Pharmacokinetics and Safety of Posaconazole Tablet in Participants at High Risk for Invasive Fungal Infections (MK-5592-065/P05615)

Pharmacokinetics and Safety of Solid Oral Posaconazole (SCH 56592) in Subjects at High Risk for Invasive Fungal Infections (Phase 1b; Protocol No. P05615)

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01777763

Enrollment

230

Registered

2013-01-29

Start date

2009-06-30

Completion date

2012-02-29

Last updated

2017-04-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fungal Infections

Brief summary

The purpose of this study is to collect pharmacokinetic (PK) information related to how well posaconazole tablet is distributed in the body and to determine the safety of this new formulation. The study consists of a Phase 1B study that includes participants with neutropenia undergoing chemotherapy for acute myelogenous leukemia (AML) or myelodysplasia (MDS) and a Phase 3 study that includes participants who are undergoing chemotherapy for AML or MDS and participants who are recipients of allogeneic hematopoietic stem cell transplant (HSCT).

Detailed description

Participants with a blood disease or cancer that can affect their infection-fighting white blood cells and those who have undergone a hematopoietic stem cell transplant (HSCT) and are receiving immunosuppressive therapy and have or are at risk of graft-vs-host disease (GVHD) are eligible for the study. These blood diseases and their treatments can weaken the immune system and may put individuals at high risk for a serious fungal infection of their internal organs or blood (invasive fungal infection). As these infections can be hard to detect early and can be life-threatening, many physicians believe that individuals diagnosed with these diseases should receive antifungal therapy to try to lower their risk of getting this type of infection. Enrollment into this study will take place in several stages (parts). The determination of which part a participant will be in is based on which part is open at the site at the time of enrollment.

Interventions

DRUGPosaconazole 200 mg

DRUGPosaconazole 300 mg

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

PREVENTION

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Body weight \>34 kg (75 lb) and of any race/ethnicity * Able to swallow oral tablets whole * Anticipated (likely to develop within 3-5 days) or documented neutropenia due to chemotherapy, chemotherapy for a new diagnosis of acute myelogenous leukemia (AML), or AML in first relapse; myelodysplastic syndromes (MDS) in transformation to AML; allogeneic hematopoietic stem cell transplant (HSCT) participants in the pre-engraftment period or in the post-engraftment period if they are receiving immunosuppressive therapy for graft versus host disease

Exclusion criteria

\- Female must not be pregnant, must not intend to become pregnant during the study, and must not be nursing * History of hypersensitivity to azoles * Moderate or severe liver dysfunction defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal (ULN), AND a total bilirubin level greater than two times the ULN * Electrocardiogram (ECG) with corrected QTc interval greater than 500 msec * Posaconazole within 10 days before study enrollment * Receipt of systemic antifungal therapy within 30 days of study enrollment for reasons other than antifungal prophylaxis * Evidence of known or suspected invasive or systemic fungal infection at baseline * Known or suspected history of Gilbert's disease * Creatinine clearance levels below 30 mL/min

Design outcomes

Primary

Measure	Time frame	Description
Apparent Total Body Clearance (CL/F) for Posaconazole Tablet	Predose on Day 1 up to 24 hours postdose on Day 8	Blood samples for the assessment of CL/F, the rate at which posaconazole was removed from the body, were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.
Average Concentration (Cavg) of Posaconazole Tablet	Predose on Day 1 up to 24 hours postdose on Day 8	Posaconazole steady-state concentrations of posaconazole in the plasma reached after regular and repeated dosing were used to estimate pharmacokinetic (PK) parameters for each participant where Cavg was defined as area under the plasma concentration versus time curve divided by the dosing interval. Blood samples for the assessment of Cavg were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.
Minimum Concentration (Cmin) of Posaconazole Tablet	Predose on Day 1 up to 24 hours postdose on Day 8	Cmin was defined as posaconazole trough level immediately before a participant received the dose of posaconazole tablets on the specified day. Trough (Cmin) level blood samples for determination of posaconazole in plasma were collected for all participants on Day 1, Day 2, Day 3, and Day 8. On Day 1, the trough level sample was collected the before the first dose of study drug. On Day 2, trough samples were collected approximately 12 hours after the second dose of study drug was administered on Day 1. On all subsequent days, trough samples were collected approximately 24 hours following the previous day's dose of study drug.
Maximum Concentration (Cmax) of Posaconazole Tablet	Predose on Day 1 up to 24 hours postdose on Day 8	Blood samples for the assessment of Cmax were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.
Time to Maximum Concentration (Tmax) of Posaconazole Tablet	Predose on Day 1 up to 24 hours postdose on Day 8	Blood samples for the assessment of Tmax were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.

Other

Measure	Time frame	Description
Number of Participants With Treatment-Emergent Adverse Events (AEs)	Up to Day 65	AEs are any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not considered related to this study drug. Treatment-emergent AEs are any events not present before starting study drug treatment or any events that were present before treatment that worsened in either intensity or frequency after exposure to study drug.
Number of Participants With Treatment-Related AEs	Up to Day 65	AEs are any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not considered related to this study drug. Treatment-related AEs were considered by the investigator to be related to the study drug.
Number of Participants Discontinuing Study Treatment Due to an AE	Up to Day 28	AEs are any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not considered related to this study drug. These AEs resulted in participants stopping study drug treatment. This measure includes participants who discontinued due to AEs and also includes treatment failures that were attributed to AEs.
Number of Participants Surviving at Day 65	Day 65	Number of Participants Alive at Day 65

Participant flow

Participants by arm

Arm	Count
Posaconazole 200 mg Posaconazole 200 mg (two 100 mg tablets) twice daily (BID) on Day 1 followed by 200 mg (two 100 mg tablets) once daily (QD) for up to 28 days.	20
Posaconazole 300 mg Posaconazole 300 mg (three 100 mg tablets) BID on Day 1 followed by 300 mg (three 100 mg tablets) QD for up to 28 days.	210
Total	230

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	2	32
Overall Study	Protocol Violation	1	7
Overall Study	Treatment Failure	1	6
Overall Study	Withdrawal by Subject	0	2

Baseline characteristics

Characteristic	Posaconazole 200 mg	Posaconazole 300 mg	Total
Age, Continuous	51.0 years STANDARD_DEVIATION 13.2	51.0 years STANDARD_DEVIATION 14.1	51.0 years STANDARD_DEVIATION 14
Sex: Female, Male Female	8 Participants	79 Participants	87 Participants
Sex: Female, Male Male	12 Participants	131 Participants	143 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	20 / 20	186 / 210
serious Total, serious adverse events	6 / 20	69 / 210

Outcome results

Primary

Apparent Total Body Clearance (CL/F) for Posaconazole Tablet

Blood samples for the assessment of CL/F, the rate at which posaconazole was removed from the body, were collected on Day 1 and Day 8 predose and then at specified time points up to 24 hours postdose.