Pharmacokinetics, Safety, and Tolerability of Intravenous Posaconazole Solution Followed by Oral Posaconazole Suspension in Subjects at High Risk for Invasive Fungal Infections (P05520)

Study Overview
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Brief Summary
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The purpose of this study is to collect pharmacokinetic (PK) information related to how well intravenous Posaconazole (POS IV), is distributed in the body and to determine the safety and tolerability of this new formulation. In addition, the PK, safety, and tolerability of switching from taking POS IV to taking Posaconazole Oral Suspension (POS Oral) will be evaluated. The data collected in this study will be compared to data collected in previous studies. Individuals who have been diagnosed by their physicians with a blood disease or cancer that can affect their infection-fighting white blood cells will be asked to participate in the trial. Since these blood diseases and their treatments can weaken the immune system, they may put these individuals at a high risk for getting a serious fungal infection of their internal organs or blood (invasive fungal infection). As these fungal infections can be hard to detect early and can be life-threatening, many physicians believe that individuals diagnosed with these diseases should receive antifungal therapy to try to lower their risk of getting this type of infection. Enrollment into this study will take place in several stages (cohorts). The determination of which cohort an individual will be asked to participate in is based on which cohort is open at the site at the time the individual is approached to consider study participation.

Official Title
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Pharmacokinetics, Safety, and Tolerability of Intravenous Posaconazole Solution Followed by Oral Posaconazole Suspension (SCH 56592) in Subjects at High Risk for Invasive Fungal Infections (Phase 1b; Protocol No. P05520)

Conditions
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Fungal Infection

Intervention / Treatment
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* Drug: Posaconazole
* Drug: Dextrose 5% in water


