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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Schizophrenia	Drug: Iloperidone crystalline formulation; Drug: Iloperidone microparticle formulation; Drug: Oral iloperidone	Phase 1; Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	81 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	April 2011
Actual Primary Completion Date :	July 2012
Actual Study Completion Date :	July 2012

Arms and Interventions

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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: Iloperidone microparticle formulation; Iloperidone was formulated as microparticles 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 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: Iloperidone microparticle formulation; Iloperidone was formulated as microparticles 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 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: Iloperidone microparticle formulation; Iloperidone was formulated as microparticles 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 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: Iloperidone microparticle formulation; Iloperidone was formulated as microparticles 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.

Outcome Measures

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Primary Outcome Measures :

1. Maximum Observed Plasma Concentration (Cmax) of Iloperidone Divided by the Average Plasma Concentration (Cav) of Iloperidone (Cmax/Cav) - Phase B [ Time Frame: Pre-dose to 26 days post-dose ]
   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.
2. The Average Plasma Concentration (Cav) of Iloperidone - Phase C [ Time Frame: Pre-dose to 26 days post-dose ]
   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.

Secondary Outcome Measures :

1. Time to Reach the Maximum Plasma Concentration (Tmax) of Iloperidone - Phase B [ Time Frame: Pre-dose to 26 days post-dose ]
   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.
2. Maximum Observed Plasma Concentration (Cmax) of Iloperidone - Phase B [ Time Frame: Pre-dose to 26 days post-dose ]
   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.
3. Area Under the Plasma Concentration-time Curve From 0 to the End of the Dosing Period (AUCtau) of Iloperidone - Phase B [ Time Frame: Pre-dose to 26 days post-dose ]
   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).
4. Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) of Iloperidone - Phase B [ Time Frame: Pre-dose to 26 days post-dose ]
   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.
5. The Average Plasma Concentration (Cav) of Iloperidone - Phase B [ Time Frame: Pre-dose to 26 days post-dose ]
   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.
6. Duration That the Concentration of Iloperidone Was Above 4 ng/mL (Teff) - Phase B [ Time Frame: Pre-dose to 26 days post-dose ]
   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.
7. Time to Reach the Maximum Plasma Concentration (Tmax) of Iloperidone - Phase C [ Time Frame: Pre-dose to 26 days post-dose ]
   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.
8. Maximum Observed Plasma Concentration (Cmax) of Iloperidone - Phase C [ Time Frame: Pre-dose to 26 days post-dose ]
   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.
9. Area Under the Plasma Concentration-time Curve From 0 to the End of the Dosing Period (AUCtau) of Iloperidone - Phase C [ Time Frame: Pre-dose to 26 days post-dose ]
   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).
10. The Average Plasma Concentration (Cav) of Iloperidone Divided by Dose - Phase C [ Time Frame: Pre-dose to 26 days post-dose ]
    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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Novartis Pharmaceuticals

Vanda Pharmaceuticals

Investigators

Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

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Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT01348100 History of Changes
Other Study ID Numbers:	CILO522E2101
First Posted:	May 5, 2011
Results First Posted:	October 8, 2013
Last Update Posted:	January 22, 2014
Last Verified:	December 2013

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Schizophrenia; Iloperidone; Depot; Injection

Additional relevant MeSH terms:

Schizophrenia; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders