Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome in transformation (MDSit) who receive antifungal profylaxis during their treatment with an intensive chemotherapy regimen, including induction / consolidation / salvage remission therapy.
Conditions
Interventions
Product Name: Posaconazole
Pharmaceutical Form: Gastro-resistant tablet
INN or Proposed INN: Posaconazole
CAS Number: 171228-49-2
Other descriptive name: POSACONAZOLE
Concentration unit: mg milligram(
Sponsors
Centre Hospitalier Universitaire Vaudois
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed Informed Consent according to national/local regulations. 2. Age > or = 18 years. 3. Diagnosis of AML or MDSit treated with an intensive chemotherapy regimen, including induction / consolidation / salvage remission chemotherapy. 4. Planned hospital admission for the duration of the neutropenic phase (ANC=65 years) yes F.1.3.1 Number of subjects for this age range 121
Exclusion criteria
Exclusion criteria: 1. Patients with neutropenia (ANC5x upper limit of normality: and/or total bilirubin above >3x upper limit of normality. 7. Patients with an ECG with a prolonged QTc interval: QTc greater than 450 msec for men and greater than 470 msec for women. 8. 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). 9. Serious uncontrolled concomitant disease or comorbidity that, in the opinion of the investigator, may compromise adherence to the study protocol. 10. Receipt of a prior allogeneic HCT. 11. Previous exposure to mold-active prophylaxis (>48 hours within 7 days of inclusion).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to determine whether the absolute risk reduction (ARR) in the cumulative incidence (CI) of probable and proven invasive mold infections (IMI) in AML/MDSit patients is higher when the use of posaconazole versus fluconazole prophylaxis is allocated on a genetically predicted risk stratification to be either at high-risk or at low-risk of IMI. Accordingly, the study aims to demonstrate a reduction in the number of patients needed-to-treat (NNT being the inverse of ARR) with antifungal prophylaxis to avoid one IMI event in high-risk compared to low-risk patients.;Secondary Objective: 1. Determine whether the ARR in the CI of possible IMI in posaconazoletreated (P+) patients compared to non-posaconazole-treated (P-) patients is higher in high-risk versus low-risk patients in the intention-to-treat (ITT) AML population during the treatment period (days 0-180). 2. Determine whether the ARR in the CI of proven and probable IFI in P+ patients compared to P- patients is higher in high-risk versus low-risk patients in the ITT AML/MDSit population during the treatment period (days 0-180), specifically: a) All IFI b) IA only c) IC only 3. Determine whether the CI of mortality in P+ patients compared to P- patients is higher according to high-risk versus low-risk stratification in the ITT AML/MDSit population during the treatment period (days 0-180). 4. Assess that the overall CI of Adverse Events (AE) associated with antifungal prophylaxis in P+ patient compared to P- patients in the ITT AML/MDSit population during the treatment period (days 0-180).;Primary end point(s): The cumulative incidence of proven and probable IMI* in the intention-to-treat (ITT) population. *Invasive fungal infections (IFI), invasive mold infections (IMI), invasive aspergillosis (IA) and invasive candidiasis (IC) will be defined based on published consensus guidelines by the EORTC/MSG (45) (Annexes 1 & 2) and after validation by an independent A | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. The cumulative incidence of possible IMI* by day 180 in the ITT population. 2. The cumulative incidence of probable and proven IFI*, namely: (a) all IFI, (b) IA only and (c) IC only in the ITT patient population by day 180. 3. The time to probable and proven IMI* during 180 days in the ITT population. 4. The overall survival in the ITT population by day 180. 5. The time to use and number of patient-days of amphotericin B or an echinocandin in the ITT population during 180 days. 6. The frequency and distribution of AE of interest in posaconazole and fluconazole treated participants in the ITT population during 180 days, namely: a) 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 b) New QTc prolongation, defined as QTc >450 msec for men and >470 msec for women 7. The cumulative incidence of probable and proven IFI*, namely: all IFI, all IMI, IA only and IC only in the per protocol (PP) population by day 180. *Invasive fungal infections (IFI), invasive mold infections (IMI), invasive aspergillosis (IA) and invasive candidiasis (IC) will be defined based on published consensus guidelines by the EORTC/MSG (45) (Annexes 1 & 2) and after validation by an independent AC of infectious disease experts blinded to treatment arms.;Timepoint(s) of evaluation of this end point: The assessment of the secundary outcomes will take place by day 180. Day 0 is defined as the first day of antifungal prophylaxis administration (within 24h of the 1st day of neutropenia, defined as an absolute neutrophil count, ANC<500 cells/mm3) | — |
Countries
Belgium, France, Switzerland
Contacts
Public ContactStudiebureau Hematologie
University Hospitals Leuven
Outcome results
None listed