An interventional study of Posaconazole and Fluconazole in Candidiasis, Fungal Infection and Acute Myeloid Leukemia, sponsored by Bochud Pierre-Yves. Recruiting at 9 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-12-09.
Sponsored by Bochud Pierre-Yves · Not applicable, Interventional, and Prevention
This is a prospective genetically-stratified randomized double-blind event-driven multicentre clinical trial to assess the efficacy of posaconazole-based antifungal prophylaxis allocation strategies for patients with acute myeloid leukemia who receive induction chemotherapy. Allocation strategy based on an invasive mold infection genetic risk will be double-blinded.
Background:
Invasive mold infections (IMI, grouping infections due to Aspergillus spp [IA] and non-Aspergillus mold) are a major concern in hematological patients, such as those with acute myeloid leukemia (AML) or myelodysplastic syndrome in transformation (MDSit), collectively named AML/MDSit in this protocol, or those undergoing hematopoietic cell transplantation (HCT), with incidence and mortality rates ranging between 3-15% and 25-45%, respectively. Primary antifungal prophylaxis has become the standard of care in such patients. Historically, fluconazole (inactive against IA) was used as prophylaxis and allowed for significant decrease in invasive candidiasis (IC). More recently, posaconazole (a broad-spectrum azole active against IA and other non-Aspergillus filamentous molds) was approved for primary antifungal prophylaxis in high-risk patient categories. However, universal prophylaxis with posaconazole has been challenged, based on the relatively low incidence of IMI and the large number of patients needed to treat. Moreover, administration of broad-spectrum azoles is costly and associated with a large number of complications. Hence, there is an urgent need to optimize antifungal prophylaxis by identifying those patients with the highest risk for IMI to receive a broad-spectrum azole. Pentraxin-3 (PTX3), a pattern recognition receptor, recognizes and binds to Aspergillus conidia, facilitates opsonization and subsequently leads to complement and phagocyte activation. Two single nucleotide polymorphisms (SNPs) in the gene encoding PTX3 have been identified as strong predictors for IA and/or IMI in human studies. What makes PTX3 SNPs different and important in clinical practice is: (i) the extent and reproducibility of basic science data with regards to PTX3 and IA, (ii) the validation of PTX3 SNPs associations with IA in many different patient populations, and (iii) the high frequency of minor allele in the general population. The investigators hypothesize that PTX3 SNPs could be used to identify patients at high risk for IMI, who will benefit the most from antifungal prophylaxis with broad-spectrum azoles.
Overall objective:
The overall aim of this project is to assess the effectiveness of the use of posaconazole-based antifungal prophylaxis in AML/MDSit patients in high risk group (single or double single homozygotes PTX-3 SNPs). Exploratory objectives are to assess the effectiveness of PTX3 SNPs testing to stratify the use of posaconazole-based antifungal prophylaxis in AML/MDSit patients according to low or high risk genotypes.
Methods:
Eligible patients will be tested by competitive allele-specific Polymerase Chain Reaction (PCR) from blood-extracted DNA samples for the presence of PTX3 SNPs rs230561 and rs3816527. Randomisation based on genetic testing will be performed at the latest 24h after the first neutropenia day (D0). Patients will be stratified based on genotyping results in two unbalanced strata: stratum A (high-risk PTX3 SNPs) to be randomized 1:1 posaconazole prophylaxis vs fluconazole and stratum-B (low-risk PTX3 SNPs) to be randomized 1:3 in favour of Fluconazole. Patients will be assessed for a diagnosis of possible, probable or proven Invasive Fungal Infections (IFI) based on consensus definition guidelines by the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) groups during 180 days after prophylaxis initiation.
Impact:
The results of this study may contribute to the optimization of primary antifungal prophylaxis, by preventing IMI while limiting the use of broad-spectrum azoles, thus decreasing complications and costs. This study is one of the first interventional clinical trials to use genetic factors for risk stratification in the field of hematology and infectious diseases, a concept frequently emphasized, however barely transcribed in practice, as precision medicine. Furthermore, the scope of the proposed study expands beyond the specific patient population. The results of this study could be used in the design and initiation of similar efforts in other high-risk patient categories, including allogeneic HCT and solid organ transplant (SOT) recipients.
