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Safety and Efficacy Study of Posaconazole vs. Fluconazole for Prevention of Invasive Fungal Infection (P05387 AM1)(COMPLETED)

Primary Purpose

Leukopenia

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Posaconazole
Fluconazole
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Leukopenia focused on measuring high-risk leukopenic patients

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Participants must be 18-70 years of age of either sex

  • Persistent neutropenia (Absolute Neutrophil Count [ANC] < 500/mm^3 [0.5x10^9/L]）or probable neutropenia in 3-5 days is anticipated. Neutropenia >= 7 days caused by the following reasons

    • Standard or dose-intense chemotherapy, anthracyclines or other acceptable chemotherapies ( any investigational drug is not permitted) for Acute Myelogenous Leukemia (AML) treatment
    • Retreatment of chemotherapy in case of AML recurrence
    • Myelodysplastic syndrome (MDS) shifts to AML and bone marrow arrest induction chemotherapy is required (not including acute phase of chronic myelogenous leukemia [CML])
  • Informed consent obtained from participant or legal guardian

Exclusion Criteria:

  • Participants previously treated with amphotericin B (AMB), fluconazole (FLZ), or itraconazole (ITZ) within 30 days of enrollment.

  • Participants who have taken the following drugs:

    • terfenadine, cisapride, and ebastine within 24 hours before entry
    • astemizole at entry or within 10 days before entry
    • cimetidine, rifampin, carbamazepine, phenytoin, rifabutin, barbiturates, isoniazid atharanthine and anthracyclines within 24 hours before entry
  • The above drugs are refrained during the investigation
  • Serious organ diseases except hematological disorder such as cardiac or neurologic disorders or impairment expected to be unstable or progressive during the course of this study (eg, seizures or demyelinating syndromes, acute myocardial infarction within 3 months of study entry, myocardial ischemia, congestive heart failure, atrial fibrillation with ventricular rate <60/min, or history of torsades de pointes, symptomatic ventricular or sustained arrhythmias), unstable electrolyte abnormalities.
  • Participants who have used any investigational drugs or biologic agents other than their chemotherapy regimens within 30 days of study entry.
  • Prior enrollment in this study.
  • Participants with known or suspected hypersensitivity or idiosyncratic reaction to azole agents or amphotericin B.
  • Participants with known or suspected invasive fungal infection (IFI) at screen
  • Participants with severe renal insufficiency (estimated creatinine clearance less than 50 mL/minute or likely to require dialysis during the study), Alanine transaminase (ALT), Aspartate transaminase (AST), alkaline phosphatase or total bilirubin are >2× (Upper Limit of Normal) ULN.
  • Participants having an electrocardiogram (ECG) with a prolonged QTc interval: QTc greater than 450 msec for men and greater than 470 msec for women.
  • Participants with AML or CML history.
  • Participants with a history of allogeneic hematopoietic stem cell, bone marrow transplantation, autologous stem cell transplantation history.
  • Female participants who are pregnant or are nursing.
  • Alcohol and/or drug abuse.
  • Participants cannot be compliant in the opinion of the investigator.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Active Comparator

    Arm Label

    Posaconazole

    Fluconazole

    Arm Description

    Posaconazole oral suspension 200 mg three times a day (TID)

    Fluconazole 400 mg once daily (QD)

    Outcomes

    Primary Outcome Measures

    Number of Participants With Proven or Probable Diagnosis of Invasive Fungal Infection (IFI) During the Treatment Period
    Number of participants developing a proven or probable IFI from randomization to the last dosage date (up to 12 weeks [84 days]) plus 7 days. IFI diagnosis criteria may include: persistent fever, failure of appropriate broad-spectrum antibiotic treatment concomitant with lower respiratory tract infection symptoms, microbiological criteria with corresponding clinical signs and symptoms.

    Secondary Outcome Measures

    Number of Participants With Proven or Probable Diagnosis of IFI Within 100 Days From Randomization
    Number of participants who developed a proven or probable IFI from randomization date to Day 100 of follow-up visit. IFI diagnosis criteria may include: persistent fever, failure of appropriate broad-spectrum antibiotic treatment concomitant with lower respiratory tract infection symptoms, microbiological criteria with corresponding clinical signs and symptoms.
    Time From Randomization to the First Onset of Proven or Probable IFI
    The time measured in days to the first occurrence of proven/probable IFI diagnosis in the entire FAS population from randomization to Day 100 of follow-up visit. Participants may not have accepted immediate antifungal treatment and later received antifungal treatment based upon further investigator review of the participant's IFI condition. IFI diagnosis criteria may include: persistent fever, failure of appropriate broad-spectrum antibiotic treatment concomitant with lower respiratory tract infection symptoms, positive blood/biopsy cultures with corresponding clinical signs and symptoms.
    Time From Randomization to Administration of First Systemic Antifungal Intravenous (IV) Therapy
    The time measured in days from randomization to the administration of the first concomitant systemic anti-fungal therapy in the entire FAS population. Not all participants who accepted systemic anti-fungal therapy may have had a IFI clinical diagnosis. IFI diagnosis criteria for antifungal therapy administration may include: persistent fever, failure of appropriate broad-spectrum antibiotic treatment concomitant with lower respiratory tract infection symptoms, microbiological criteria with corresponding clinical signs and symptoms.
    Number of Participants With Clinical Failure During Treatment
    Clinical failure was defined as follows: Presence of a proven or probable IFI Systemic antifungal treatment (IV) for 4 consecutive days or more than 10 days total Discontinuation due to adverse event (AE) possibly or probably related to study drug Lost-to-follow-up or discontinuation from the study for any reason with loss to follow-up during the Treatment Phase
    Number of Participants in Whom All-cause Mortality Occurred Within 100 Days From Randomization
    Death from any cause.
    Number of Participants in Whom Mortality is Unlikely, Possibly, and Probably Related to Fungal Infection Occurred Within 100 Days From Randomization
    Exact Causes of Death and Their Relationship to IFI Episode Were As Follows: Unlikely related: participant completed treatment and cause of death was due to primary disease or complication Possibly related: IFI undergoing treatment without stabilization, or with failure to have a complete remission, where cause of death might have been due to IFI, including progression or relapse of primary disease Probably related: autopsy or clinical signs suggested that progression of IFI was the probable cause of death

