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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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Posaconazole | Active Comparator | Posaconazole oral suspension 200 mg three times a day (TID) |
|
| Fluconazole | Active Comparator | Fluconazole 400 mg once daily (QD) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Posaconazole | Drug | 40 mg/mL; 200 mg (5 mL) TID Treatment was continued with each cycle of chemotherapy until:
|
| 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 |
| 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. |
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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
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:
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.
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23924680 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Posaconazole | Posaconazole oral suspension (40 mg/ml), 200 mg (5mL) three times a day (TID) with meals |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Posaconazole | Posaconazole oral suspension (40 mg/ml), 200 mg (5mL) three times a day (TID) with meals |
| BG001 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 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. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Number | participants | Up to 12 Weeks (84 days) plus 7 days |
|
From screening to the last dosage date plus 30 days
Safety analysis set (SS) included randomized participants who received at least one dose of study drug and had valid data of safety endpoints available for at least one follow-up visit after treatment.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Posaconazole | Posaconazole oral suspension (40 mg/ml), 200 mg (5mL) three times a day (TID) with meals |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bone marrow depression | Blood and lymphatic system disorders |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bone marrow depression | Blood and lymphatic system disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme Corp. | ClinicalTrialsDisclosure@merck.com |
| ID | Term |
|---|---|
| D007970 | Leukopenia |
| ID | Term |
|---|---|
| D000095542 | Cytopenia |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007960 | Leukocyte Disorders |
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| ID | Term |
|---|---|
| C101425 | posaconazole |
| D015725 | Fluconazole |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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|
| Fluconazole | Drug | 50 mg/capsule (2 capsules), 150 mg/capsule (2 capsules); 400 mg QD Treatment was continued with each cycle of chemotherapy until:
|
|
| 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:
| 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:
| From randomization date to Day 100 |
| Did Not Take Study Drug |
|
| Without Primary Efficacy Endpoint Data |
|
| Investigator Decision |
|
| Poor Compliance |
|
| BG002 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| participants |
|
| Sex: Female, Male | 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. | Count of Participants | Participants |
|
| OG001 | 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 |
|
|
|
| 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. | 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. | Posted | Number | participants | From randomization date to Day 100 |
|
|
|
|
| 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. | 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. | Posted | Number | Days | From randomization date to Day 100 |
|
|
|
| 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. | 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. | Posted | Number | Days | Up to 12 weeks (84 days) |
|
|
|
| Secondary | Number of Participants With Clinical Failure During Treatment | Clinical failure was defined as follows:
| 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. | Posted | Number | participants | Up to 12 weeks (84 days) |
|
|
|
|
| Secondary | Number of Participants in Whom All-cause Mortality Occurred Within 100 Days From Randomization | Death from any cause. | 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. | Posted | Number | participants | Randomization date to Day 100 |
|
|
|
|
| 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:
| 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. | Posted | Number | participants | From randomization date to Day 100 |
|
|
|
| 7 |
| 124 |
| 82 |
| 124 |
| EG001 | 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 | 10 | 121 | 81 | 121 |
| Intestinal haemorrhage | Gastrointestinal disorders |
|
| Death | General disorders |
|
| Oedema | General disorders |
|
| Sepsis | Infections and infestations |
|
| Septic shock | Infections and infestations |
|
| Cerebellar haemorrhage | Nervous system disorders |
|
| Cerebral infarction | Nervous system disorders | One participant developed an SAE of life-threatening Respiratory Failure due to Cerebral Infarction, in the AE tables it was counted as a Cerebral Infarction |
|
| Consciousness disturbance | Nervous system disorders |
|
| Haemoptysis | Respiratory, thoracic and mediastinal disorders |
|
| Respiratory tract infection | Respiratory, thoracic and mediastinal disorders |
|
| Cerebral haemorrhage | Vascular disorders |
|
| Abdominal discomfort | Gastrointestinal disorders |
|
| Anal disorder | Gastrointestinal disorders |
|
| Constipation | Gastrointestinal disorders |
|
| Diarrhoea | Gastrointestinal disorders |
|
| Gingivitis | Gastrointestinal disorders |
|
| Mucosal inflammation | Gastrointestinal disorders |
|
| Nausea | Gastrointestinal disorders |
|
| Vomiting | Gastrointestinal disorders |
|
| Chest discomfort | General disorders |
|
| Pain | General disorders |
|
| Pyrexia | General disorders |
|
| Hepatic function abnormal | Investigations |
|
| Electrolyte imbalance | Metabolism and nutrition disorders |
|
| Dizziness | Nervous system disorders |
|
| Headache | Nervous system disorders |
|
| Cough | Respiratory, thoracic and mediastinal disorders |
|
| ENT disorder | Respiratory, thoracic and mediastinal disorders |
|
| Respiratory tract infection | Respiratory, thoracic and mediastinal disorders |
|
| Haemorrhage subcutaneous | Skin and subcutaneous tissue disorders |
|
| Rash | Skin and subcutaneous tissue disorders |
|
The Principal Investigator agrees not to publish or publicly present any interim results of the Protocol study without the prior written consent of the SPONSOR. The Principal Investigator further agrees to provide to the
SPONSOR thirty (30) days prior to submission for publication or presentation, review copies of abstracts or manuscripts for publication that report any results of the Protocol study.
| Percentage of Participants |
| 13.68 |
| 2-Sided |
| 95 |
| 8.0 |
| 21.3 |
IFI Incidence for the Fluconazole group = (# of participants affected with proven or probable IFI/ # of participants in the FAS population at risk)*100% |
| Superiority or Other |
| Percentage of Participants |
| 41.88 |
| 2-Sided |
| 95 |
| 32.8 |
| 51.4 |
IFI Incidence for the Fluconazole group = (# of participants affected with proven or probable IFI/ # of participants in the FAS population at risk)*100% |
| Superiority or Other |
| Percentage of Participants |
| 5.98 |
| 2-Sided |
| 95 |
| 2.4 |
| 11.9 |
All-Cause Mortality Rate is the percentage of participants with mortality from any cause. |
| Superiority or Other |