Exclusion Criteria:
risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): homozygous for rs230561 and/or rs381652
Drug: Posaconazole · Drug: Fluconazole
risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): other than homozygous for rs230561 and/or rs381652
Drug: Posaconazole · Drug: Fluconazole
Posaconazole is a triazole with broad-spectrum activity, to include Candida species, Aspergillus species, and other fungal pathogens, including the Zygomycetes. Posaconazole is available as slow release tablets (300mg/day) and as intravenous (IV) formulation (300mg/day) and is licensed and approved in Switzerland for the prevention of IFI, including mold and yeast infections, in patients \>18 years who are at high risk of developing these types of infection (patients with long-term neutropenia or HCT recipients). Furthermore, international guidelines recommend posaconazole for primary antifungal prophylaxis in high-risk patients, such as AML patients with prolonged neutropenia. Posaconazole is available in Switzerland under the name of Noxafil® in capsules of 100mg, suspension of 40mg/mL and intravenous formulation of 300mg/16.7 mL.
Also known as: Noxafil
Fluconazole is an antifungal with activity against most Candida species. Fluconazole is licensed and approved in Switzerland for prophylaxis of IC in patients with neutropenia induced by chemotherapy or radiotherapy at a daily dose of 200 to 400 mg once daily. Fluconazole (200 mg or 400 mg once daily) is still currently used as primary antifungal prophylaxis (standard of care) in all 7 centers participating in this trial. Fluconazole is available in Switzerland under the name of Diflucan® in capsules of 50 mg, 150 mg and 200 mg and in powder for preparation of suspension (50 mg/5 ml and 200 mg/5 ml (forte)) or perfusion (2 mg/1 ml). Several generics of Diflucan® are authorized in Switzerland. Prescribing Diflucan® or any of its generics will remain at the discretion of and based on the standard operating procedures (SOP) at each institution.
Also known as: Diflucan
Cumulative incidence of proven and probable invasive mold infection (IMI)
The cumulative incidence of proven and probable invasive mold infection (IMI) (based on published consensus guidelines by the EORTC/MSG groups and after validation by an independent adjudication committee of infectious disease experts blinded to treatment arms) in the intention-to-treat (ITT) population by day 180.
Time frame: Day 180
Cumulative incidence of possible invasive mold infection (IMI)
The cumulative incidence of possible invasive mold infection (IMI) (based on published consensus guidelines by the EORTC/MSG groups and after validation by an independent adjudication committee of infectious disease experts blinded to treatment arms) by day 180 in the ITT population.
Time frame: Day 180
Cumulative incidence of probable and proven Invasive Fungal Infections (IFI)
The cumulative incidence of probable and proven Invasive Fungal Infections (IFI) (based on published consensus guidelines by the EORTC/MSG groups and after validation by an independent adjudication committee of infectious disease experts blinded to treatment arms), namely: (a) all IFI, (b) Invasive Aspergillosis (IA) only and (c) Invasive Candidiasis (IC) only in the ITT patient population by day 180.
Time frame: Day 180
Time to probable and proven invasive mold infection (IMI)
The time to probable and proven invasive mold infection (IMI) (based on published consensus guidelines by the EORTC/MSG groups and after validation by an independent adjudication committee of infectious disease experts blinded to treatment arms) during 180 days in the ITT population
Time frame: Day 180
Cumulative incidence of mortality
The cumulative incidence of mortality in the ITT population by day 180.
Time frame: Day 180
Time to first use and number of patient-days of amphotericin B/echinocandin
The time to use of amphotericin B/echinocandin in the ITT population during 180 days.
Time frame: Day 180
Frequency/distribution of adverse events (AE) of interest
The frequency/distribution of AE of interest in posaconazole and fluconazole treated participants in the ITT population during 180 days, namely: 1. Hepatotoxicity, defined by elevation of at least one of the following markers above \>5x upper limit of normal: transaminases, alkaline phosphatase and/or above \>3x upper limit of normal total bilirubin 2. New QTc prolongation, defined as QTc \>450 msec for men and \>470 msec for women
Time frame: Day 180
Treatment success versus failure
Treatment failure was defined as any of the following: proven or probable IFI, administration of any other systemically administered antifungal treatment for more than 10 consecutive days, discontinuation of prophylaxis for any other reason (e.g. severe adverse event associated with the study medication), death, loss to follow-up, or withdrawal from the study.
Time frame: Day 180
Cumulative incidence of probable and proven invasive fungal infections (IFI) in per protocol population
The cumulative incidence of probable and proven invasive fungal infections (IFI) (based on published consensus guidelines by the EORTC/MSG groups and after validation by an independent adjudication committee of infectious disease experts blinded to treatment arms) , namely: all Invasive Fungal Infections (IFI), all Invasive Mold Infections (IMI), Invasive Aspergillosis (IA) only and Invasive Candidiasis (IC) only in the per protocol (PP) population by day 180.
Time frame: Day 180
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