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

NCT02452034 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: 5592-0972014-002807-10MK-5592-097
• Study Type: interventional
• Target: 118
• Locations: 0 countries
• Sites: N/A

Brief Summary

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

Conditions

Neutropenia

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (2)

• Number of Participants With an Adverse Event (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)

  Up to 28 days

Study Arms (6)

3.5 mg/kg POS (2<7 years old)

EXPERIMENTAL

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; Drug: Posaconazole powder for oral suspension

4.5 mg/kg POS (2<7 years old)

EXPERIMENTAL

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; Drug: Posaconazole powder for oral suspension

3.5 mg/kg POS (7-17 years old)

EXPERIMENTAL

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; Drug: Posaconazole powder for oral suspension

4.5 mg/kg POS (7-17 years old)

EXPERIMENTAL

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; Drug: Posaconazole powder for oral suspension

6 mg/kg POS (2<7 years old)

EXPERIMENTAL

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; Drug: Posaconazole powder for oral suspension

6 mg/kg POS (7-17 years old)

EXPERIMENTAL

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; Drug: Posaconazole powder for oral suspension

Interventions

Posaconazole IV solution DRUG

Posaconazole by IV solution twice on Day 1, then once daily on Days 2-10.

Also known as: Noxafil

3.5 mg/kg POS (2<7 years old); 3.5 mg/kg POS (7-17 years old); 4.5 mg/kg POS (2<7 years old); 4.5 mg/kg POS (7-17 years old); 6 mg/kg POS (2<7 years old); 6 mg/kg POS (7-17 years old)

Posaconazole powder for oral suspension DRUG

Posaconazole once daily by PFS for a minimum of 10 days

Also known as: Noxafil

3.5 mg/kg POS (2<7 years old); 3.5 mg/kg POS (7-17 years old); 4.5 mg/kg POS (2<7 years old); 4.5 mg/kg POS (7-17 years old); 6 mg/kg POS (2<7 years old); 6 mg/kg POS (7-17 years old)

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• 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.

  PMID: 32682946 DERIVED

MeSH Terms

Conditions

Neutropenia

Interventions

posaconazole; Suspensions

Condition Hierarchy (Ancestors)

Agranulocytosis; Leukopenia; Cytopenia; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukocyte Disorders

Intervention Hierarchy (Ancestors)

Colloids; Complex Mixtures; Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2015
• First Posted: May 22, 2015
• Study Start: September 7, 2015
• Primary Completion: June 26, 2018
• Study Completion: September 3, 2018
• Last Updated: July 26, 2019
• Results First Posted: July 26, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will share