PTX3 Genetically Stratified Randomized Double-blinded Allocation Event-driven Clinical Trial for Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 410
- 试验地点
- 9
- 主要终点
- Cumulative incidence of proven and probable invasive mold infection (IMI)
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The investigational medicinal products will be known by all roles but the arm allocation based on a genetic analysis will be blinded.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed Informed Consent according to national/local regulations.
- •Age ≥18 years.
- •Diagnosis of Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome in transformation (MDSit) treated with an intensive chemotherapy regimen, including induction / consolidation / salvage remission chemotherapy.
- •Planned hospital admission for the duration of the neutropenic phase (absolute neutrophils count <500 cells/mm3).
排除标准
- •Patients with neutropenia (absolute neutrophils count<500 cells/mm3) upon presentation and prior to chemotherapy initiation.
- •Patients with a diagnosis of acute promyelocytic leukemia (APL) or AML-M
- •Patients with known history of allergy, hypersensitivity or serious reaction to azole antifungals
- •Women who are pregnant (positive blood/urine pregnancy test within 10 days before randomization) or breast-feeding.
- •Diagnosis and treatment for an Invasive Fungal Infection (IFI) within 3 months prior to study enrolment and an Invasive Mold Infection (IMI) at any point prior to or at the time of enrolment.
- •Severe liver dysfunction, defined as at least one of the following markers: Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) or alkaline phosphatase above >5x upper limit of normality: and/or total bilirubin above >3x upper limit of normality.
- •Patients with an ECG with a prolonged QTc interval: QTc greater than 450 msec for men and greater than 470 msec for women.
- •Patients who are receiving and cannot discontinue the following drugs at least 24 hours prior to randomization: terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine (because of the possibility of QT prolongation), sirolimus, rifampin, rifabutin, carbamazepine, long-acting barbiturates (e.g., phenobarbital, mephobarbital), ritonavir, efavirenz, or ergot alkaloids (e.g., ergotamine, dihydroergotamine).
- •Serious uncontrolled concomitant disease or comorbidity that, in the opinion of the investigator, may compromise adherence to the study protocol.
- •Receipt of a prior allogeneic Hematopoietic Cell Transplantation (HCT).
- •Previous exposure to mold-active prophylaxis (>48 hours within 7 days of inclusion).
- •Patients with relapsed leukemia already included in the trial.
- •Patient not affiliated to the French social security system
- •Patient under legal protection (guardianship, curatorship)
研究组 & 干预措施
high-risk PTX3 SNPs
risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): homozygous for rs230561 and/or rs381652
干预措施: Posaconazole (Drug)
high-risk PTX3 SNPs
risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): homozygous for rs230561 and/or rs381652
干预措施: Fluconazole (Drug)
low-risk PTX3 SNPs
risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): other than homozygous for rs230561 and/or rs381652
干预措施: Posaconazole (Drug)
low-risk PTX3 SNPs
risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): other than homozygous for rs230561 and/or rs381652
干预措施: Fluconazole (Drug)
结局指标
主要结局
Cumulative incidence of proven and probable invasive mold infection (IMI)
时间窗: Day 180
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.
次要结局
- Cumulative incidence of possible invasive mold infection (IMI)(Day 180)
- Time to probable and proven invasive mold infection (IMI)(Day 180)
- Time to first use and number of patient-days of amphotericin B/echinocandin(Day 180)
- Cumulative incidence of probable and proven Invasive Fungal Infections (IFI)(Day 180)
- Cumulative incidence of mortality(Day 180)
- Frequency/distribution of adverse events (AE) of interest(Day 180)
- Treatment success versus failure(Day 180)
- Cumulative incidence of probable and proven invasive fungal infections (IFI) in per protocol population(Day 180)
研究者
Bochud Pierre-Yves
Associate Professor
Centre Hospitalier Universitaire Vaudois