    Full Information

    First Posted
    December 18, 2008
    Last Updated
    March 9, 2017
    Sponsor
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00811928
    Brief Title
    Safety and Efficacy Study of Posaconazole vs. Fluconazole for Prevention of Invasive Fungal Infection (P05387 AM1)(COMPLETED)
    Official Title
    A Randomized, Open Label Parallel Controlled, Multicenter Study to Evaluate Safety and Efficacy of Posaconazole Oral Suspension Vs. Fluconazole (Capsule) in High-risk Leukopenic Patients for Prevention of Invasive Fungal Infection
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2017
    Overall Recruitment Status
    Completed
    Study Start Date
    November 2008 (undefined)
    Primary Completion Date
    May 2010 (Actual)
    Study Completion Date
    May 2010 (Actual)

    3. Sponsor/Collaborators

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

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    A randomized, open label parallel controlled, multicenter study to evaluate safety and efficacy of Posaconazole oral suspension vs Fluconazole (capsule) in high-risk leukopenic patients for prevention of invasive fungal infection

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Leukopenia
    Keywords
    high-risk leukopenic patients

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    252 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Posaconazole
    Arm Type
    Active Comparator
    Arm Description
    Posaconazole oral suspension 200 mg three times a day (TID)
    Arm Title
    Fluconazole
    Arm Type
    Active Comparator
    Arm Description
    Fluconazole 400 mg once daily (QD)
    Intervention Type
    Drug
    Intervention Name(s)
    Posaconazole
    Other Intervention Name(s)
    Noxafil, SCH 056592
    Intervention Description
    40 mg/mL; 200 mg (5 mL) TID Treatment was continued with each cycle of chemotherapy until: The onset of a proven or probable diagnosis of invasive fungal infection (IFI) 3 chemotherapy cycles or Total treatment duration up to 12 weeks (84 days)
    Intervention Type
    Drug
    Intervention Name(s)
    Fluconazole
    Intervention Description
    50 mg/capsule (2 capsules), 150 mg/capsule (2 capsules); 400 mg QD Treatment was continued with each cycle of chemotherapy until: The onset of a proven or probable diagnosis of invasive fungal infection (IFI) 3 chemotherapy cycles or Total treatment duration up to 12 weeks (84 days)
    Primary Outcome Measure Information:
    Title
    Number of Participants With Proven or Probable Diagnosis of Invasive Fungal Infection (IFI) During the Treatment Period
    Description
    Number of participants developing a proven or probable IFI from randomization to the last dosage date (up to 12 weeks [84 days]) plus 7 days. IFI diagnosis criteria may include: persistent fever, failure of appropriate broad-spectrum antibiotic treatment concomitant with lower respiratory tract infection symptoms, microbiological criteria with corresponding clinical signs and symptoms.
    Time Frame
    Up to 12 Weeks (84 days) plus 7 days
    Secondary Outcome Measure Information:
    Title
    Number of Participants With Proven or Probable Diagnosis of IFI Within 100 Days From Randomization
    Description
    Number of participants who developed a proven or probable IFI from randomization date to Day 100 of follow-up visit. IFI diagnosis criteria may include: persistent fever, failure of appropriate broad-spectrum antibiotic treatment concomitant with lower respiratory tract infection symptoms, microbiological criteria with corresponding clinical signs and symptoms.
    Time Frame
    From randomization date to Day 100
    Title
    Time From Randomization to the First Onset of Proven or Probable IFI
    Description
    The time measured in days to the first occurrence of proven/probable IFI diagnosis in the entire FAS population from randomization to Day 100 of follow-up visit. Participants may not have accepted immediate antifungal treatment and later received antifungal treatment based upon further investigator review of the participant's IFI condition. IFI diagnosis criteria may include: persistent fever, failure of appropriate broad-spectrum antibiotic treatment concomitant with lower respiratory tract infection symptoms, positive blood/biopsy cultures with corresponding clinical signs and symptoms.
    Time Frame
    From randomization date to Day 100
    Title
    Time From Randomization to Administration of First Systemic Antifungal Intravenous (IV) Therapy
    Description
    The time measured in days from randomization to the administration of the first concomitant systemic anti-fungal therapy in the entire FAS population. Not all participants who accepted systemic anti-fungal therapy may have had a IFI clinical diagnosis. IFI diagnosis criteria for antifungal therapy administration may include: persistent fever, failure of appropriate broad-spectrum antibiotic treatment concomitant with lower respiratory tract infection symptoms, microbiological criteria with corresponding clinical signs and symptoms.
    Time Frame
    Up to 12 weeks (84 days)
    Title
    Number of Participants With Clinical Failure During Treatment
    Description
    Clinical failure was defined as follows: Presence of a proven or probable IFI Systemic antifungal treatment (IV) for 4 consecutive days or more than 10 days total Discontinuation due to adverse event (AE) possibly or probably related to study drug Lost-to-follow-up or discontinuation from the study for any reason with loss to follow-up during the Treatment Phase
    Time Frame
    Up to 12 weeks (84 days)
    Title
    Number of Participants in Whom All-cause Mortality Occurred Within 100 Days From Randomization
    Description
    Death from any cause.
    Time Frame
    Randomization date to Day 100
    Title
    Number of Participants in Whom Mortality is Unlikely, Possibly, and Probably Related to Fungal Infection Occurred Within 100 Days From Randomization
    Description
    Exact Causes of Death and Their Relationship to IFI Episode Were As Follows: Unlikely related: participant completed treatment and cause of death was due to primary disease or complication Possibly related: IFI undergoing treatment without stabilization, or with failure to have a complete remission, where cause of death might have been due to IFI, including progression or relapse of primary disease Probably related: autopsy or clinical signs suggested that progression of IFI was the probable cause of death
    Time Frame
    From randomization date to Day 100

