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

Primary Purpose

Fungal Infections

Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Posaconazole 200 mg
Posaconazole 300 mg
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Fungal Infections

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Experimental

    Arm Label

    Posaconazole 200 mg

    Posaconazole 300 mg

    Arm Description

    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

    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

    Outcomes

    Primary Outcome Measures

    Average Concentration (Cavg) of Posaconazole Tablet
    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
    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
    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
    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.
    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.

    Secondary Outcome Measures

    Full Information

    First Posted
    January 25, 2013
    Last Updated
    March 9, 2017
    Sponsor
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01777763
    Brief Title
    Pharmacokinetics and Safety of Posaconazole Tablet in Participants at High Risk for Invasive Fungal Infections (MK-5592-065/P05615)
    Official Title
    Pharmacokinetics and Safety of Solid Oral Posaconazole (SCH 56592) in Subjects at High Risk for Invasive Fungal Infections (Phase 1b; Protocol No. P05615)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2017
    Overall Recruitment Status
    Completed
    Study Start Date
    June 2009 (undefined)
    Primary Completion Date
    February 2012 (Actual)
    Study Completion Date
    February 2012 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Merck Sharp & Dohme LLC

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Fungal Infections

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 1
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    230 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Posaconazole 200 mg
    Arm Type
    Experimental
    Arm Description
    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
    Arm Title
    Posaconazole 300 mg
    Arm Type
    Experimental
    Arm Description
    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
    Intervention Type
    Drug
    Intervention Name(s)
    Posaconazole 200 mg
    Other Intervention Name(s)
    SCH 056592, MK-5592, Noxafil®
    Intervention Type
    Drug
    Intervention Name(s)
    Posaconazole 300 mg
    Other Intervention Name(s)
    SCH 056592, MK-5592, Noxafil®
    Primary Outcome Measure Information:
    Title
    Average Concentration (Cavg) of Posaconazole Tablet
    Description
    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.
    Time Frame
    Predose on Day 1 up to 24 hours postdose on Day 8
    Title
    Minimum Concentration (Cmin) of Posaconazole Tablet
    Description
    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.
    Time Frame
    Predose on Day 1 up to 24 hours postdose on Day 8
    Title
    Maximum Concentration (Cmax) of Posaconazole Tablet
    Description
    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 Frame
    Predose on Day 1 up to 24 hours postdose on Day 8
    Title
    Time to Maximum Concentration (Tmax) of Posaconazole Tablet
    Description
    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.
    Time Frame
    Predose on Day 1 up to 24 hours postdose on Day 8
    Title
    Apparent Total Body Clearance (CL/F) for Posaconazole Tablet
    Description
    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.
    Time Frame
    Predose on Day 1 up to 24 hours postdose on Day 8
    Other Pre-specified Outcome Measures:
    Title
    Number of Participants Surviving at Day 65
    Description
    Number of Participants Alive at Day 65
    Time Frame
    Day 65
    Title
    Number of Participants With Treatment-Emergent Adverse Events (AEs)
    Description
    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.
    Time Frame
    Up to Day 65
    Title
    Number of Participants With Treatment-Related AEs
    Description
    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.
    Time Frame
    Up to Day 65
    Title
    Number of Participants Discontinuing Study Treatment Due to an AE
    Description
    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.
    Time Frame
    Up to Day 28

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf http://engagezone.msd.com/ds_documentation.php
    Citations:
    PubMed Identifier
    25049247
    Citation
    Duarte RF, Lopez-Jimenez J, Cornely OA, Laverdiere M, Helfgott D, Haider S, Chandrasekar P, Langston A, Perfect J, Ma L, van Iersel ML, Connelly N, Kartsonis N, Waskin H. Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia. Antimicrob Agents Chemother. 2014 Oct;58(10):5758-65. doi: 10.1128/AAC.03050-14. Epub 2014 Jul 21.
    Results Reference
    result
    Citation
    Cornely OA, Duarte RF, Haider S, Chandrasakar P, Helfgott D, Lopez J, Candoni A, Raad I, Laverdiere M, Langston A, Van Iersel M, Connelly N, Waskin H. Phase 3 Pharmacokinetics and Safety Study of Posaconazole Tablet in Patients at Risk for Invasive Fungal Infection. J Antimicrob Chemother. 2015;[e-pub 26Nov2015]. doi: 10.1093/jac/dkv380
    Results Reference
    result
    PubMed Identifier
    26612870
    Citation
    Cornely OA, Duarte RF, Haider S, Chandrasekar P, Helfgott D, Jimenez JL, Candoni A, Raad I, Laverdiere M, Langston A, Kartsonis N, Van Iersel M, Connelly N, Waskin H. Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. J Antimicrob Chemother. 2016 Mar;71(3):718-26. doi: 10.1093/jac/dkv380. Epub 2015 Nov 26. Erratum In: J Antimicrob Chemother. 2016 Jun;71(6):1747.
    Results Reference
    derived

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

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