Clinical trial NCT01677377: Multiple Ascending Dose Study of the Safety, Tolerability, Pharmacokinetic/Efficacy
Official title: A Phase 2A, Open-Label, Multiple Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics, and Primary Pharmacodynamic Markers of Efficacy of 60mg, 90mg, and 120mg of Risperidone in RBP-7000 Subcutaneous Injections in Subjects With Clinically Stable Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Schizophrenia
Keywords: Schizophrenia
Schizophrenic
Schizophrenias
Lead sponsor: Indivior Inc.
Sponsor class: INDUSTRY
First posted: 2012-09-03
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: Evaluate the safety and tolerability of multiple subcutaneous injections of various dosages of risperidone with clinically stable schizophrenia

Detailed description: This will be an open-label, Phase 2A, multiple ascending dose study in 1 to 3 sites, designed to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple subcutaneous injections of 60mg, 90mg, and 120mg doses of risperidone in the RBP-7000 formulation, in subjects with clinically-stable schizophrenia who are on a once daily stable dose of 2mg, 3mg, or 4mg of oral risperidone.

Eligibility criteria: Inclusion Criteria:

* Male and female
* \> 18 to \< 65 years
* Diagnosis of paranoid, residual, or undifferentiated schizophrenia as defined by Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR) criteria

  * Status: clinically stable subjects defined as subjects with no hospitalizations for acute exacerbations within 3 months of screening and screening total Positive and Negative Syndrome Scale (PANSS) score \< 60
* Subjects who have given written informed consent

Exclusion Criteria:

* Subjects taking any risperidone sustained release formulation within the 60 days prior to study screening
* Subjects taking the following concurrent medication/over-the-counter products:
* Inducers or inhibitors of cytochrome P450 2D6 (CYP-2D6) within 14 days or 7 half - lives (whichever occurs last) prior to study screening
* Bupropion, chlorpheniramine, cimetidine, clomipramine, doxepin, or quinidine within 30 days prior to study screening
* Clozapine, phenothiazines, aripiprazole, haloperidol, or any other antipsychotic other than oral risperidone within 14 days prior to study screening
* Selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine) or serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine, desvenlafaxine, duloxetine) within 30 days prior to study screening
* Opioids or opioid-containing analgesics within 14 days prior to study screening
* Medications, in addition to those listed above, which may be expected to significantly interfere with the metabolism or excretion of risperidone and/or 9-hydroxyrisperidone, that may be associated with a significant drug interaction with risperidone, or that may pose a significant risk to subjects' participation in the study
* Subjects with a history of cancer (with the exception of resected basal cell or squamous cell carcinoma of the skin) unless they have been disease free for \>5 years
* Subjects with another active medical condition or organ disease that may either compromise subject safety and/or outcome evaluation of the study drug
* Subjects with evidence or history of a significant hepatic disorder that may either compromise subject safety or interfere with the safety and/or outcome evaluation of the study drug. Individuals with acute hepatitis (including but not limited to B or C); or individuals with 1) total bilirubin \>1.5x the upper limit of normal and/or 2) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2x upper limit of normal (ULN) will be excluded
* Subjects with hepatitis C antibody and AST, ALT, or alkaline phosphatase \>2x and total bilirubin \>1.3 mg/dL will be excluded
* Subjects with a history of renal disease, or a creatinine clearance of less than 80 mL/min (as determined by the Cockcroft Gault formula)
* Subjects with an international normalized ratio \>2.0 at screening
* Subjects with corrected QT interval (Bazett's - QTcB) \>450 msec (male) or \>470 msec (female) at screening. Subjects with a QTc above these levels due to a benign right bundle branch block can be included in the study at the discretion of the PI
* Subjects who are known to have AIDS or to be HIV positive
* Subjects with suicidal ideation with intent and plan (Columbia-Suicide Severity Rating Scale (C-SSRS) affirmative answers to questions 4 and 5 of the ideation section) or suicide attempts within the last six months as noted on the C-SSRS, or subjects with uncontrolled depression in the opinion of the investigator
* Subjects with known diagnosis of type 1 or 2 diabetes or subjects with Hemoglobin A1c \>7.0 at screening
* Subjects who have participated in a clinical trial within 30 days prior to study screening
* Subjects who meet the DSM-IV-TR criteria for alcohol abuse or dependence within the last six months of screening

