Leukopenia
Conditions
Keywords
high-risk leukopenic patients
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
Interventions
DRUGPosaconazole
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)
DRUGFluconazole
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)
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Proven or Probable Diagnosis of Invasive Fungal Infection (IFI) During the Treatment Period | Up to 12 Weeks (84 days) plus 7 days | 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
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to the First Onset of Proven or Probable IFI | From randomization date to Day 100 | 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 | Up to 12 weeks (84 days) | 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 Proven or Probable Diagnosis of IFI Within 100 Days From Randomization | From randomization date to Day 100 | 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. |
| Number of Participants in Whom All-cause Mortality Occurred Within 100 Days From Randomization | Randomization date to Day 100 | 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 | From randomization date to Day 100 | 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 |
| Number of Participants With Clinical Failure During Treatment | Up to 12 weeks (84 days) | 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 |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Posaconazole Posaconazole oral suspension (40 mg/ml), 200 mg (5mL) three times a day (TID) with meals | 117 |
| Fluconazole Fluconazole 400 mg daily (QD), given as 2 capsules of 50 mg and 2 capsules of 150 mg (a total of 4 capsules) with or without food | 117 |
| Total | 234 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | AEs and SAEs Including Death | 7 | 11 |
| Overall Study | Did Not Take Study Drug | 3 | 0 |
| Overall Study | Investigator Decision | 2 | 1 |
| Overall Study | Poor Compliance | 2 | 5 |
| Overall Study | Withdrawal by Subject | 18 | 12 |
| Overall Study | Without Primary Efficacy Endpoint Data | 7 | 4 |
Baseline characteristics
| Characteristic | Posaconazole | Fluconazole | Total |
|---|---|---|---|
| Age, Continuous | 39.3 participants STANDARD_DEVIATION 13.01 | 40.6 participants STANDARD_DEVIATION 12.5 | 40.4 participants STANDARD_DEVIATION 12.73 |
| Sex: Female, Male Female | 62 Participants | 65 Participants | 127 Participants |
| Sex: Female, Male Male | 55 Participants | 52 Participants | 107 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 82 / 124 | 81 / 121 |
| serious Total, serious adverse events | 7 / 124 | 10 / 121 |
Outcome results
Primary
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.
Time frame: Up to 12 Weeks (84 days) plus 7 days
Population: The full analysis set (FAS) included all of those randomized participants who received at least one dose of study drug, and had at least one post-treatment follow-up data of primary efficacy variable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Number of Participants With Proven or Probable Diagnosis of Invasive Fungal Infection (IFI) During the Treatment Period | 4 participants |
| Fluconazole | Number of Participants With Proven or Probable Diagnosis of Invasive Fungal Infection (IFI) During the Treatment Period | 11 participants |
95% CI: [-12.21, 0.25]
Secondary
Number of Participants in Whom All-cause Mortality Occurred Within 100 Days From Randomization
Death from any cause.
Time frame: Randomization date to Day 100
Population: The full analysis set (FAS) included all of those randomized participants who received at least one dose of study drug, and had at least one post-treatment follow-up data of primary efficacy variable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Number of Participants in Whom All-cause Mortality Occurred Within 100 Days From Randomization | 3 participants |
| Fluconazole | Number of Participants in Whom All-cause Mortality Occurred Within 100 Days From Randomization | 8 participants |
95% CI: [0.5, 7.3]
95% CI: [2.4, 11.9]
Secondary
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
Time frame: From randomization date to Day 100
Population: The full analysis set (FAS) included all of those randomized participants who received at least one dose of study drug, and had at least one post-treatment follow-up data of primary efficacy variable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Number of Participants in Whom Mortality is Unlikely, Possibly, and Probably Related to Fungal Infection Occurred Within 100 Days From Randomization | 0 participants |
| Fluconazole | Number of Participants in Whom Mortality is Unlikely, Possibly, and Probably Related to Fungal Infection Occurred Within 100 Days From Randomization | 0 participants |
Secondary
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
Time frame: Up to 12 weeks (84 days)
Population: The full analysis set (FAS) included all of those randomized participants who received at least one dose of study drug, and had at least one post-treatment follow-up data of primary efficacy variable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Number of Participants With Clinical Failure During Treatment | 37 participants |
| Fluconazole | Number of Participants With Clinical Failure During Treatment | 51 participants |
95% CI: [23.3, 40.9]
95% CI: [32.8, 51.4]
Secondary
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 frame: From randomization date to Day 100
Population: The full analysis set (FAS) included all of those randomized participants who received at least one dose of study drug, and had at least one post-treatment follow-up data of primary efficacy variable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Number of Participants With Proven or Probable Diagnosis of IFI Within 100 Days From Randomization | 5 participants |
| Fluconazole | Number of Participants With Proven or Probable Diagnosis of IFI Within 100 Days From Randomization | 16 participants |
95% CI: [1.4, 9.7]
95% CI: [8, 21.3]
Secondary
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.
Time frame: Up to 12 weeks (84 days)
Population: The full analysis set (FAS) included all of those randomized participants who received at least one dose of study drug, and had at least one post-treatment follow-up data of primary efficacy variable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Time From Randomization to Administration of First Systemic Antifungal Intravenous (IV) Therapy | 4 Days |
| Fluconazole | Time From Randomization to Administration of First Systemic Antifungal Intravenous (IV) Therapy | 1 Days |
Secondary
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 frame: From randomization date to Day 100
Population: The full analysis set (FAS) included all of those randomized participants who received at least one dose of study drug, and had at least one post-treatment follow-up data of primary efficacy variable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Time From Randomization to the First Onset of Proven or Probable IFI | 8 Days |
| Fluconazole | Time From Randomization to the First Onset of Proven or Probable IFI | 2 Days |