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    70 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Participants must be 18-70 years of age of either sex Persistent neutropenia (Absolute Neutrophil Count [ANC] < 500/mm^3 [0.5x10^9/L]）or probable neutropenia in 3-5 days is anticipated. Neutropenia >= 7 days caused by the following reasons Standard or dose-intense chemotherapy, anthracyclines or other acceptable chemotherapies ( any investigational drug is not permitted) for Acute Myelogenous Leukemia (AML) treatment Retreatment of chemotherapy in case of AML recurrence Myelodysplastic syndrome (MDS) shifts to AML and bone marrow arrest induction chemotherapy is required (not including acute phase of chronic myelogenous leukemia [CML]) Informed consent obtained from participant or legal guardian Exclusion Criteria: Participants previously treated with amphotericin B (AMB), fluconazole (FLZ), or itraconazole (ITZ) within 30 days of enrollment. Participants who have taken the following drugs: terfenadine, cisapride, and ebastine within 24 hours before entry astemizole at entry or within 10 days before entry cimetidine, rifampin, carbamazepine, phenytoin, rifabutin, barbiturates, isoniazid atharanthine and anthracyclines within 24 hours before entry The above drugs are refrained during the investigation Serious organ diseases except hematological disorder such as cardiac or neurologic disorders or impairment expected to be unstable or progressive during the course of this study (eg, seizures or demyelinating syndromes, acute myocardial infarction within 3 months of study entry, myocardial ischemia, congestive heart failure, atrial fibrillation with ventricular rate <60/min, or history of torsades de pointes, symptomatic ventricular or sustained arrhythmias), unstable electrolyte abnormalities. Participants who have used any investigational drugs or biologic agents other than their chemotherapy regimens within 30 days of study entry. Prior enrollment in this study. Participants with known or suspected hypersensitivity or idiosyncratic reaction to azole agents or amphotericin B. Participants with known or suspected invasive fungal infection (IFI) at screen Participants with severe renal insufficiency (estimated creatinine clearance less than 50 mL/minute or likely to require dialysis during the study), Alanine transaminase (ALT), Aspartate transaminase (AST), alkaline phosphatase or total bilirubin are >2× (Upper Limit of Normal) ULN. Participants having an electrocardiogram (ECG) with a prolonged QTc interval: QTc greater than 450 msec for men and greater than 470 msec for women. Participants with AML or CML history. Participants with a history of allogeneic hematopoietic stem cell, bone marrow transplantation, autologous stem cell transplantation history. Female participants who are pregnant or are nursing. Alcohol and/or drug abuse. Participants cannot be compliant in the opinion of the investigator.

    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
    23924680
    Citation
    Shen Y, Huang XJ, Wang JX, Jin J, Hu JD, Yu K, Wu DP, Wang SJ, Yu L, Chen XQ, Liu T, Liang YM, Chen FP, Li Y, Shen ZX. Posaconazole vs. fluconazole as invasive fungal infection prophylaxis in China: a multicenter, randomized, open-label study. Int J Clin Pharmacol Ther. 2013 Sep;51(9):738-45. doi: 10.5414/CP201880.
    Results Reference
    derived

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    Safety and Efficacy Study of Posaconazole vs. Fluconazole for Prevention of Invasive Fungal Infection (P05387 AM1)(COMPLETED)

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