Primary outcomes:
measure: Summary of Participants With Treatment-Emergent Adverse Events (TEAE)
timeFrame: Day 1 to Day 106
measure: Total Risperidone PK: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24)
timeFrame: Day 1-2, Day 57-58
measure: Total Risperidone PK: Maximum Plasma Concentration (Cmax) During Initial Peak
timeFrame: Day 1-2, Day 57-58
measure: Total Risperidone PK: Time of Maximum Plasma Concentration (Tmax) During Initial Peak
timeFrame: Day 1-2, Day 57-58
measure: Total Risperidone PK: Area Under the Plasma Concentration-Time Curve From Time Zero to Time Tau (Where Tau=28 Days) (AUCtau)
timeFrame: Day 1-28, Day 57-84
measure: Total Risperidone PK: Average Plasma Concentration (Cavg) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Total Risperidone PK: Maximum Plasma Concentration (Cmax) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Total Risperidone PK: Minimum Plasma Concentration (Cmin) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Total Risperidone PK: Percent Fluctuation Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Total Risperidone PK: Swing Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Total Risperidone PK: Time of the Maximum Plasma Concentration (Tmax) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Total Risperidone PK: Accumulation Index Between Injections 1 and 3 In Terms of Area Under the Plasma Concentration Curve (Rac(AUC))
timeFrame: Day 1-28, Day 57-84
measure: Total Risperidone PK: Accumulation Index Between Injections 1 and 3 In Terms of Maximum Plasma Concentrations (Rac(Cmax))
timeFrame: Day 1-28, Day 57-84
measure: Total Risperidone PK: Area Under the Plasma Concentration-Time Curve From Day 2-29 Post Injection (AUC Day 2-29)
timeFrame: Day 2-29, Day 58-85
measure: Total Risperidone PK: Average Plasma Concentration Over the Secondary Peak (Cavg, Day 2-29)
timeFrame: Day 2-29, Day 58-85
measure: Total Risperidone PK: Maximum Plasma Concentration Over the Secondary Peak (Cmax)
timeFrame: Day 2-29, Day 58-85
measure: Total Risperidone PK: Minimum Plasma Concentration (Cmin) Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: Total Risperidone PK: Percent Fluctuation Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: Total Risperidone PK: Swing Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: Total Risperidone PK: Time of the Maximum Plasma Concentration (Tmax) Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: Risperidone PK: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24)
timeFrame: Day 1-2, Day 57-58
measure: Risperidone PK: Maximum Plasma Concentration (Cmax) During Initial Peak
timeFrame: Day 1-2, Day 57-58
measure: Risperidone PK: Time of Maximum Plasma Concentration (Tmax) During Initial Peak
timeFrame: Day 1-2, Day 57-58
measure: Risperidone PK: Area Under the Plasma Concentration-Time Curve From Time Zero to Time Tau (Where Tau=28 Days) (AUCtau)
timeFrame: Day 1-28, Day 57-84
measure: Risperidone PK: Average Plasma Concentration (Cavg) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Risperidone PK: Maximum Plasma Concentration (Cmax) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Risperidone PK: Minimum Plasma Concentration (Cmin) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Risperidone PK: Percent Fluctuation Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Risperidone PK: Swing Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Risperidone PK: Time of the Maximum Plasma Concentration (Tmax) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: Risperidone PK: Accumulation Index Between Injections 1 and 3 In Terms of Area Under the Plasma Concentration Curve (Rac(AUC))
timeFrame: Day 1-28, Day 57-84
measure: Risperidone PK: Accumulation Index Between Injections 1 and 3 In Terms of Maximum Plasma Concentrations (Rac(Cmax))
timeFrame: Day 1-28, Day 57-84
measure: Risperidone PK: Area Under the Plasma Concentration-Time Curve From Day 2-29 Post Injection (AUC Day 2-29)
timeFrame: Day 2-29, Day 58-85
measure: Risperidone PK: Average Plasma Concentration Over the Secondary Peak (Cavg, Day 2-29)
timeFrame: Day 2-29, Day 58-85
measure: Risperidone PK: Maximum Plasma Concentration Over the Secondary Peak (Cmax)
timeFrame: Day 2-29, Day 58-85
