Posaconazole (MK-5592) Intravenous and Oral in Children (<2 Years) With Invasive Fungal Infection (MK-5592-127)

Study Overview
=================
Brief Summary
-----------------
This study aims to estimate the pharmacokinetics (PK) of posaconazole (POS, MK-5592) intravenous (IV) and powder for oral suspension (PFS) formulations in pediatric participants <2 years of age with invasive fungal infection (IFI).

Detailed Description
-----------------
There are 2 panels in this study. In Panel A, POS IV will be evaluated in ≥8 participants. In Panel B, both POS IV and POS PFS will be evaluated in ≥14 participants, including ≥6 who are <3 months of age and ≥5 who transition to the PFS formulation of POS.

Official Title
-----------------
A Phase 2, Open-Label, Single-Arm, Sequential-Panel Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Posaconazole (POS, MK-5592) Intravenous and Powder for Oral Suspension Formulations in Pediatric Participants From Birth to Less Than 2 Years of Age With Possible, Probable, or Proven Invasive Fungal Infection

Conditions
-----------------
Invasive Fungal Infection

Intervention / Treatment
-----------------
* Drug: Posaconazole IV 6 mg/kg
* Drug: Posaconazole PFS 6 mg/kg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Panel A: is undergoing treatment for possible, probable, or proven IFI known or suspected to be cause by fungal pathogens against which POS has demonstrated activity (which can include candidiasis) Panel B: has an investigator-assessed diagnosis of possible, probable, or proven IFI known or suspected to be cause by fungal pathogens against which POS has demonstrated activity (and cannot include candidiasis) Has a central line (eg, central venous catheter, peripherally-inserted central catheter) in place or planned to be in place before beginning IV study intervention. Has a body weight of ≥500 g The participant (or legally acceptable representative) has provided documented informed consent for the study. Exclusion Criteria Has received POS within 30 days before Day 1 Has cystic fibrosis, pulmonary sarcoidosis, aspergilloma, or allergic bronchopulmonary aspergillosis Has a known hereditary problem of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption Has known or suspected active COVID-19 infection Has a known hypersensitivity or other serious adverse reaction to any azole antifungal therapy, or to any other ingredient of the study intervention used Has any known history of torsade de pointes, unstable cardiac arrhythmia or proarrhythmic conditions, a history of recent myocardial infarction, congenital or acquired QT interval (QT) prolongation, or cardiomyopathy in the context of cardiac failure within 90 days of first dose of study intervention Has received any listed prohibited medications within the specified timeframes before the start of study intervention Has a known hereditary problem of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption (Part B) Has suspected/proven invasive candidiasis (Part B) Has enrolled previously in the current study and been discontinued Has QTc prolongation at screening >500 msec Has significant liver dysfunction Is hemodynamically unstable, exhibits hemodynamic compromise, or is not expected to survive at least 5 days

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 2 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel A: POS IV<br>Posaconazole 6 mg/kg body weight administered in a single dose by IV infusion on Day 1. | Drug: Posaconazole IV 6 mg/kg<br>* POS 6 mg/kg body weight by IV infusion<br>* Other names: SCH56592;|
| Experimental: Panel B: POS IV<br>Posaconazole 6 mg/kg body weight administered twice daily by IV infusion on Day 1, and then once daily from Day 2 to a maximum 84 days. | Drug: Posaconazole IV 6 mg/kg<br>* POS 6 mg/kg body weight by IV infusion<br>* Other names: SCH56592;|
| Experimental: Panel B: POS PFS<br>Following a minimum of 7 days IV dosing, participants as clinically able will be transitioned from POS IV to POS PFS nominal 6 mg/kg body weight based on weight bands administered on Day 8, once daily to a maximum 84 days. | Drug: Posaconazole PFS 6 mg/kg<br>* POS nominal 6 mg/kg body weight based on weight bands taken orally<br>* Other names: SCH56592;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average concentration (Cavg) of single-dose IV POS (Panel A) | The Cavg of IV POS is based on population PK analysis. | Predose, 0.25 and 24 hours post-infusion on Day 1 | 
| Maximum concentration (Cmax) of single-dose IV POS (Panel A) | The Cmax of IV POS is based on population PK analysis. | Predose, 0.25 and 24 hours post-infusion on Day 1 | 
| Time to maximum concentration (Tmax) of single-dose IV POS (Panel A) | The Tmax of IV POS is based on population PK analysis. | Predose, 0.25 and 24 hours post-infusion on Day 1 | 
| Area under the plasma concentration-time curve from dosing to 24 hours postdose (AUC0-24) of single-dose IV POS (Panel A) | The AUC 0-24 of IV POS is based on population PK analysis. | Predose, 0.25 and 24 hours post-infusion on Day 1 | 
| Clearance (CL) of single-dose IV POS (Panel A) | The clearance (CL) of IV POS is based on population PK analysis. | Predose, 0.25 and 24 hours post-infusion on Day 1 | 
| Area under the plasma concentration-time curve from dosing to infinity (AUC0-∞) of single-dose IV POS (Panel A) | The AUC0-∞ of IV POS is based on population PK analysis. | Predose, 0.25 and 24 hours post-infusion on Day 1 | 
| Cavg of multiple-dose IV POS (Panel B) | The Cavg of IV POS is based on population PK analysis. | Predose and 0.25 post-infusion on Day 1; Weeks 1, 2, 4, 6, 9, and 12 | 
| Cmax of multiple-dose IV POS (Panel B) | The Cmax of IV POS is based on population PK analysis. | Predose and 0.25 post-infusion on Day 1; Weeks 1, 2, 4, 6, 9, and 12 | 
| Tmax of multiple-dose IV POS (Panel B) | The Tmax of IV POS is based on population PK analysis. | Predose and 0.25 post-infusion on Day 1; Weeks 1, 2, 4, 6, 9, and 12 | 
| AUC0-24 of multiple-dose IV POS (Panel B) | The AUC0-24 of IV POS is based on population PK analysis. | Predose and 0.25 post-infusion on Day 1; Weeks 1, 2, 4, 6, 9, and 12 | 
| CL of multiple-dose IV POS (Panel B) | The CL of IV POS is based on population PK analysis. | Predose and 0.25 post-infusion on Day 1; Weeks 1, 2, 4, 6, 9, and 12 | 
| Cavg of multiple-dose PFS POS (Panel B) | The Cavg of PFS POS is based on population PK analysis. | Predose and 0.25 post-infusion on Day 1; Weeks 1, 2, 4, 6, 9, and 12 | 
| Cmax of multiple-dose PFS POS (Panel B) | The Cmax of PFS POS is based on population PK analysis. | Predose and 0.25 post-infusion on Day 1; Weeks 1, 2, 4, 6, 9, and 12 | 
| AUC0-24 of multiple-dose PFSPOS (Panel B) | The AUC0-24 of PFS POS is based on population PK analysis. | Predose and 0.25 post-infusion on Day 1; Weeks 1, 2, 4, 6, 9, and 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cavg of IV POS in neonates and infants <2 years of age compared to adults and older pediatric populations (Panel B) | The Cavg of IV POS is based on population PK analysis. Comparisons between participants in Panel B will be made to data that was previously collected in older participants. | Predose and 0.25 post-infusion on Day 1; Weeks 1, 2, 4, 6, 9, and 12 | 
| Percentage of participants with an ≥ 1 adverse event (AE) [Panels A and B] | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to 98 days | 
| Percentage of participants who discontinued study therapy due to an AE (Panels A and B) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to 84 days | 
| Percentage of participants with a drug-related AE (Panels A and B) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to 98 days | 
| Percentage of participants with all-cause mortality (ACM) [Panel B] | The percentage of participants with ACM will be reported. | Up to 28 days | 
| Percentage of participants with need for systemic antifungal therapy (other than POS) during the study period (Panel B) | Percentage of participants who received additional antifungal therapy in Panel B will be reported. | Up to 84 days |