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

• ClinicalTrials.gov Identifier: NCT02452034
• Recruitment Status: Completed
• First Posted: May 22, 2015
• Results First Posted: July 26, 2019
• Last Update Posted: July 26, 2019
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Neutropenia	Drug: Posaconazole IV solution; Drug: Posaconazole powder for oral suspension	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 118 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: September 7, 2015
• Actual Primary Completion Date: June 26, 2018
• Actual Study Completion Date: September 3, 2018

Arms and Interventions

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 Name: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Name: 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 Name: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Name: 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 Name: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Name: 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 Name: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Name: 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 Name: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Name: 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 Name: Noxafil; Drug: Posaconazole powder for oral suspension; Posaconazole once daily by PFS for a minimum of 10 days; Other Name: Noxafil

Outcome Measures

Primary Outcome Measures :

1. Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS [ Time Frame: 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 ]
   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.
2. Maximum Plasma Concentration (Cmax) for POS [ Time Frame: 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 ]
   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.
3. Minimum Plasma Concentration (Cmin) for POS [ Time Frame: 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 ]
   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.
4. Average Steady-state Plasma Concentration (Cavg) for POS [ Time Frame: 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 ]
   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.
5. Time of Maximum Plasma Concentration (Tmax) for POS [ Time Frame: 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 ]
   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.
6. Total Body Clearance (CL) for POS Administered by IV [ Time Frame: 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 ]
   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.
7. Apparent Total Body Clearance (CL/F) for POS Administered by PFS [ Time Frame: 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 ]
   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.

Secondary Outcome Measures :

1. Number of Participants With an Adverse Event (AE) [ Time Frame: 14 days after end of treatment (Up to 42 days) ]
   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.
2. Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE) [ Time Frame: Up to 28 days ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme Corp.:

Study Protocol and Statistical Analysis Plan  [PDF] May 10, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT02452034
• Other Study ID Numbers: 5592-097; 2014-002807-10 ( EudraCT Number ); MK-5592-097 ( Other Identifier: Merck Protocol Number )
• First Posted: May 22, 2015
• Results First Posted: July 26, 2019
• Last Update Posted: July 26, 2019
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neutropenia; Agranulocytosis; Leukopenia; Leukocyte Disorders; Hematologic Diseases; Posaconazole; Antifungal Agents; Anti-Infective Agents; Trypanocidal Agents; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs