Pharmacokinetics and Tolerability Study of Risperidone ISM® in Schizophrenia (PRISMA-2)

Multicenter, Open-label, Two-arm, Parallel-design, Repeat-dose Clinical Trial to Evaluate the PK, Safety, and Tolerability of Four Intramuscular Injections of Risperidone ISM® 75 mg, at 28 Day Intervals in Patients With Schizophrenia

To characterize the pharmacokinetics (PK) of the injectable intramuscular (IM) long-acting formulation (in situ microparticle, ISM) of risperidone over four IM injections in the gluteal and deltoid muscle at 28-day intervals and at one dose strength (75 mg) in patients with schizophrenia.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Risperidone ISM

Detailed Description

This was a multicenter, open-label, two-arm, parallel-design, repeat-dose clinical study designed to evaluate the PK, safety, and tolerability of Risperidone ISM®, a new long-acting injectable formulation of the licensed drug risperidone, administered in the gluteal muscle or the deltoid muscle. Participants were patients with a diagnosis of schizophrenia capable of understanding, signing, and consenting to study participation on their own.

Objectives:

Primary Objective

• To characterize the pharmacokinetics (PK) of the injectable intramuscular (IM) long-acting formulation of risperidone over four IM injections in the gluteal and deltoid muscle at 28 day intervals and at one dose strength (75 mg) in patients with schizophrenia.

Secondary Objectives

• To document the attainment of steady-state exposure by the injectable formulation ISM® of risperidone over four IM injections in the gluteal and deltoid muscle at 28-day intervals and at one dose strength (75 mg) in patients with schizophrenia.
• To perform a descriptive comparison of the PK data between the gluteal and the deltoid muscle administration of the injectable formulation ISM® of risperidone over four IM injections at 28-day intervals and at one dose strength (75 mg) in patients with schizophrenia.
• To evaluate the safety and tolerability of the injectable formulation ISM® of risperidone after four IM injections in the gluteal muscle or deltoid muscle at 28-day intervals at one dose strength (75 mg) in patients with schizophrenia.

Exploratory Objectives

• To explore the efficacy of once every four weeks of the injectable formulation ISM® of risperidone after four IM injections in the gluteal muscle or deltoid muscle at 28-day (± 1 day) intervals at one dose strength (75 mg) in patients with schizophrenia.
• To characterize patients' metabolic phenotype (cytochrome P450 [CYP]2D6, CYP3A4) to explain any potential unexpected outlying PK value, and/or explore its relationship with any potential safety or tolerability issue.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • St Louis Clinical Trials, LC

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:

1. Capable of providing informed consent.
2. Male or female aged ≥18 years to ≤65 years.
3. Current diagnosis of schizophrenia, according to Diagnostic and Statistical Manual
4. Body mass index (BMI) ≥17 kg/m2 but ≤35 kg/m2.
5. Medically stable over the last month, and psychiatrically stable
6. On oral stable dosage of risperidone ≥4 mg daily as maintenance therapy.
7. Total score ≤70 on the Positive and Negative Syndrome Scale.
8. Using a medically accepted contraceptive method
9. Agrees to washout all prohibited medications prior to baseline (day -1)

Exclusion Criteria:

1. Informed consent obtained from a third party.
2. Prisoners or patients who are compulsorily detained.
3. Females who are breast-feeding and/or who have a positive pregnancy test.
4. Presence of an uncontrolled, unstable clinically significant medical condition.
5. Positive serology for Hepatitis B, Hepatitis C or anti-HIV 1 and 2 at screening.
6. History of neuroleptic malignant syndrome.
7. Current or past history of tardive dyskinesia.
8. Positive urine drug or alcohol screen finding.
9. Risk of committing self-harm or harm based on Columbia Suicidal Rating Scale.
10. Taking more than one antidepressant.
11. Use of depot antipsychotics within the last three months.
12. Use of strong or moderate cytochrome P450 isoenzyme 3A4inducers
13. Use of electroconvulsive therapy (ECT) within the last three months.
14. Receipt of any investigational drugs within the last three months.
15. Known or suspected allergy or hypersensitivity to risperidone
16. Previous non-responder to risperidone treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gluteus (Risperidone ISM); Risperidone ISM (75 mg) injection in the gluteal muscle at 28-day intervals	Drug: Risperidone ISM; Four doses of 75 mg of Risperidone ISM as intramuscular (IM) injection into the deltoid muscle at 28-day intervals. Four doses of 75 mg of Risperidone ISM as intramuscular injections into the gluteal muscle at 28-day intervals.; Other Names: No other names
Experimental: Deltoid (Risperdione ISM); Risperidone ISM (75 mg) injection in the deltoid muscle at 28-day intervals	Drug: Risperidone ISM; Four doses of 75 mg of Risperidone ISM as intramuscular (IM) injection into the deltoid muscle at 28-day intervals. Four doses of 75 mg of Risperidone ISM as intramuscular injections into the gluteal muscle at 28-day intervals.; Other Names: No other names

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Plasma Concentration (Cmax) for Active Moiety		Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.
Trough Plasma Concentration (Cmin) for Active Moiety		Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.
Area Under the Curve to the Last Quantified Concentration (AUClast) for Active Moiety		Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.
Area Under the Curve Extrapolated to Infinity (AUC∞) for Active Moiety		Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.
AUCτ for Active Moiety	AUCτ is the area under the curve over the dosing interval (τ), where the dosing interval is 28 days	Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.
Time to Peak Concentration (Tmax) for Active Moiety		Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.
Terminal Half-life (t1/2) for Active Moiety		Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.
PTF for Active Moiety	Peak to Trough Fluctuation ratio for the Active Moiety	Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Accumulation Ratio (RA) for Active Moiety	Defined as AUC (0-28 days) after the 4th dose divided by the AUC (0-28 days) of the first dose.	Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive and Negative Syndrome Scale (PANSS) Total Score	The change in PANSS score from Baseline by visit 48. The PANSS combines 3 subscales: The positive scale (7 items), the negative scale (7 items) and the general psychopathology scale (16 items). PANSS Items Scores: 1 = Absent, 2 = Minimal, 3 = Mild, 4 = Moderate, 5 = Moderate Severe, 6 = Severe, 7 = Extreme. Subscales are summed to compute a total score Range for each of the subscales: Positive scale (7-49); Negative scale (7-49); General psychopathology scale (16-112) Range for the PANSS total scale: 30-210 PANSS total score ≤70: stable schizophrenia PANSS total score between >70: decompensated schizophrenia	Baseline, Days 5, 7, 10, 14, 18, and 21 post Dose 1; Dose 2, 3 and 4 post dose; Days 5, 7, 10, 14, 18, and 21 post Dose 2, 3, and 4; Days 25, 28, 32, 37, 42, 60, 75, 90, and 105 post Dose 4; Day 120 post Dose 4 or early termination.

Collaborators and Investigators

• Sponsor: Rovi Pharmaceuticals Laboratories
• Investigators: Study Chair: Jordi Llaudó, M.D, Rovi Laboratorios Farmacéuticos

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: February 10, 2014
• First Submitted That Met QC Criteria: March 11, 2014
• First Posted (Estimate): March 13, 2014

Study Record Updates

• Last Update Posted (Actual): July 13, 2017
• Last Update Submitted That Met QC Criteria: June 14, 2017
• Last Verified: May 1, 2015

More Information

Terms related to this study

• 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: ROV-RISP-2011-02

Plan for Individual participant data (IPD)

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