measure: Risperidone PK: Minimum Plasma Concentration (Cmin) Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: Risperidone PK: Percent Fluctuation Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: Risperidone PK: Swing Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: Risperidone PK: Time of the Maximum Plasma Concentration (Tmax) Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: 9-hydroxyrisperidone PK: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24)
timeFrame: Day 1-2, Day 57-58
measure: 9-hydroxyrisperidone PK: Maximum Plasma Concentration (Cmax) During Initial Peak
timeFrame: Day 1-2, Day 57-58
measure: 9-hydroxyrisperidone PK: Time of Maximum Plasma Concentration (Tmax) During Initial Peak
timeFrame: Day 1-2, Day 57-58
measure: 9-hydroxyrisperidone PK: Area Under the Plasma Concentration-Time Curve From Time Zero to Time Tau (Where Tau=28 Days) (AUCtau)
timeFrame: Day 1-28, Day 57-84
measure: 9-hydroxyrisperidone PK: Average Plasma Concentration (Cavg) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: 9-hydroxyrisperidone PK: Maximum Plasma Concentration (Cmax) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: 9-hydroxyrisperidone PK: Minimum Plasma Concentration (Cmin) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: 9-hydroxyrisperidone PK: Percent Fluctuation Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: 9-hydroxyrisperidone PK: Swing Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: 9-hydroxyrisperidone PK: Time of the Maximum Plasma Concentration (Tmax) Over the PK Profile
timeFrame: Day 1-28, Day 57-84
measure: 9-hydroxyrisperidone PK: Accumulation Index Between Injections 1 and 3 In Terms of Area Under the Plasma Concentration Curve (Rac(AUC))
timeFrame: Day 1-28, Day 57-84
measure: 9-hydroxyrisperidone PK: Accumulation Index Between Injections 1 and 3 In Terms of Maximum Plasma Concentrations (Rac(Cmax))
timeFrame: Day 1-28, Day 57-84
measure: 9-hydroxyrisperidone PK: Area Under the Plasma Concentration-Time Curve From Day 2-29 Post Injection (AUC Day 2-29)
timeFrame: Day 2-29, Day 58-85
measure: 9-hydroxyrisperidone PK: Average Plasma Concentration Over the Secondary Peak (Cavg, Day 2-29)
timeFrame: Day 2-29, Day 58-85
measure: 9-hydroxyrisperidone PK: Maximum Plasma Concentration Over the Secondary Peak (Cmax)
timeFrame: Day 2-29, Day 58-85
measure: 9-hydroxyrisperidone PK: Minimum Plasma Concentration (Cmin) Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: 9-hydroxyrisperidone PK: Percent Fluctuation Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: 9-hydroxyrisperidone PK: Swing Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
measure: 9-hydroxyrisperidone PK: Time of the Maximum Plasma Concentration (Tmax) Over the Secondary Peak
timeFrame: Day 2-29, Day 58-85
Secondary outcomes:
measure: Positive and Negative Syndrome Scale (PANSS) Scores at Baseline and Days 28, 56, 84 and 106
timeFrame: Baseline (Day -1), Days 28, 56, 84, and End of Study (Day 106 or early termination visit)
measure: Clinical Global Impression (CGI) Scores (Severity of Illness and Global Improvement) at Baseline and Days 28, 56, 84 and 106
timeFrame: Baseline (Day -1), Days 28, 56, 84, and End of Study (Day 106 or early termination visit)
measure: Global Assessment of the Abnormal Involuntary Movement Scale (AIMS) for Tardive Dyskinesia at Baseline and Days 28, 56, 84 and 106
timeFrame: Baseline (Day -1), Days 28, 56, 84, and End of Study (Day 106 or early termination visit)
measure: Total Simpson-Angus Scale (SAS) Score at Baseline and Days 28, 56, 84 and 106
timeFrame: Baseline (Day -1), Days 28, 56, 84, and End of Study (Day 106 or early termination visit)
measure: Global Clinical Assessment of Akathisia Using the Barnes Akathisia Scale (BAS) at Baseline and Days 28, 56, 84 and 106
timeFrame: Baseline (Day -1), Days 28, 56, 84, and End of Study (Day 106 or early termination visit)
measure: Participants With Suicidal Ideation or Behavior as Identified Using the Columbia-Suicide Severity Rating Scale (C-SSRS) Score at Baseline and Days 28, 56, 84 and 106
timeFrame: Baseline (Day -1), Days 28, 56, 84, and End of Study (Day 106 or early termination visit)
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Woodland International Research Group, Inc.
state: Alaska
city: Long Beach
country: United States
facility: Ocean View Psychiatric Health Facility
state: California
Study officials:
affiliation: Pharmaceutical Research Associates
name: Philippa Whitelaw, Sr. Dir of Proj Deliver
role: STUDY_DIRECTOR
affiliation: Pharmaceutical Research Associates
name: Ashley Huston, PMP
role: STUDY_DIRECTOR
References: