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

Neutropenia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02452034
• Other study ID #: 5592-097
• Secondary ID: 2014-002807-10MK
• Status: Completed
• Phase: Phase 1
• Start date: September 7, 2015
• Est. completion date: September 3, 2018

Study information

• Verified date: May 2019
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 118
• Est. completion date: September 3, 2018
• Est. primary completion date: June 26, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Neutropenia

Intervention

Drug:
• Posaconazole IV solution
Posaconazole by IV solution twice on Day 1, then once daily on Days 2-10.
• Posaconazole powder for oral suspension
Posaconazole once daily by PFS for a minimum of 10 days

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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)
Secondary	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