Safety and Pharmacokinetics of Intravenous and Oral Posaconazole in Immunocompromised Children (MK-5592-097)

A Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous (IV) and Powder for Oral Suspension Formulations of Posaconazole (POS) in Immunocompromised Pediatric Subjects With Neutropenia

This study aims to evaluate the pharmacokinetics of posaconazole (POS) administered intravenously (IV) or orally to immunocompromised pediatric participants.

Study Overview

• Status: Completed
• Conditions: Neutropenia
• Intervention / Treatment: Drug: Posaconazole IV solution; Drug: Posaconazole powder for oral suspension

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have documented or anticipated neutropenia expected to last for at least 7 days, following treatment in at least one of the following clinical situations: acute leukemia, myelodysplasia, severe aplastic anemia, recipients of Autologous Hematopoietic Stem Cell Transplant (HSCT), high risk neuroblastoma, advanced stage non-Hodgkin's lymphoma, hemophagocytic lymphohistiocytosis
• Have a central line in place prior to IV study therapy
• Participants of reproductive potential agree to remain abstinent, or use a medically accepted method of birth control

Exclusion Criteria:

• Has a proven or probable invasive fungal infection
• Has received any formulation of POS within prior 10 days
• Is receiving any prohibited drugs
• Has laboratory results that are outside of normal limits at screening, as follows: a) Moderate or severe liver dysfunction, as defined as: Aspartate Aminotransferase (AST) > 5 times the upper limit of normal (ULN), OR Alanine Aminotransferase (ALT) > 5 times the ULN, OR Serum total bilirubin >2.5 times the ULN, OR AST or ALT > 3 times ULN with total bilirubin > 2 times ULN; b) Calculated creatinine clearance <30 mL/min.
• Has QTc (QT interval corrected for rate) prolongation defined as: a) Symptomatic QTc prolongation >450 msec (males) or >470 msec (females) OR b) Any QTc prolongation of >500 msec
• Is pregnant, intends to become pregnant during study, or is breastfeeding
• Has a history of anaphylaxis attributed to the azole class of antifungal agents
• Is not expected to receive a minimum of 10 days of POS IV solution
• Has participated in any Phase 1 Investigational New Drug (IND) study within prior 30 days or expects to do so within the following 60 days
• Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 3.5 mg/kg POS (2<7 years old); Children 2 to less than 7 years of age will receive POS at 3.5 mg/kg by intravenous (IV) solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 3.5 mg/kg POS once daily by powder for oral suspension (PFS) for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV.	Drug: Posaconazole IV solution; Posaconazole by IV solution twice on Day 1, then once daily on Days 2-10.; Other Names: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Names: Noxafil
EXPERIMENTAL: 4.5 mg/kg POS (2<7 years old); Children 2 to less than 7 years of age will receive POS at 4.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 4.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV.	Drug: Posaconazole IV solution; Posaconazole by IV solution twice on Day 1, then once daily on Days 2-10.; Other Names: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Names: Noxafil
EXPERIMENTAL: 3.5 mg/kg POS (7-17 years old); Children 7 to 17 years of age will receive POS at 3.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 3.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV.	Drug: Posaconazole IV solution; Posaconazole by IV solution twice on Day 1, then once daily on Days 2-10.; Other Names: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Names: Noxafil
EXPERIMENTAL: 4.5 mg/kg POS (7-17 years old); Children 7 to 17 years of age will receive POS at 4.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 4.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV.	Drug: Posaconazole IV solution; Posaconazole by IV solution twice on Day 1, then once daily on Days 2-10.; Other Names: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Names: Noxafil
EXPERIMENTAL: 6 mg/kg POS (2<7 years old); Children 2 to less than 7 years of age will receive POS at 6 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 6 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV.	Drug: Posaconazole IV solution; Posaconazole by IV solution twice on Day 1, then once daily on Days 2-10.; Other Names: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Names: Noxafil
EXPERIMENTAL: 6 mg/kg POS (7-17 years old); Children 7 to 17 years of age will receive POS at 6 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This will be followed by treatment with 6 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they are unwilling or unable to tolerate POS PFS, continued treatment with POS IV.	Drug: Posaconazole IV solution; Posaconazole by IV solution twice on Day 1, then once daily on Days 2-10.; Other Names: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Names: Noxafil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS	Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma AUC from time 0-24 hours post-dose (AUC0-24hr) of posaconazole. A non compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.	Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Maximum Plasma Concentration (Cmax) for POS	Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cmax of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.	Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Minimum Plasma Concentration (Cmin) for POS	Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cmin of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.	Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Average Steady-state Plasma Concentration (Cavg) for POS	Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cavg of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.	Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Time of Maximum Plasma Concentration (Tmax) for POS	Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Tmax of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.	Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Total Body Clearance (CL) for POS Administered by IV	Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma CL of posaconazole administered by IV. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for participants that received IV treatment.	Any day from Day 7 to Day 10 of therapy (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Apparent Total Body Clearance (CL/F) for POS Administered by PFS	Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma CL/F of posaconazole administered by PFS. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for participants that received PFS treatment.	Any day from Day 7 to Day 10 of therapy (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With an Adverse Event (AE)	An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.	14 days after end of treatment (Up to 42 days)
Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE)	An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.	Up to 28 days

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Groll AH, Abdel-Azim H, Lehrnbecher T, Steinbach WJ, Paschke A, Mangin E, Winchell GA, Waskin H, Bruno CJ. Pharmacokinetics and safety of posaconazole intravenous solution and powder for oral suspension in children with neutropenia: an open-label, sequential dose-escalation trial. Int J Antimicrob Agents. 2020 Sep;56(3):106084. doi: 10.1016/j.ijantimicag.2020.106084. Epub 2020 Jul 17.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 7, 2015
• Primary Completion (ACTUAL): June 26, 2018
• Study Completion (ACTUAL): September 3, 2018

Study Registration Dates

• First Submitted: May 20, 2015
• First Submitted That Met QC Criteria: May 20, 2015
• First Posted (ESTIMATE): May 22, 2015

Study Record Updates

• Last Update Posted (ACTUAL): July 26, 2019
• Last Update Submitted That Met QC Criteria: May 28, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Neutropenia; 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: 5592-097; 2014-002807-10 (EUDRACT_NUMBER); MK-5592-097 (OTHER: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No