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

Phase 1

Completed

• Conditions: Neutropenia
• Interventions: Drug: Posaconazole IV solution; Drug: Posaconazole powder for oral suspension

• Registration Number: NCT02452034
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-05-20
• Study First Submitted QC: 2015-05-20
• Study First Posted: 2015-05-22
• Study Start: 2015-09-07
• Primary Completion: 2018-06-26
• Study Completion: 2018-09-03
• Results First Submitted: 2019-02-21
• Status Verified: 2019-05
• Results First Submitted QC: 2019-05-28
• Last Update Submitted: 2019-05-28
• Results First Posted: 2019-07-26
• Last Update Posted: 2019-07-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 118

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
3.5 mg/kg POS (2<7 years old)	Posaconazole powder for oral suspension	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.
4.5 mg/kg POS (2<7 years old)	Posaconazole powder for oral suspension	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.
4.5 mg/kg POS (7-17 years old)	Posaconazole IV solution	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.
6 mg/kg POS (2<7 years old)	Posaconazole IV solution	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.
3.5 mg/kg POS (7-17 years old)	Posaconazole powder for oral suspension	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.
4.5 mg/kg POS (7-17 years old)	Posaconazole powder for oral suspension	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.
6 mg/kg POS (2<7 years old)	Posaconazole powder for oral suspension	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.
3.5 mg/kg POS (7-17 years old)	Posaconazole IV solution	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.
3.5 mg/kg POS (2<7 years old)	Posaconazole IV solution	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.
4.5 mg/kg POS (2<7 years old)	Posaconazole IV solution	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.
6 mg/kg POS (7-17 years old)	Posaconazole IV solution	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.
6 mg/kg POS (7-17 years old)	Posaconazole powder for oral suspension	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.

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS	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.
Maximum Plasma Concentration (Cmax) for POS	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.
Minimum Plasma Concentration (Cmin) for POS	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.
Average Steady-state Plasma Concentration (Cavg) for POS	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.
Time of Maximum Plasma Concentration (Tmax) for POS	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.
Total Body Clearance (CL) for POS Administered by IV	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.
Apparent Total Body Clearance (CL/F) for POS Administered by PFS	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

Name	Time	Method
Number of Participants With an Adverse Event (AE)	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.
Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE)	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.