-in or conversion period with oral risperidone. On Day 1 of the open-label study (which is Day 57 of Study RB-US-09-0010), patients will receive their first injection (120 mg) of open label RBP-7000.

Official Title
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An Open-Label, Long-Term Safety and Tolerability Study of RBP-7000 in the Treatment of Subjects With Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: RBP-7000


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: De Novo Patients Diagnosis of schizophrenia as defined by Diagnostic and Statistical Manual, Edition 4, text revision (DSM-IV-TR) criteria Total PANSS score <=70 at the time of screening (Visit 1) Otherwise healthy on the basis of physical examinatIon Provided written informed consent Roll-over Patients Provided written consent to participate in this study Be considered eligible to enroll based on End of Study (EOS) (Day 57 of Study RB-US-09-0010) assessments and the medical judgment of the investigator Exclusion Criteria: De Novo Patients Patients taking daily oral risperidone at a dose plus/minus 6 mg/day Patients taking any risperidone or 9-hydroxyrisperidone long-acting injectable formulation within 120 days of study screening (Visit 1) Patients who have received a long-acting injectable antipsychotic within 120 days of screening (Visit 1) Patients with evidence or history (in the past six months prior to screening) of a significant hepatic disorder that may either compromise patient safety or interfere with the safety and/or outcome evaluation of the study drug, including: Acute or chronic hepatitis, including but not limited to hepatitis B or C Total bilirubin greater than 1.5 times the upper limit of normal (ULN), or Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2 times ULN Patients with a history of drug-induced leukopenia Patients with other medical conditions including, but not limited to, history of heart attack (myocardial infarction) or brain injury (traumatic injury with loss of consciousness and/or cerebrovascular accident), and clinically significant low blood pressure or arrhythmias as interpreted by the primary investigator (PI) or medically qualified sub-investigator Patients with epilepsy or other seizure disorders, Parkinson's disease or dementia Roll-over Patients Patients requiring an inpatient treatment setting at the end of Study RB-US-09-0010 Patients with an unstable medical condition developed during Study RB-US-09-0010 Women of childbearing potential who have a positive pregnancy test at screening (Visit 1), who are pregnant or breastfeeding, seeking pregnancy, or failing to use adequate contraceptive methods during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RBP-7000 - 120-mg dose<br>RBP-7000 120-mg subcutaneous (SC) injections every 28 days for 13 doses as open-label therapy. Patients enter the study as 'roll-over' patients from study RB-US-09-0010, or de novo patients. Pre-study procedures vary for de novo patients depending on previous therapy. | Drug: RBP-7000<br>* 120-mg RBP-7000 dose delivered by subcutaneous injection every 28 days for a total of 13 injections (for roll-over participants, the first two injections took place under study RB-US-09-0010). A one-time down-titration to 90 mg RBP-7000 is permitted at the investigator's discretion should the participant have tolerability issues. Participants who received the 90-mg dose of RBP-7000 and exhibited a worsening in psychiatric symptoms could receive a one-time up-titration back to 120 mg RBP-7000 at the discretion of the investigator. RBP-7000 is a combination of the ATRIGEL Delivery System and risperidone. The ATRIGEL Delivery System allows for sustained-release of risperidone in a controlled manner.<br>* Other names: Long-acting Risperidone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 up to week 52 | 
| Participants With Injection Site-Related Treatment-Emergent Adverse Events (TEAEs) | 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. Adverse events were coded using MedDRA version 17.0. Preferred terms linked to injection site AEs are reported. Although a participant may have had 2 or more AEs, the subject is counted only once in each preferred term category. The same subject may appear in different preferred term categories. | Day 1 up to week 52 | 
| Participants With Markedly Abnormal Weight Gain Anytime During the Study as Compared to Baseline | Participants who were found to have gain >=7% and >=10% of their baseline weight at any point during the study (including unscheduled assessments) once treatment began. | Baseline (Day 0), Treatment (Day 1 up to Week 52) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score to Days 29, 169 and End of Study | 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. | Baseline (Day 0), Day 29, Day 169 and End of Study (approximately Week 52) | 
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Subscale Scores to End of Study | PANSS subscales: Positive scale assesses 7 items: delusions, conceptual disorganization, hallucinations, excitement, grandiosity, suspiciousness/persecution, and hostility. Scale: 7 (absent) to 49 (extreme psychopathology) Negative scale assesses 7 items: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking. Scale: 7 (absent) to 49 (extreme psychopathology) General Psychopathology scale assesses 16 items: somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, and active social avoidance. Scale: 16 (absent) to 112 (extreme psychopathology) Negative change from baseline scores indicate improvements. | Baseline (Day 0), End of Study (approximately Week 52) | 
| Change From Baseline in Clinical Global Impression - Severity Scores (CGI-S) to Days 29, 169 and End of Study | 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. | Baseline (Day 0), Baseline (Day 0), Day 29, Day 169 and End of Study (approximately Week 52) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Schizophrenic, Schizophrenias, Risperidone, Long-acting Risperidone, Atrigel, Subcutaneous