Cresemba® in Treating Chinese Patients With IFD Caused by Aspergillus Species or Other Filamentous Fungi

Pfizer70 enrolled

Overview

This study is a post-approval commitment study, and is designed to further evaluate the safety and efficacy of isavuconazole in a relatively larger Chinese population who will receive isavuconazole treatment in a post-marketing setting. This is a single arm, prospective, multi-center study. This study is seeking Chinese patients with proven, probable or possible Invasive Fungal Disease (IFD) caused by Aspergillus species or other filamentous fungi. All the participants will receive isavuconazole treatment. The longest treatment duration in this study is 84 days (up to 180 days for participants diagnosed with IM). The primary objective is to characterize the safety and tolerability of isavuconazole through observing the treatment emergent adverse events.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Invasive Fungal Disease

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * proven, probable, or possible IFD caused by Aspergillus species, Mucorales species or other filamentous fungi * body weight \>40 kg at screening Exclusion Criteria: * either chronic aspergillosis, aspergilloma, or ABPA * Advanced HIV infection with CD4 count \< 200 or acquired immunodeficiency syndrome-defining condition * people who are unlikely to survive 5 days or participants on mechanical ventilation * severe hepatic impairment (Child-Pugh Class C) * familial short QT syndrome * Concomitant use of efavirenz, ritonavir, etravirine, rifampicin/rifampin, rifabutin, nafcillin, ketoconazole, or St. John's Wort in the 5 days prior to first administration of study intervention

Locations (14)

The First Affiliated Hospital of USTC, Anhui Province Hospital

Hefei, Anhui, China

The First Affiliated Hospital of Guangzhou Medical University

Guangzhou, Guangdong, China

Guangzhou First People's Hospital

Guangzhou, Guangdong, China

ZhuJiang Hospital of Southern Medical University

Guangzhou, Guangdong, China

Jieyang People's Hospital

Jieyang, Guangdong, China

Henan provincial people's hospital

Zhengzhou, Henan, China

Liaocheng people's Hospital

Liaocheng, Shandong, China

Zibo Central Hospital

Zibo, Shandong, China

Huashan Hospital, Fudan University

Shanghai, Shanghai Municipality, China

Institute of Hematology, Chinese Academy of Medical Sciences

Tianjin, Tianjin Municipality, China

...and 4 more locations

Outcomes

Primary Outcomes

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A TEAE was an AE that started on or after the first administration of study intervention until 28 days after last dose of study intervention. AEs included both serious (SAE) and all non-serious adverse events (non-SAEs).

Time frame: From start of study intervention on Day 1 up to 28 days after last dose of study intervention (For Isavuconazole IA group: approximately up to 112 days, for Isavuconazole IM group: approximately up to 208 days)

Secondary Outcomes

All-cause Mortality Rate Through Day 42

All-cause mortality included any death that occurred after first dose of study drug through Day 42 as following: a) known deaths: any death that occurred after first dose of study intervention through Day 42 and b) unknown deaths: unknown (not actual deaths but the numbers were used in calculating all-cause mortality rate): participant was censored and was included in the reported data for this outcome measure if participant's survival status was missing or the last known alive date was before Day 42. All-cause mortality rate was defined as the percentage of participants with all-cause mortality (known deaths \[actual\] and unknown deaths \[not actual but treated as deaths\]) among the overall number of participants analyzed.

Time frame: After first dose of study intervention (Day 1) through Day 42

All-cause Mortality Rate Through Day 84

All-cause mortality included any death that occurred after first dose of study drug through Day 84 as following: a) known deaths: any death that occurred after first dose of study intervention through Day 84 and b) unknown (not actual deaths but the numbers were used in calculating all-cause mortality rate): participant was censored and was included in the reported data for this outcome measure if participant's survival status was missing or the last known alive date was before Day 84. All-cause mortality rate was defined as the percentage of participants with all-cause mortality (known deaths \[actual\] and unknown deaths \[not actual but treated as deaths\]) among the overall number of participants analyzed.

