Safety, Tolerability, and Pharmacokinetics of Iloperidone Depot in Schizophrenic Patients

An Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Two Iloperidone Depot Formulations Followed by a Dose-ranging Phase of One Selected Formulation in Schizophrenic Patients Given Depot Injections Every 28 Days

This study is designed as a 3-part trial to evaluate the safety of a novel depot formulation of iloperidone, compare 2 depot dosage forms, and perform dose ranging of 1 chosen form in support of a monthly depot dosing regimen. In Phase A, the study is designed to evaluate the safety of a crystalline iloperidone depot formulation. In Phase B, the pharmacokinetic and safety profile of 2 depot clinical dosage forms will be compared, and 1 form will be selected for assessment in Phase C. Phase C of this study is designed to define the dose-exposure relationship of the selected form and to provide information that will permit a comparison of the risk-benefit ratio of several doses of the study drug to enable optimal dose selection for later studies.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Iloperidone crystalline formulation; Drug: Oral iloperidone; Drug: Iloperidone microparticle formulation

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • Novartis Investigative Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19149
      • Novartis Investigative Site

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:

• Patients with schizophrenia that have been stable for 3 months.

Exclusion Criteria:

• Women who can become or are currently pregnant or lactating.
• Hypersensitivity to iloperidone or related drugs.

Other protocol-defined inclusion/exclusion criteria may apply.

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

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Iloperidone 50 mg crystalline formulation - Phase A; Participants received a crystalline formulation of iloperidone 50 mg in a depot intramuscular (IM) injection 1 time. Prior to receiving IM iloperidone, participants were gradually titrated up with oral iloperidone for at least 7 days to stable doses of 12 to 24 mg daily.	Drug: Iloperidone crystalline formulation; Iloperidone was formulated as 100 µm crystals for IM depot injection.; Drug: Oral iloperidone; Prior to receiving an intramuscular (IM) injection of iloperidone, patients were gradually titrated up with oral iloperidone to stable doses of 12 to 24 mg daily. In Phase A, oral iloperidone dosing lasted for at least 7 days and, in Phases B and C, for at least 10 to 14 days.
Experimental: Iloperidone 125 mg crystalline formulation - Phase A; Participants received a crystalline formulation of iloperidone 125 mg in a depot IM injection 1 time. Prior to receiving IM iloperidone, participants were gradually titrated up with oral iloperidone for at least 7 days to stable doses of 12 to 24 mg daily.	Drug: Iloperidone crystalline formulation; Iloperidone was formulated as 100 µm crystals for IM depot injection.; Drug: Oral iloperidone; Prior to receiving an intramuscular (IM) injection of iloperidone, patients were gradually titrated up with oral iloperidone to stable doses of 12 to 24 mg daily. In Phase A, oral iloperidone dosing lasted for at least 7 days and, in Phases B and C, for at least 10 to 14 days.
Experimental: Iloperidone 250 mg crystalline formulation - Phase B; Participants received a crystalline formulation of iloperidone 250 mg in a depot IM injection 1 time. Prior to receiving IM iloperidone, participants were gradually titrated up with oral iloperidone for at least 10 to 14 days to stable doses of 12 to 24 mg daily.	Drug: Iloperidone crystalline formulation; Iloperidone was formulated as 100 µm crystals for IM depot injection.; Drug: Oral iloperidone; Prior to receiving an intramuscular (IM) injection of iloperidone, patients were gradually titrated up with oral iloperidone to stable doses of 12 to 24 mg daily. In Phase A, oral iloperidone dosing lasted for at least 7 days and, in Phases B and C, for at least 10 to 14 days.
Experimental: Iloperidone 250 mg microparticle formulation - Phase B; Participants received a microparticle formulation of iloperidone 250 mg in a depot IM injection 1 time. Prior to receiving IM iloperidone, participants were gradually titrated up with oral iloperidone for at least 10 to 14 days to stable doses of 12 to 24 mg daily.	Drug: Oral iloperidone; Prior to receiving an intramuscular (IM) injection of iloperidone, patients were gradually titrated up with oral iloperidone to stable doses of 12 to 24 mg daily. In Phase A, oral iloperidone dosing lasted for at least 7 days and, in Phases B and C, for at least 10 to 14 days.; Drug: Iloperidone microparticle formulation; Iloperidone was formulated as microparticles for IM depot injection.
Experimental: Iloperidone 250 mg microparticle formulation - Phase C; Participants received a microparticle formulation of iloperidone 250 mg in a depot IM injection 2 times 28 days apart. Prior to receiving IM iloperidone, participants were gradually titrated up with oral iloperidone for at least 10 to 14 days to stable doses of 12 to 24 mg daily.	Drug: Oral iloperidone; Prior to receiving an intramuscular (IM) injection of iloperidone, patients were gradually titrated up with oral iloperidone to stable doses of 12 to 24 mg daily. In Phase A, oral iloperidone dosing lasted for at least 7 days and, in Phases B and C, for at least 10 to 14 days.; Drug: Iloperidone microparticle formulation; Iloperidone was formulated as microparticles for IM depot injection.
Experimental: Iloperidone 500 mg microparticle formulation - Phase C; Participants received a microparticle formulation of iloperidone 500 mg in a depot IM injection 2 times 28 days apart. Prior to receiving IM iloperidone, participants were gradually titrated up with oral iloperidone for at least 10 to 14 days to stable doses of 12 to 24 mg daily.	Drug: Oral iloperidone; Prior to receiving an intramuscular (IM) injection of iloperidone, patients were gradually titrated up with oral iloperidone to stable doses of 12 to 24 mg daily. In Phase A, oral iloperidone dosing lasted for at least 7 days and, in Phases B and C, for at least 10 to 14 days.; Drug: Iloperidone microparticle formulation; Iloperidone was formulated as microparticles for IM depot injection.
Experimental: Iloperidone 625 mg microparticle formulation - Phase C; Participants received a microparticle formulation of iloperidone 625 mg in a depot IM injection 2 times 28 days apart. Prior to receiving IM iloperidone, participants were gradually titrated up with oral iloperidone for at least 10 to 14 days to stable doses of 12 to 24 mg daily.	Drug: Oral iloperidone; Prior to receiving an intramuscular (IM) injection of iloperidone, patients were gradually titrated up with oral iloperidone to stable doses of 12 to 24 mg daily. In Phase A, oral iloperidone dosing lasted for at least 7 days and, in Phases B and C, for at least 10 to 14 days.; Drug: Iloperidone microparticle formulation; Iloperidone was formulated as microparticles for IM depot injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Iloperidone Divided by the Average Plasma Concentration (Cav) of Iloperidone (Cmax/Cav) - Phase B	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. PK parameters were calculated from plasma concentration-time data using non-compartmental methods.	Pre-dose to 26 days post-dose
The Average Plasma Concentration (Cav) of Iloperidone - Phase C	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. Blood samples were collected after each depot injection. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Cav was calculated as AUC0-672h/672 h.	Pre-dose to 26 days post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Reach the Maximum Plasma Concentration (Tmax) of Iloperidone - Phase B	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. PK parameters were calculated from plasma concentration-time data using non-compartmental methods.	Pre-dose to 26 days post-dose
Maximum Observed Plasma Concentration (Cmax) of Iloperidone - Phase B	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. PK parameters were calculated from plasma concentration-time data using non-compartmental methods.	Pre-dose to 26 days post-dose
Area Under the Plasma Concentration-time Curve From 0 to the End of the Dosing Period (AUCtau) of Iloperidone - Phase B	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. The area under the curve was calculated using a linear trapezoidal method. The end of the dosing period was 672 hours (28 days).	Pre-dose to 26 days post-dose
Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) of Iloperidone - Phase B	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. The area under the curve was calculated using a linear trapezoidal method.	Pre-dose to 26 days post-dose
The Average Plasma Concentration (Cav) of Iloperidone - Phase B	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Cav was calculated as AUC0-672h/672 h.	Pre-dose to 26 days post-dose
Duration That the Concentration of Iloperidone Was Above 4 ng/mL (Teff) - Phase B	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. The duration that the concentration of iloperidone was above 4 ng/mL was calculated by linear interpolation. PK/pharmacodynamic analysis performed in other studies suggests that iloperidone plasma levels of 4 ng/mL or above provide clinical efficacy.	Pre-dose to 26 days post-dose
Time to Reach the Maximum Plasma Concentration (Tmax) of Iloperidone - Phase C	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. Blood samples were collected after each depot injection. PK parameters were calculated from plasma concentration-time data using non-compartmental methods.	Pre-dose to 26 days post-dose
Maximum Observed Plasma Concentration (Cmax) of Iloperidone - Phase C	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. Blood samples were collected after each depot injection. PK parameters were calculated from plasma concentration-time data using non-compartmental methods.	Pre-dose to 26 days post-dose
Area Under the Plasma Concentration-time Curve From 0 to the End of the Dosing Period (AUCtau) of Iloperidone - Phase C	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. Blood samples were collected after each depot injection. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. The area under the curve was calculated using a linear trapezoidal method. The end of the dosing period was 672 hours (28 days).	Pre-dose to 26 days post-dose
The Average Plasma Concentration (Cav) of Iloperidone Divided by Dose - Phase C	Blood samples for pharmacokinetic (PK) evaluation were drawn pre-dose and at 3, 6, and 12 hours on Day 1; at 0 and 12 hours on Day 2; and on Days 3, 4, 6, 8, 10, 14, 18, 22, and 26 following administration of iloperidone. Blood samples were collected after each depot injection. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Cav was calculated as AUC0-672h/672 h.	Pre-dose to 26 days post-dose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: Vanda Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: April 28, 2011
• First Submitted That Met QC Criteria: May 3, 2011
• First Posted (Estimate): May 5, 2011

Study Record Updates

• Last Update Posted (Estimate): January 22, 2014
• Last Update Submitted That Met QC Criteria: December 17, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Schizophrenia; Injection; Iloperidone; Depot
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Iloperidone
• Other Study ID Numbers: CILO522E2101