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult subjects greater than or equal to 18 years of age (weighing greater than 34 kg [75 lb]), of either sex and of any race/ethnicity. Disease definition for each subject: Anticipated (likely to develop within 3 days to 5 days) or documented prolonged neutropenia (absolute neutrophil count [ANC] <500/mm^3 [0.5 x 10^9/L]) at Baseline and likely to last for at least 7 days due to: a. Standard intensive chemotherapy, anthracycline-based or other accepted regimen (excluding any investigational agent), for a new diagnosis of acute myelogenous leukemia (AML); b. Chemotherapy for AML in first relapse; or c. Therapy for myelodysplastic syndromes in transformation to AML or other diagnoses of secondary AML (therapy related, antecedent hematological disorders) or chronic myelogenous leukemia in blast crisis Disease definition for each Cohort 3 subject: In addition to subjects defined above, allogeneic hematopoietic stem cell transplant (HSCT) subjects may be randomized in either the pre-engraftment period (i.e., after they have received their conditioning regimen for the transplant, but while they are still neutropenic) or in the post-engraftment period if they are receiving immunosuppressive therapy for prevention or treatment of graft-versus-host disease (e.g., steroids, tacrolimus, cyclosporin, mycophenolate mofetil, and antithymocyte globulin). Exclusion Criteria: A female subject must not be pregnant, must not intend to become pregnant during the study, or must not be nursing. Excluded prior treatments. A subject must not have received systemic antifungal therapy (oral, intravenous, or inhaled) for the treatment of proven or probable IFI within 30 days of Enrollment. A subject must not have moderate or severe liver dysfunction at Baseline, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal (ULN), AND a total bilirubin level greater than two times the ULN. For Cohorts 1 and 2, a subject must not have a known or suspected history of Gilbert's disease. A subject must not have an electrocardiogram (ECG) with a prolonged QTc interval by manual reading: QTc greater than 500 msec. A subject must not have prior enrollment in this study, or other POS studies within 90 days of study entry. A subject must not have a known or suspected invasive or systemic fungal infection at Baseline. Those subjects receiving empiric anti-fungal therapy within 7 days prior to Baseline must have had a diagnostic work-up that ruled out a possible invasive fungal infection. A subject must not have creatinine clearance levels (measured or calculated) below 50 mL/min. A subject must not have a history of Type I hypersensitivity or idiosyncratic reactions to azole agents.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: POS IV 200 mg single dose (Cohort 0)<br>POS 200 mg IV single dose infused over 1.5 hours on Day 1 followed 12 hours later by POS oral 400 mg, then by POS oral 400 mg BID on Days 2 through 6 and a single morning dose on Day 7 (Cohort 0) | Drug: Posaconazole<br> <br> * Other names: SCH 056592;|
| Placebo Comparator: Dextrose 5% in water (Cohort 0)<br>Placebo IV single dose infused over 1.5 hours on Day 1 followed 12 hours later by POS oral 400 mg, then by POS oral 400 mg BID on Days 2 through 6 and a single morning dose on Day 7 (Cohort 0) | Drug: Posaconazole<br> <br> * Other names: SCH 056592;Drug: Dextrose 5% in water<br> <br> * Other names: SCH 056592 (2);|
| Experimental: POS IV 200 mg BID (Cohort 1)<br>POS 200 mg IV infused over 1.5 hours BID on Day 1, followed by POS 200 mg IV once daily on Days 2 through 14, then by POS 400 mg oral BID through Day 28 (Cohort 1) | Drug: Posaconazole<br> <br> * Other names: SCH 056592;|
| Experimental: POS IV 300 mg BID (Cohort 2)<br>POS 300 mg IV infused over 1.5 hours BID on Day 1, followed by POS 300 mg IV once daily on Days 2 through 14, then by POS 400 mg oral BID through Day 28 (Cohort 2). After Day 5, POS IV was administered continuously or intermittently, depending on oral tolerability. | Drug: Posaconazole<br> <br> * Other names: SCH 056592;|
| Experimental: POS IV 300 mg BID (Cohort 3)<br>POS 300 mg IV infused over 1.5 hours BID on Day 1, followed by POS 300 mg IV once daily on Days 2 through 5, then by POS 200 mg oral TID or POS 400 mg oral BID through Day 28, or POS 200-300 mg IV once daily as required (Cohort 3). After Day 5, POS IV was administered continuously or intermittently, depending on oral tolerability. | Drug: Posaconazole<br> <br> * Other names: SCH 056592;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single Dose Trough Concentration of IV Posaconazole (Cmin) | Blood samples were collected from participants for the determination of plasma POS concentration. | 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2) | 
| Steady State Trough Concentration of IV Posaconazole (Cmin) | Blood samples were collected from participants for the determination of plasma POS concentration. | 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | 
| Single Dose Maximum Concentration of IV Posaconazole (Cmax) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2) | 
| Steady State Maximum Concentration of IV Posaconazole (Cmax) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | 
| Single Dose Time of Observed Maximum Concentration of IV Posaconazole (Tmax) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0 and 1) | 
| Steady State Time of Observed Maximum Concentration of IV Posaconazole (Tmax) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | 
| Single Dose Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2) | 
| Steady State Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 1, 1.5, 1.75, 4, 8, 12, and 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | 
| Steady State Average Concentration of IV Posaconazole (Cavg) | Blood samples were collected from participants for the determination of plasma POS concentration. Cavg was calculated as steady state AUC / dosing interval (24 hours). | Predose and 1, 1.5, 1.75, 4, 8, 12, and 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | 
| Steady State Total Body Clearance of IV Posaconazole (CL) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | 
| Steady State Trough Concentration of Oral Posaconazole (Cmin) | Blood samples were collected from participants for the determination of plasma POS concentration. | 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | 
| Steady State Maximum Concentration of Oral Posaconazole (Cmax) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | 
| Steady State Time of Observed Maximum Concentration of Oral Posaconazole (Tmax) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | 
| Steady State Area Under the Concentration Versus Time Curve of Oral Posaconazole (AUC) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | 
| Steady State Average Concentration of Oral Posaconazole (Cavg) | Blood samples were collected from participants for the determination of plasma POS concentration. Cavg was calculated as steady state AUC / dosing interval (12 hours). | Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | 
| Steady State Apparent Total Body Clearance of Oral Posaconazole (CL/F) | Blood samples were collected from participants for the determination of plasma POS concentration. | Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antifungal Agents pharmacokinetics, Mycoses prevention and control