Time frame: After first dose of study intervention (Day 1) through Day 84

Overall Success Rate Based on Investigator's Assessment at Day 42, Day 84 and End of Treatment (EOT): Modified Intent-to-Treat (mITT) Population

Successful response was based on any one criterion from clinical, radiological or mycological response to be considered to have an overall outcome of success as the following. Criteria for:a)clinical response:1)resolution of all attributable clinical symptoms and physical findings 2)resolution of some attributable clinical symptoms and physical findings;b)A success radiological response means:1) greater than equal to(\>=) 90 percent (%)improvement from screening,2)\>= 50% to less than(\<)90% improvement from screening for visits on Day 42, Day 84 and EOT(that is after Day 42), 3)\>=25% to \<50% improvement from screening (For Day 42 and EOT (that is before Day 180) for participants with proven or probable IFD and at Day 84, this would be considered unsuccessful) and 4) no signs on radiological images at screening (proven IFD only);c)mycological response:1)eradication and 2)presumed eradication. Overall success rate: percentage of participants with overall success at specified time points.

Time frame: Day 42, Day 84 and EOT (any day before or at Day 180)

Overall Success Rate Based on Investigator's Assessment at Day 42, Day 84 and EOT: Mycological Intent-to-Treat IA (myITT-IA) Population

Successful response was based on any one criterion from clinical, radiological or mycological response to be considered to have an overall outcome of success as the following. Criteria for: a)clinical response:1)resolution of all attributable clinical symptoms and physical findings 2)resolution of some attributable clinical symptoms and physical findings; b)A success radiological response means:1) \>= 90 percent (%)improvement from screening, 2)\>= 50% to \< 90% improvement from screening for visits on Day 42, Day 84 and EOT(that is after Day 42), 3)\>=25% to \<50% improvement from screening (For Day 42 and EOT (that is before Day 84) for participants with proven or probable IFD and at Day 84, this would be considered unsuccessful) and 4) no signs on radiological images at screening (proven IFD only);c) mycological response:1)eradication and 2)presumed eradication. Overall success rate: percentage of participants with overall success at specified time points.

Time frame: Day 42, Day 84 and EOT (any day before or at Day 84)

Clinical Success Rate at Day 42, Day 84 and EOT: mITT Population

Clinical response was categorized into: success, failure, and not applicable. Clinical success was based on any one of the following criteria: 1) resolution of all attributable clinical symptoms and physical findings and 2) resolution of some attributable clinical symptoms and/or physical findings. Assessment was based on investigator's assessment. Clinical success rate: percentage of participants with clinical success at specified time points.

Time frame: Day 42, Day 84 and EOT (any day before or at Day 180)

Clinical Success Rate at Day 42, Day 84 and EOT: myITT-IA Population

Time frame: Day 42, Day 84 and EOT (any day before or at Day 84)

Mycological Success Rate at Day 42, Day 84 and EOT: mITT Population

Mycological response was categorized into: success, failure, and not applicable. Success mycological response was based on any one of the following criteria: 1) eradication: eradication of the original causative organism cultured or identified by histology/cytology at baseline and 2) presumed eradication: missing documentation of the eradication of the original causative organism at baseline plus resolution of all or some clinical symptoms and physical findings of IFD present at baseline and/or of those that appeared at a subsequent visit. Success rate: percentage of participants with successful mycological response at specified time points.

Time frame: Day 42, Day 84 and EOT (any day before or at Day 180)

Mycological Success Rate at Day 42, Day 84 and EOT: myITT-IA Population

Time frame: Day 42, Day 84 and EOT (any day before or at Day 84)

Radiological Success Rate at Day 42, Day 84 and EOT: mITT Population

Radiological response was categorized into: success, failure, and not applicable. A successful radiological response was based on any one of the following criteria: 1) \>=90% improvement from screening, (2) \>=50% to \<90% improvement from screening for visits on Day 42, Day 84, and EOT (that is after Day 42), (3) \>=25% to \<50% improvement from screening for Day 42 and EOT (that is before Day 180). Success rate: percentage of participants with successful radiological response at specified time points.

Time frame: Day 42, Day 84 and EOT (any day or at before Day 180)

Radiological Success Rate at Day 42, Day 84 and EOT: myITT-IA Population

Radiological response was categorized into: success, failure, and not applicable. A successful radiological response was based on any one of the following criteria: 1) \>=90% improvement from screening, (2) \>=50% to \<90% improvement from screening for visits on Day 42, Day 84, and EOT (that is after Day 42), (3) \>=25% to \<50% improvement from screening for Day 42 and EOT (that is before Day 84). Success rate: percentage of participants with successful radiological response at specified time points.

Time frame: Day 42, Day 84 and EOT (any day before Day 84)

Number of Participants With Treatment Related TEAEs

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A TEAEs was an AE with that started on or after the first administration of study intervention until 28 days after last dose of study intervention. Treatment related TEAEs were TEAEs related to study intervention. AEs included both serious and all non-SAEs.

Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs)

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A SAE was defined as any untoward medical occurrence that, at any dose, met one or more of the criteria: resulted in death, is life-threatening, required in-participant hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity and was a congenital anomaly/birth defect. A TEAEs was an AE with that started on or after the first administration of study intervention until 28 days after last dose of study intervention.

Number of Participants With TEAEs Leading to Study Intervention Discontinuation

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A TEAEs was an AE with that started on or after the first administration of study intervention until 28 days after last dose of study intervention. In this outcome measure, number of participants with TEAEs leading to study intervention discontinuation (during study treatment) were reported.

Number of Participants With TEAEs Leading to Death

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A TEAEs was defined as an AE with an onset date on or after the date of informed consent until 28 days after discontinuation of drug. In this outcome measure, number of participants with TEAEs leading to death (during study treatment) were reported.

Number of Participants With Death

Number of participants with death due to any cause were reported in this outcome measure.

Number of Participants With Laboratory Test Abnormalities

Clinical laboratory abnormalities test criteria included, a) hematology: hemoglobin with primary criteria of \<0.8\* lower limit of normal (LLN), erythrocytes \<0.8\* LLN, platelets \<0.5\* LLN \>1.75\* upper limit of normal (ULN), leukocytes \< 0.6\* LLN and \> 1.5\* ULN, lymphocytes and neutrophils \< 0.8\* LLN and \> 1.2\* ULN. b) Chemistry: bilirubin and direct bilirubin \>1.5\* ULN, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase \>3.0\* ULN, urea nitrogen, urea and creatinine \>1.3\* ULN, sodium \<0.95\* LLN and potassium\<0.9\* LLN. c) urinalysis: pH, urine glucose, ketones, urine protein, urine hemoglobin and bilirubin, urobilinogen, nitrite leukocyte esterase \>= 1. Number of participants with any laboratory abnormalities were reported in this outcome measure.

Number of Participants With Clinically Significant Abnormalities in Vital Signs

Vital signs included systolic and diastolic blood pressures and pulse rate. Clinical significance of vital signs was judged by the investigator.

Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters as Per Pre-defined Criteria

Predefined ECG criteria of clinical significance: a) heart rate (beats per minute \[bpm\]): value \<40 and value \>120; b) PR interval (millisecond \[(msec)\]: value\>280; c) QRS interval (msec): value\>120 d) QTc corrected using Fridericia's formula (QTcF) (msec): value \>500 and new prolongation value \>480 or increase \>= 60. Only those pre-defined ECG categories for which non-zero data were available have been reported below.

Number of Participants With Abnormal Eye Examination

The eye examination included visual acuity, confrontational visual field testing and color perception testing. Any abnormality was assessed by a qualified ophthalmologist.

Plasma Concentration of Isavuconazole at Days 3, 7, 14 and EOT Visit

Observed plasma concentrations of Isavuconazole were reported in this outcome measure.

Time frame: Pre-dose (0 hours) and 1.5 hours post-dose on Day 3; pre-dose (0 hours) and 1.5, 3, 6, 12, 24 hours post dose on Days 7 and 14; pre-dose (0 hours) or 24 hours post-dose at EOT (any day before or at Day 180)