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

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

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 Overview

• Status: Completed
• Conditions: Leukopenia
• Intervention / Treatment: Drug: Posaconazole; Drug: Fluconazole

• Study Type: Interventional
• Enrollment (Actual): 252
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Posaconazole; Posaconazole oral suspension 200 mg three times a day (TID)	Drug: Posaconazole; 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); Other Names: Noxafil; SCH 056592
Active Comparator: Fluconazole; Fluconazole 400 mg once daily (QD)	Drug: Fluconazole; 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 12 Weeks (84 days) plus 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization date to Day 100
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.	From randomization date to Day 100
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.	Up to 12 weeks (84 days)
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	Up to 12 weeks (84 days)
Number of Participants in Whom All-cause Mortality Occurred Within 100 Days From Randomization	Death from any cause.	Randomization date to Day 100
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	From randomization date to Day 100

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: December 18, 2008
• First Submitted That Met QC Criteria: December 18, 2008
• First Posted (Estimate): December 19, 2008

Study Record Updates

• Last Update Posted (Actual): April 7, 2017
• Last Update Submitted That Met QC Criteria: March 9, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: high-risk leukopenic patients
• Additional Relevant MeSH Terms: Infections; Hematologic Diseases; Bacterial Infections and Mycoses; Leukocyte Disorders; Mycoses; Invasive Fungal Infections; Leukopenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Posaconazole; Fluconazole
• Other Study ID Numbers: P05387

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD 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