Pharmacokinetics and Safety of Posaconazole Tablet in Participants at High Risk for Invasive Fungal Infections (MK-5592-065/P05615)

Pharmacokinetics and Safety of Solid Oral Posaconazole (SCH 56592) in Subjects at High Risk for Invasive Fungal Infections (Phase 1b; Protocol No. P05615)

The purpose of this study is to collect pharmacokinetic (PK) information related to how well posaconazole tablet is distributed in the body and to determine the safety of this new formulation. The study consists of a Phase 1B study that includes participants with neutropenia undergoing chemotherapy for acute myelogenous leukemia (AML) or myelodysplasia (MDS) and a Phase 3 study that includes participants who are undergoing chemotherapy for AML or MDS and participants who are recipients of allogeneic hematopoietic stem cell transplant (HSCT).

Study Overview

• Status: Completed
• Conditions: Fungal Infections
• Intervention / Treatment: Drug: Posaconazole 200 mg; Drug: Posaconazole 300 mg

Detailed Description

Participants with a blood disease or cancer that can affect their infection-fighting white blood cells and those who have undergone a hematopoietic stem cell transplant (HSCT) and are receiving immunosuppressive therapy and have or are at risk of graft-vs-host disease (GVHD) are eligible for the study. These blood diseases and their treatments can weaken the immune system and may put individuals at high risk for a serious fungal infection of their internal organs or blood (invasive fungal infection). As these 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 (parts). The determination of which part a participant will be in is based on which part is open at the site at the time of enrollment.

• Study Type: Interventional
• Enrollment (Actual): 230
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Body weight >34 kg (75 lb) and of any race/ethnicity
• Able to swallow oral tablets whole
• Anticipated (likely to develop within 3-5 days) or documented neutropenia due to chemotherapy, chemotherapy for a new diagnosis of acute myelogenous leukemia (AML), or AML in first relapse; myelodysplastic syndromes (MDS) in transformation to AML; allogeneic hematopoietic stem cell transplant (HSCT) participants in the pre-engraftment period or in the post-engraftment period if they are receiving immunosuppressive therapy for graft versus host disease

Exclusion Criteria:

- Female must not be pregnant, must not intend to become pregnant

during the study, and must not be nursing

• History of hypersensitivity to azoles
• Moderate or severe liver dysfunction 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
• Electrocardiogram (ECG) with corrected QTc interval greater than 500 msec
• Posaconazole within 10 days before study enrollment
• Receipt of systemic antifungal therapy within 30 days of study enrollment for reasons other than antifungal prophylaxis
• Evidence of known or suspected invasive or systemic fungal infection at baseline
• Known or suspected history of Gilbert's disease
• Creatinine clearance levels below 30 mL/min

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Posaconazole 200 mg; Posaconazole 200 mg (two 100 mg tablets) twice daily (BID) on Day 1 followed by 200 mg (two 100 mg tablets) once daily (QD) for up to 28 days	Drug: Posaconazole 200 mg; Other Names: SCH 056592; MK-5592; Noxafil®
Experimental: Posaconazole 300 mg; Posaconazole 300 mg (three 100 mg tablets) BID on Day 1 followed by 300 mg (three 100 mg tablets) QD for up to 28 days	Drug: Posaconazole 300 mg; Other Names: SCH 056592; MK-5592; Noxafil®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Concentration (Cavg) of Posaconazole Tablet	Posaconazole steady-state concentrations of posaconazole in the plasma reached after regular and repeated dosing were used to estimate pharmacokinetic (PK) parameters for each participant where Cavg was defined as area under the plasma concentration versus time curve divided by the dosing interval. Blood samples for the assessment of Cavg were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.	Predose on Day 1 up to 24 hours postdose on Day 8
Minimum Concentration (Cmin) of Posaconazole Tablet	Cmin was defined as posaconazole trough level immediately before a participant received the dose of posaconazole tablets on the specified day. Trough (Cmin) level blood samples for determination of posaconazole in plasma were collected for all participants on Day 1, Day 2, Day 3, and Day 8. On Day 1, the trough level sample was collected the before the first dose of study drug. On Day 2, trough samples were collected approximately 12 hours after the second dose of study drug was administered on Day 1. On all subsequent days, trough samples were collected approximately 24 hours following the previous day's dose of study drug.	Predose on Day 1 up to 24 hours postdose on Day 8
Maximum Concentration (Cmax) of Posaconazole Tablet	Blood samples for the assessment of Cmax were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.	Predose on Day 1 up to 24 hours postdose on Day 8
Time to Maximum Concentration (Tmax) of Posaconazole Tablet	Blood samples for the assessment of Tmax were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.	Predose on Day 1 up to 24 hours postdose on Day 8
Apparent Total Body Clearance (CL/F) for Posaconazole Tablet	Blood samples for the assessment of CL/F, the rate at which posaconazole was removed from the body, were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.	Predose on Day 1 up to 24 hours postdose on Day 8

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Surviving at Day 65	Number of Participants Alive at Day 65	Day 65
Number of Participants With Treatment-Emergent Adverse Events (AEs)	AEs are any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not considered related to this study drug. Treatment-emergent AEs are any events not present before starting study drug treatment or any events that were present before treatment that worsened in either intensity or frequency after exposure to study drug.	Up to Day 65
Number of Participants With Treatment-Related AEs	AEs are any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not considered related to this study drug. Treatment-related AEs were considered by the investigator to be related to the study drug.	Up to Day 65
Number of Participants Discontinuing Study Treatment Due to an AE	AEs are any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not considered related to this study drug. These AEs resulted in participants stopping study drug treatment. This measure includes participants who discontinued due to AEs and also includes treatment failures that were attributed to AEs.	Up to Day 28

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Duarte RF, Lopez-Jimenez J, Cornely OA, Laverdiere M, Helfgott D, Haider S, Chandrasekar P, Langston A, Perfect J, Ma L, van Iersel ML, Connelly N, Kartsonis N, Waskin H. Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia. Antimicrob Agents Chemother. 2014 Oct;58(10):5758-65. doi: 10.1128/AAC.03050-14. Epub 2014 Jul 21.
• Cornely OA, Duarte RF, Haider S, Chandrasekar P, Helfgott D, Jimenez JL, Candoni A, Raad I, Laverdiere M, Langston A, Kartsonis N, Van Iersel M, Connelly N, Waskin H. Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. J Antimicrob Chemother. 2016 Mar;71(3):718-26. doi: 10.1093/jac/dkv380. Epub 2015 Nov 26. Erratum In: J Antimicrob Chemother. 2016 Jun;71(6):1747.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: January 25, 2013
• First Submitted That Met QC Criteria: January 25, 2013
• First Posted (Estimate): January 29, 2013

Study Record Updates

• Last Update Posted (Actual): April 7, 2017
• Last Update Submitted That Met QC Criteria: March 9, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections and Mycoses; Infections; Communicable Diseases; Mycoses; Invasive Fungal Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Posaconazole
• Other Study ID Numbers: P05615; 2008-006684-36 (EudraCT Number); 5592-065 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf

http://engagezone.msd.com/ds_documentation.php