PK, Safety, and Tolerability Study of RBP-7000 of Different Molecular Weight Polymer in Subjects With Schizophrenia

A Multicenter, Randomized, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of RBP-7000 Using Poly (DL-lactide-co-glycolide) Polymer of Two Different Molecular Weights (Low and High Molecular Weights as Test Treatments) Compared to Intermediate Molecular Weight (Reference Treatment) Polymer in Subjects With Schizophrenia

Primary Objective: To assess the relative bioavailability of RBP-7000 formulated with 2 different molecular weights (MW) (low and high MW as test treatments) of poly (DL-lactide-co-glycolide) with a carboxylic acid end group (PLGH) polymer compared to intermediate MW PLGH polymer following single subcutaneous (SC) injection of RBP-7000 in subjects with stable schizophrenia.

Secondary Objective:

To evaluate the safety and tolerability of single SC injections of RBP-7000 using a PLGH polymer of 2 different MW (low and high MW as test treatments) compared to intermediate MW polymer in subjects with stable schizophrenia.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: RBP-7000

Detailed Description

This is a multicenter, randomized, open-label, single-dose, parallel-group study in subjects with clinically stable schizophrenia who are not currently taking risperidone. A total of approximately 48 subjects (16 per group) will be randomized to receive a single subcutaneous (SC) injection of RBP-7000 120 mg formulated with PLGH polymer of either 21 kilodaltons (kDa) (low MW group), 29 kDa of PLGH polymer (high MW group), or 26 kDa of PLGH polymer (intermediate MW group).

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Garden Grove, California, United States, 92845
      • Collaborative Neuroscience Network, LLC
    • Torrance, California, United States, 90502
      • Collaborative NeuroScience Network

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of schizophrenia as defined by DSM-5 criteria.
• Clinically stable schizophrenia, as evidenced by the investigator evaluation, outpatient status for at least 30 days prior to screening, and confirmation of stability by a caregiver who has regular supportive contact with the subject.
• Otherwise healthy on the basis of physical examination.
• Body mass index (BMI) between 18 and 35 kg/m^2 and weight of at least 49.9 kg at screening.

Exclusion Criteria:

