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PTX3-targeted Antifungal Prophylaxis (PTX3AML)

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ClinicalTrials.gov Identifier: NCT03828773
Recruitment Status : Recruiting
First Posted : February 4, 2019
Last Update Posted : March 10, 2020
Sponsor:
Collaborator:
Swiss National Science Foundation
Information provided by (Responsible Party):
Bochud Pierre-Yves, Centre Hospitalier Universitaire Vaudois

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Candidiasis Fungal Infection Acute Myeloid Leukemia Genetic Predisposition Aspergillosis Drug: Posaconazole Drug: Fluconazole Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: prospective genetically-stratified randomized double-blind event-driven multicentre clinical trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The investigational medicinal products will be known by all roles but the arm allocation based on a genetic analysis will be blinded.
Primary Purpose: Prevention
Official Title: PTX3 Genetically Stratified Randomized Double-blinded Allocation Event-driven Clinical Trial for Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia
Actual Study Start Date : February 11, 2019
Estimated Primary Completion Date : July 31, 2022
Estimated Study Completion Date : July 31, 2022


Arm Intervention/treatment
high-risk PTX3 SNPs
risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): homozygous for rs230561 and/or rs381652
Drug: Posaconazole
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.
Other Name: Noxafil

Drug: Fluconazole
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.
Other Name: Diflucan

low-risk PTX3 SNPs
risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): other than homozygous for rs230561 and/or rs381652
Drug: Posaconazole
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.
Other Name: Noxafil

Drug: Fluconazole
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.
Other Name: Diflucan




Primary Outcome Measures :
  1. Cumulative incidence of proven and probable invasive mold infection (IMI) [ Time Frame: 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.


Secondary Outcome Measures :
  1. Cumulative incidence of possible invasive mold infection (IMI) [ Time Frame: Day 180 ]
    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.

  2. Cumulative incidence of probable and proven Invasive Fungal Infections (IFI) [ Time Frame: Day 180 ]
    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.

  3. Time to probable and proven invasive mold infection (IMI) [ Time Frame: Day 180 ]
    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

  4. Overall survival in the ITT population [ Time Frame: Day 180 ]
    The overall survival in the ITT population by day 180.

  5. Time to use of amphotericin B/echinocandin [ Time Frame: Day 180 ]
    The time to use of amphotericin B/echinocandin in the ITT population during 180 days.

  6. Number of patient-days of amphotericin B/echinocandin [ Time Frame: Day 180 ]
    The number of patient-days of amphotericin B/echinocandin in the ITT population during 180 days.

  7. Frequency/distribution of adverse events (AE) of interest [ Time Frame: Day 180 ]

    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

  8. Cumulative incidence of probable and proven invasive fungal infections (IFI) in per protocol population [ Time Frame: Day 180 ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed Informed Consent according to national/local regulations.
  2. Age ≥18 years.
  3. Diagnosis of Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome in transformation (MDSit) treated with an intensive chemotherapy regimen, including induction / consolidation / salvage remission chemotherapy.
  4. Planned hospital admission for the duration of the neutropenic phase (absolute neutrophils count <500 cells/mm3).

Exclusion Criteria:

  1. Patients with neutropenia (absolute neutrophils count<500 cells/mm3) upon presentation and prior to chemotherapy initiation.
  2. Patients with a diagnosis of acute promyelocytic leukemia (APL) or AML-M3.
  3. Patients with known history of allergy, hypersensitivity or serious reaction to azole antifungals
  4. Women who are pregnant (positive blood pregnancy test within 10 days before randomization) or breast-feeding.
  5. 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.
  6. 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.
  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 Hematopoietic Cell Transplantation (HCT).
  11. Previous exposure to mold-active prophylaxis (>48 hours within 7 days of inclusion).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03828773


Contacts
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Contact: Pierre-Yves Bochud, MD 0041 213144379 Pierre-Yves.Bochud@chuv.ch

Locations
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Belgium
University Hospital Leuven (UZ Leuven) Recruiting
Leuven, Belgium, 3000
Contact: Johan Maertens, Prof    +32 16 34 68 89    johan.maertens@uzleuven.be   
Switzerland
University Hospital of Lausanne / Centre Hospitalier Universitaire Vaudois (CHUV) Recruiting
Lausanne, Vaud, Switzerland, 1011
Contact: Pierre-Yves Bochud, MD    +41213144379    Pierre-Yves.Bochud@chuv.ch   
Cantonal Hospital Aarau Recruiting
Aarau, Switzerland, 5001
Contact: Anna Conen, MD PD    +41 62 838 59 02    anna.conen@ksa.ch   
University Hospital Basel Recruiting
Basel, Switzerland, 4031
Contact: Nina Khanna, Prof    +41 61 328 73 25    nina.khanna@usb.ch   
Cantonal Hospital HFR Recruiting
Fribourg, Switzerland, 1708
Contact: Véronique Erard, MD    +41 26 306 08 36    veronique.erard@h-fr.ch   
University Hospital of Geneva (HUG) Recruiting
Geneva, Switzerland, 1211
Contact: Dionysios Neofytos, MD    +41223729839    dionysios.neofytos@hcuge.ch   
Sponsors and Collaborators
Bochud Pierre-Yves
Swiss National Science Foundation
Investigators
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Principal Investigator: Pierre-Yves Bochud, MD Centre Hospitalier Universitaire Vaudois
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Responsible Party: Bochud Pierre-Yves, Associate Professor, Centre Hospitalier Universitaire Vaudois
ClinicalTrials.gov Identifier: NCT03828773    
Other Study ID Numbers: 2018-01671
First Posted: February 4, 2019    Key Record Dates
Last Update Posted: March 10, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Candidiasis
Mycoses
Aspergillosis
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Genetic Predisposition to Disease
Neoplasms by Histologic Type
Neoplasms
Disease Susceptibility
Disease Attributes
Pathologic Processes
Fluconazole
Posaconazole
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents