Posaconazole for Pulmonary Fungal Infection Prophylaxis in Hematopoietic Stem Cell Transplantation Patients

Study Overview
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Brief Summary
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This open, prospective, observational multicenter cohort study aims to evaluate the efficacy, safety as well as the effective serum concentration of Posaconazole for prevention of pulmonary fungal infections in patients with hematopoietic stem cell transplantation. The correlation of UGT1A4*3 genotype and Cmin of Posaconazole, as well as invasive fungal disease (IFD) breakthrough rates will be utilized to evaluate the efficacy while the safety of Posaconazole will be assessed by the overall incidence and severity of adverse events in patients.

Detailed Description
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This open, prospective, observational multicenter cohort study aims to study the efficacy, safety and effective concentration of Posaconazole tablets for prevention of pulmonary fungal infection in patients with hematopoietic stem cell transplantation. A total of 360 hematopoietic stem cell transplantation patients receiving Posaconazole tablets are expected to be enrolled. Posaconazole tablets will be taken orally from the day of transplantation (300 mg Q12h D1) followed by 300 mg Qd, until 90 days after transplantation. The total duration of the study is estimated to be 24 months, with each patient participating for an estimated 3 months. The relationships between UGT1A4*3 genotype and drug serum concentration, IFD incidence, Aspergillus infection rate, IFD-related mortality rate, IFD-free survival rate, and overall survival rate will be used to evaluate the effectiveness of Posaconazole tablets in preventing invasive pulmonary fungal infection in patients with hematopoietic stem cell transplantation. Safety of Posaconazole tablet will be validated by the overall incidence and severity of adverse events in patients.

Official Title
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Efficacy, Safety and Serum Concentration of Posaconazole Tablets for Prevention of Pulmonary Fungal Infections in Patients With Hematopoietic Stem Cell Transplantation: An Open, Prospective, Observational, Multicenter Cohort Study

Conditions
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Pulmonary Fungal Infection

Intervention / Treatment
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* Drug: Oral Posaconazole tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 13 years old The primary causes of hematopoietic stem cell transplantation include aplastic anemia, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, or other hematologic diseases in patients pretreated for hematopoietic stem cell transplantation. The types of transplantation include autologous transplantation, syngeneic transplantation, matched sibling donor transplantation, unrelated donor transplantation and haploidentical transplantation The patients themselves or their authorized clients agree to participate in the clinical study and sign the informed consent Exclusion Criteria: Those with evidence of active fungal infection within 3 weeks prior to enrollment Allergic to azole drugs Severe abnormal liver function Rifampicin, isoniazid, phenytoin, carbamazepine, and long-acting barbiturates were used in combination during the study Any predictably increased patient risk or other factors that might interfere with the outcome of a clinical trial

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Oral Posaconazole tablets|Posaconazole tablets (300 mg Q12h D1) taken orally on the day of transplantation, and followed by 300mg Qd, until 90 days after transplantation.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| UGT1A4*3 genotype and plasma concentration of posaconazole | Blood samples were drawn at baseline (day 0) for analysis of patients' UGT1A4*3 genotypes and assigned to homozygous, wild-type, and heterozygous genotypes. For posaconazole serum concentrations, blood samples were collected at day 0, 4, 8, 15 and 22. | From day 0 to day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of invasive fungal disease (IFD) and the incidence of Aspergillus infection | Patients who developed invasive fungal infections, aspergillus infections or death related with IFD infections during posaconazole prophylaxis treatment were recorded in accordance with IFD diagnostic guidelines (Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020 Sep 12;71(6):1367-1376). | 90 days posaconazole prophylaxis and 7 days after prophylaxis ending | 
| Plasma concentration of the patients who received different dosages of posaconazole as prophylaxis at different time points | Blood samples were drawn from patients at day 0, 4, 8, 15, and 22 after receiving posaconazole. | Day 0, 4, 8, 15 and 22 | 
| The influence of other combined medications for posaconazole plasma concentrations | Blood samples were drawn at day 0, 4, 8, 15 and 22 after receiving posaconazole, while all combined medications during posaconazole prophylaxis were recorded and IFD cases were monitored during the study period. | Duration of 90-day posaconazole prophylaxis | 
| Effect of GVHD grading on absorption and utilization of posaconazole tablets (plasma concentration) | Gastrointestinal GVHD grades (I-IV) were recorded according to patient symptoms and posaconazole plasma concentrations were measured using blood samples of each patient after receiving posaconazole tablets at day 0, 4, 8, 15 and 22. | Duration of 90-day posaconazole prophylaxis | 
| Effect of diarrhea on absorption and utilization of posaconazole tablets (plasma concentration) | Diarrhea (acute watery diarrhea, acute hemorrhagic diarrhea, persistent diarrhea, and diarrhea with severe malnutrition) was recorded according to patient symptoms, and posaconazole plasma concentrations were measured using blood samples of each patient after receiving posaconazole tablets at day 0, 4, 8, 15 and 22. | Duration of 90-day posaconazole prophylaxis | 
| Number/Proportion of patients with immunosuppressive agent application and adjustments | Recording of the number/proportion of patients who received immunosuppressive agents or adjustments of agents. | Duration of 90-day posaconazole prophylaxis | 
| Measurement and record of neutrophil counts | Measurement of neutrophils in blood samples of patients. | Duration of 90-day posaconazole prophylaxis | 
| Measurement and record of duration of neutropenia | Measurement of duration of neutropenia in blood samples of patients. | Duration of 90-day posaconazole prophylaxis | 
| Adverse events | Record of the number, incidence and frequency of adverse events (AE) during the study period and judge whether the AE is drug related, serious, or special interest AE. AE severity is determined according to MedDRA v23.1. | Duration of 90-day posaconazole prophylaxis |