• Subjects taking any oral risperidone product (except the test doses of 0.25 mg of risperidone); or subjects taking any risperidone or 9-hydroxyrisperidone sustained-release or depot formulation within 120 days prior to study screening; or subjects who have received the 3-month depot formulation of 9-hydroxyrisperidone within 2 years of study screening.
• Subjects taking a clinically relevant inducer or inhibitor of cytochrome P450 (CYP) 2D6, or CYP3A4, who have not undergone proper washout (minimum of 5 half-lives of the medication) of this prohibited medication prior to Day 1.
• Medications, which in the opinion of the Investigator in conjunction with the medical monitor, may be expected to significantly interfere with metabolism or excretion of risperidone and/or 9-hydroxyrisperidone; may be associated with a significant drug interaction with risperidone; or may pose a significant risk to a subject's participation in the study.
• Any natural products or herbal preparations including all vitamins and supplements throughout the study.
• Subjects with a history of cancer unless disease-free for ≥5 years (with the exception of resected basal cell or squamous cell carcinoma of the skin).
• Subjects with any other active medical condition/disorder/disease that may either compromise subject safety or interfere with the safety and/or outcome evaluation of the study drug.
• Subjects that had an exacerbation of schizophrenia in the last 30 days.
• Subjects with evidence or history (in the past 6 months prior to screening) of a significant hepatic disorder that may either compromise subject 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 >1.5 x the upper limit of normal (ULN), or
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2x ULN.
• Subjects with a history of severe renal disease, or creatinine clearance <60 mL/min
• Subjects with evidence or history of orthostatic hypotension within 6 months of screening.
• Subjects with absolute neutrophil count <1.5x 10^9/L (African and African/American <1.2x 10^9/L).
• Subjects with a history of drug-induced leucopenia.
• Subjects who have acquired immune deficiency syndrome (AIDS) or to be human immunodeficiency virus (HIV)-positive.
• Subjects 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), or clinically significant low blood pressure or arrhythmias as interpreted by the Principal Investigator or medically qualified sub-investigator.
• Subjects with congenital long QT syndrome, history of prolonged QT in the 3 months prior to screening, or a corrected QT interval (Fridericia - QTcF) >450 msec (male) or >470 msec (female) at screening (Visit 1).
• Subjects with suicidal ideation with intent or plan
• Subjects with uncontrolled depression, in the opinion of the Investigator.
• Subjects with a diagnosis of insulin-dependent diabetes, or who have a hemoglobin A1c (HbA1c) ≥8.0% at screening, or have had changes in diabetic medication regimen in the 28 days prior to signing the informed consent document.
• Subjects with prior allergic reactions, sensitivities or other known contraindications to any component of RBP-7000 (e.g., risperidone, PLGH or NMP).
• Women of childbearing potential who are pregnant or breastfeeding, seeking pregnancy, or failing to use adequate contraceptive methods during the study.
• Subjects with the presence of opioids, cocaine, amphetamines, methadone, barbiturates, benzodiazepines, methamphetamines, cannabinoids, or phencyclidine in the urine as assessed by a urine drug screen.
• Subjects with epilepsy or other seizure disorders, Parkinson's disease or dementia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: RBP-7000 PLGH A; A single subcutaneous injection of RBP-7000 containing 120 mg risperidone in the ATRIGEL® Delivery System formulated with 21 kDa PLGH polymer.	Drug: RBP-7000; A single subcutaneous injection with doses of RBP-7000 containing 120 mg risperidone and either a low, high, or intermediate molecular weight PLGH polymer.; Other Names: Risperdal
EXPERIMENTAL: RBP-7000 PLGH B; A single subcutaneous injection of RBP-7000 containing 120 mg risperidone in the ATRIGEL® Delivery System formulated with 29 kDa PLGH polymer.	Drug: RBP-7000; A single subcutaneous injection with doses of RBP-7000 containing 120 mg risperidone and either a low, high, or intermediate molecular weight PLGH polymer.; Other Names: Risperdal
ACTIVE_COMPARATOR: RBP-7000 PLGH C; A single subcutaneous injection of RBP-7000 containing 120 mg risperidone in the ATRIGEL® Delivery System formulated with 26 kDa PLGH polymer. This intermediate molecular weight treatment serves as the reference treatment.	Drug: RBP-7000; A single subcutaneous injection with doses of RBP-7000 containing 120 mg risperidone and either a low, high, or intermediate molecular weight PLGH polymer.; Other Names: Risperdal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Initial Burst Parameters: Cmax of risperidone	Maximum observed plasma concentration	approximately 0-24 hours; Day 1 to Day 2
Initial Burst Parameters: AUC0-24h of risperidone	Area under the plasma concentration-time curve from time 0 to 24 hours post-dose; calculated using the linear trapezoidal rule.	approximately 0-24 hours; Day 1 to Day 2
Secondary Peak Parameters: Cmax of risperidone	Maximum observed plasma concentration	approximately 24-672 hours; Day 2 to Day 29
Secondary Peak Parameters: AUCD2-D29 of risperidone	Area under the plasma concentration-time curve from 24 hours post-dose (Day 2) to 672 hours post-dose (Day 29); calculated using the linear trapezoidal rule.	approximately 24-672 hours; Day 2 to Day 29
Overall Parameters: Cmax of risperidone	Maximum observed plasma concentration	Day 1 to Day 29
Overall Parameters: AUCD1-D29 of risperidone	Area under the plasma concentration-time curve from time 0 (Day 1) to 672 hours post-dose (Day 29); calculated using the linear trapezoidal rule.	Day 1 to Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Initial Burst Parameters: Cmax of 9-hydroxyrisperidone	Maximum observed plasma concentration	approximately 0-24 hours; Day 1 to Day 2
Initial Burst Parameters: AUC0-24h of 9-hydroxyrisperidone	Area under the plasma concentration-time curve from time 0 to 24 hours post-dose; calculated using the linear trapezoidal rule.	approximately 0-24 hours; Day 1 to Day 2
Secondary Peak Parameters: Cmax of 9-hydroxyrisperidone	Maximum observed plasma concentration	approximately 24-672 hours; Day 2 to Day 29
Secondary Peak Parameters: AUCD2-D29 of 9-hydroxyrisperidone	Area under the plasma concentration-time curve from 24 hours post-dose (Day 2) to 672 hours post-dose (Day 29); calculated using the linear trapezoidal rule.	approximately 24-672 hours; Day 2 to Day 29
Overall Parameters: Cmax of 9-hydroxyrisperidone	Maximum observed plasma concentration	Day 1 to Day 29
Overall Parameters: AUCD1-D29 of 9-hydroxyrisperidone	Area under the plasma concentration-time curve from time 0 (Day 1) to 672 hours post-dose (Day 29); calculated using the linear trapezoidal rule.	Day 1 to Day 29
Summary of Participants with Adverse Events		Day 1 to Day 29

Collaborators and Investigators

• Sponsor: Indivior Inc.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (ACTUAL): May 1, 2016
• Study Completion (ACTUAL): May 1, 2016

Study Registration Dates

• First Submitted: February 17, 2016
• First Submitted That Met QC Criteria: February 17, 2016
• First Posted (ESTIMATE): February 23, 2016

Study Record Updates

• Last Update Posted (ESTIMATE): January 31, 2017
• Last Update Submitted That Met QC Criteria: January 30, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Schizophrenia; Long-acting Risperidone; Atrigel
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Dopamine Antagonists; Risperidone
• Other Study ID Numbers: RB-US-15-0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO