<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03828773</url>
  </required_header>
  <id_info>
    <org_study_id>2018-01671</org_study_id>
    <nct_id>NCT03828773</nct_id>
  </id_info>
  <brief_title>PTX3-targeted Antifungal Prophylaxis</brief_title>
  <acronym>PTX3AML</acronym>
  <official_title>PTX3 Genetically Stratified Randomized Double-blinded Allocation Event-driven Clinical Trial for Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bochud Pierre-Yves</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Swiss National Science Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Centre Hospitalier Universitaire Vaudois</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective genetically-stratified randomized double-blind event-driven multicentre&#xD;
      clinical trial to assess the efficacy of posaconazole-based antifungal prophylaxis allocation&#xD;
      strategies for patients with acute myeloid leukemia who receive induction chemotherapy.&#xD;
      Allocation strategy based on an invasive mold infection genetic risk will be double-blinded.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Invasive mold infections (IMI, grouping infections due to Aspergillus spp [IA] and&#xD;
      non-Aspergillus mold) are a major concern in hematological patients, such as those with acute&#xD;
      myeloid leukemia (AML) or myelodysplastic syndrome in transformation (MDSit), collectively&#xD;
      named AML/MDSit in this protocol, or those undergoing hematopoietic cell transplantation&#xD;
      (HCT), with incidence and mortality rates ranging between 3-15% and 25-45%, respectively.&#xD;
      Primary antifungal prophylaxis has become the standard of care in such patients.&#xD;
      Historically, fluconazole (inactive against IA) was used as prophylaxis and allowed for&#xD;
      significant decrease in invasive candidiasis (IC). More recently, posaconazole (a&#xD;
      broad-spectrum azole active against IA and other non-Aspergillus filamentous molds) was&#xD;
      approved for primary antifungal prophylaxis in high-risk patient categories. However,&#xD;
      universal prophylaxis with posaconazole has been challenged, based on the relatively low&#xD;
      incidence of IMI and the large number of patients needed to treat. Moreover, administration&#xD;
      of broad-spectrum azoles is costly and associated with a large number of complications.&#xD;
      Hence, there is an urgent need to optimize antifungal prophylaxis by identifying those&#xD;
      patients with the highest risk for IMI to receive a broad-spectrum azole. Pentraxin-3 (PTX3),&#xD;
      a pattern recognition receptor, recognizes and binds to Aspergillus conidia, facilitates&#xD;
      opsonization and subsequently leads to complement and phagocyte activation. Two single&#xD;
      nucleotide polymorphisms (SNPs) in the gene encoding PTX3 have been identified as strong&#xD;
      predictors for IA and/or IMI in human studies. What makes PTX3 SNPs different and important&#xD;
      in clinical practice is: (i) the extent and reproducibility of basic science data with&#xD;
      regards to PTX3 and IA, (ii) the validation of PTX3 SNPs associations with IA in many&#xD;
      different patient populations, and (iii) the high frequency of minor allele in the general&#xD;
      population. The investigators hypothesize that PTX3 SNPs could be used to identify patients&#xD;
      at high risk for IMI, who will benefit the most from antifungal prophylaxis with&#xD;
      broad-spectrum azoles.&#xD;
&#xD;
      Overall objective:&#xD;
&#xD;
      The overall aim of this project is to assess the effectiveness of PTX3 SNPs testing to&#xD;
      stratify the use of posaconazole-based antifungal prophylaxis in AML/MDSit patients according&#xD;
      to low or high risk genotypes.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      Eligible patients will be tested by competitive allele-specific Polymerase Chain Reaction&#xD;
      (PCR) from blood-extracted DNA samples for the presence of PTX3 SNPs rs230561 and rs3816527.&#xD;
      Randomisation based on genetic testing will be performed at the latest 24h after the first&#xD;
      neutropenia day (D0). Patients will be stratified based on genotyping results in two&#xD;
      unbalanced strata: stratum A (high-risk PTX3 SNPs) to be randomized 1:1 posaconazole&#xD;
      prophylaxis vs fluconazole and stratum-B (low-risk PTX3 SNPs) to be randomized 1:3 in favour&#xD;
      of Fluconazole. Patients will be assessed for a diagnosis of possible, probable or proven&#xD;
      Invasive Fungal Infections (IFI) based on consensus definition guidelines by the European&#xD;
      Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) groups&#xD;
      during 180 days after prophylaxis initiation.&#xD;
&#xD;
      Impact:&#xD;
&#xD;
      The results of this study may contribute to the optimization of primary antifungal&#xD;
      prophylaxis, by preventing IMI while limiting the use of broad-spectrum azoles, thus&#xD;
      decreasing complications and costs. This study is one of the first interventional clinical&#xD;
      trials to use genetic factors for risk stratification in the field of hematology and&#xD;
      infectious diseases, a concept frequently emphasized, however barely transcribed in practice,&#xD;
      as precision medicine. Furthermore, the scope of the proposed study expands beyond the&#xD;
      specific patient population. The results of this study could be used in the design and&#xD;
      initiation of similar efforts in other high-risk patient categories, including allogeneic HCT&#xD;
      and solid organ transplant (SOT) recipients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 11, 2019</start_date>
  <completion_date type="Anticipated">November 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">November 30, 2025</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>prospective genetically-stratified randomized double-blind event-driven multicentre clinical trial</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The investigational medicinal products will be known by all roles but the arm allocation based on a genetic analysis will be blinded.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Cumulative incidence of proven and probable invasive mold infection (IMI)</measure>
    <time_frame>Day 180</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of possible invasive mold infection (IMI)</measure>
    <time_frame>Day 180</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of probable and proven Invasive Fungal Infections (IFI)</measure>
    <time_frame>Day 180</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to probable and proven invasive mold infection (IMI)</measure>
    <time_frame>Day 180</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival in the ITT population</measure>
    <time_frame>Day 180</time_frame>
    <description>The overall survival in the ITT population by day 180.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to use of amphotericin B/echinocandin</measure>
    <time_frame>Day 180</time_frame>
    <description>The time to use of amphotericin B/echinocandin in the ITT population during 180 days.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patient-days of amphotericin B/echinocandin</measure>
    <time_frame>Day 180</time_frame>
    <description>The number of patient-days of amphotericin B/echinocandin in the ITT population during 180 days.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency/distribution of adverse events (AE) of interest</measure>
    <time_frame>Day 180</time_frame>
    <description>The frequency/distribution of AE of interest in posaconazole and fluconazole treated participants in the ITT population during 180 days, namely:&#xD;
Hepatotoxicity, defined by elevation of at least one of the following markers above &gt;5x upper limit of normal: transaminases, alkaline phosphatase and/or above &gt;3x upper limit of normal total bilirubin&#xD;
New QTc prolongation, defined as QTc &gt;450 msec for men and &gt;470 msec for women</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of probable and proven invasive fungal infections (IFI) in per protocol population</measure>
    <time_frame>Day 180</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">320</enrollment>
  <condition>Candidiasis</condition>
  <condition>Fungal Infection</condition>
  <condition>Acute Myeloid Leukemia</condition>
  <condition>Genetic Predisposition</condition>
  <condition>Aspergillosis</condition>
  <arm_group>
    <arm_group_label>high-risk PTX3 SNPs</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): homozygous for rs230561 and/or rs381652</description>
  </arm_group>
  <arm_group>
    <arm_group_label>low-risk PTX3 SNPs</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): other than homozygous for rs230561 and/or rs381652</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Posaconazole</intervention_name>
    <description>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 &gt;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.</description>
    <arm_group_label>high-risk PTX3 SNPs</arm_group_label>
    <arm_group_label>low-risk PTX3 SNPs</arm_group_label>
    <other_name>Noxafil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fluconazole</intervention_name>
    <description>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.</description>
    <arm_group_label>high-risk PTX3 SNPs</arm_group_label>
    <arm_group_label>low-risk PTX3 SNPs</arm_group_label>
    <other_name>Diflucan</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed Informed Consent according to national/local regulations.&#xD;
&#xD;
          2. Age ≥18 years.&#xD;
&#xD;
          3. Diagnosis of Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome in&#xD;
             transformation (MDSit) treated with an intensive chemotherapy regimen, including&#xD;
             induction / consolidation / salvage remission chemotherapy.&#xD;
&#xD;
          4. Planned hospital admission for the duration of the neutropenic phase (absolute&#xD;
             neutrophils count &lt;500 cells/mm3).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with neutropenia (absolute neutrophils count&lt;500 cells/mm3) upon presentation&#xD;
             and prior to chemotherapy initiation.&#xD;
&#xD;
          2. Patients with a diagnosis of acute promyelocytic leukemia (APL) or AML-M3.&#xD;
&#xD;
          3. Patients with known history of allergy, hypersensitivity or serious reaction to azole&#xD;
             antifungals&#xD;
&#xD;
          4. Women who are pregnant (positive blood pregnancy test within 10 days before&#xD;
             randomization) or breast-feeding.&#xD;
&#xD;
          5. Diagnosis and treatment for an Invasive Fungal Infection (IFI) within 3 months prior&#xD;
             to study enrolment and an Invasive Mold Infection (IMI) at any point prior to or at&#xD;
             the time of enrolment.&#xD;
&#xD;
          6. Severe liver dysfunction, defined as at least one of the following markers: Aspartate&#xD;
             Aminotransferase (AST), Alanine Aminotransferase (ALT) or alkaline phosphatase above&#xD;
             &gt;5x upper limit of normality: and/or total bilirubin above &gt;3x upper limit of&#xD;
             normality.&#xD;
&#xD;
          7. Patients with an ECG with a prolonged QTc interval: QTc greater than 450 msec for men&#xD;
             and greater than 470 msec for women.&#xD;
&#xD;
          8. Patients who are receiving and cannot discontinue the following drugs at least 24&#xD;
             hours prior to randomization: terfenadine, astemizole, cisapride, pimozide,&#xD;
             halofantrine or quinidine (because of the possibility of QT prolongation), sirolimus,&#xD;
             rifampin, rifabutin, carbamazepine, long-acting barbiturates (e.g., phenobarbital,&#xD;
             mephobarbital), ritonavir, efavirenz, or ergot alkaloids (e.g., ergotamine,&#xD;
             dihydroergotamine).&#xD;
&#xD;
          9. Serious uncontrolled concomitant disease or comorbidity that, in the opinion of the&#xD;
             investigator, may compromise adherence to the study protocol.&#xD;
&#xD;
         10. Receipt of a prior allogeneic Hematopoietic Cell Transplantation (HCT).&#xD;
&#xD;
         11. Previous exposure to mold-active prophylaxis (&gt;48 hours within 7 days of inclusion).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pierre-Yves Bochud, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre Hospitalier Universitaire Vaudois</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Pierre-Yves Bochud, MD</last_name>
    <phone>0041 213144379</phone>
    <email>Pierre-Yves.Bochud@chuv.ch</email>
  </overall_contact>
  <location>
    <facility>
      <name>Ghent University Hospital</name>
      <address>
        <city>Ghent</city>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ine Moors, Dr</last_name>
      <phone>+3293326646</phone>
      <email>ine.moors@uzgent.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospital Leuven (UZ Leuven)</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Johan Maertens, Prof</last_name>
      <phone>+32 16 34 68 89</phone>
      <email>johan.maertens@uzleuven.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Henri Mondor Hospital</name>
      <address>
        <city>Créteil</city>
        <state>Ile De France</state>
        <zip>94010</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christine Robin, Dr</last_name>
      <phone>+33149812111</phone>
      <email>christine.robin@aphp.fr</email>
    </contact>
    <contact_backup>
      <last_name>Ludovic Cabanne, Mr</last_name>
      <phone>+33149812058</phone>
      <email>ludovic.cabanne@aphp.fr</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>University Hospital of Lausanne / Centre Hospitalier Universitaire Vaudois (CHUV)</name>
      <address>
        <city>Lausanne</city>
        <state>Vaud</state>
        <zip>1011</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Pierre-Yves Bochud, MD</last_name>
      <phone>+41213144379</phone>
      <email>Pierre-Yves.Bochud@chuv.ch</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Cantonal Hospital Aarau</name>
      <address>
        <city>Aarau</city>
        <zip>5001</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anna Conen, MD PD</last_name>
      <phone>+41 62 838 59 02</phone>
      <email>anna.conen@ksa.ch</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospital Basel</name>
      <address>
        <city>Basel</city>
        <zip>4031</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Nina Khanna, Prof</last_name>
      <phone>+41 61 328 73 25</phone>
      <email>nina.khanna@usb.ch</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Cantonal Hospital HFR</name>
      <address>
        <city>Fribourg</city>
        <zip>1708</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Véronique Erard, MD</last_name>
      <phone>+41 26 306 08 36</phone>
      <email>veronique.erard@h-fr.ch</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospital of Geneva (HUG)</name>
      <address>
        <city>Geneva</city>
        <zip>1211</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dionysios Neofytos, MD</last_name>
      <phone>+41223729839</phone>
      <email>dionysios.neofytos@hcuge.ch</email>
    </contact>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>France</country>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>January 31, 2019</study_first_submitted>
  <study_first_submitted_qc>February 1, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 4, 2019</study_first_posted>
  <last_update_submitted>December 20, 2022</last_update_submitted>
  <last_update_submitted_qc>December 20, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Centre Hospitalier Universitaire Vaudois</investigator_affiliation>
    <investigator_full_name>Bochud Pierre-Yves</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Candidiasis</mesh_term>
    <mesh_term>Mycoses</mesh_term>
    <mesh_term>Aspergillosis</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Genetic Predisposition to Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fluconazole</mesh_term>
    <mesh_term>Posaconazole</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03828773
org study id: 2018-01671
nct id: NCT03828773
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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 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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: prospective genetically-stratified randomized double-blind event-driven multicentre clinical trial
primary purpose: Prevention
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.
measure: Cumulative incidence of proven and probable invasive mold infection (IMI)
time frame: Day 180
description: 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.
measure: Cumulative incidence of possible invasive mold infection (IMI)
time frame: Day 180
description: 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.
measure: Cumulative incidence of probable and proven Invasive Fungal Infections (IFI)
time frame: Day 180
description: 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.
measure: Time to probable and proven invasive mold infection (IMI)
time frame: Day 180
description: 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
measure: Overall survival in the ITT population
time frame: Day 180
description: The overall survival in the ITT population by day 180.
measure: Time to use of amphotericin B/echinocandin
time frame: Day 180
description: The time to use of amphotericin B/echinocandin in the ITT population during 180 days.
measure: Number of patient-days of amphotericin B/echinocandin
time frame: Day 180
description: The number of patient-days of amphotericin B/echinocandin in the ITT population during 180 days.
measure: Frequency/distribution of adverse events (AE) of interest
time frame: Day 180
description: The frequency/distribution of AE of interest in posaconazole and fluconazole treated participants in the ITT population during 180 days, namely:
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
New QTc prolongation, defined as QTc >450 msec for men and >470 msec for women
measure: Cumulative incidence of probable and proven invasive fungal infections (IFI) in per protocol population
time frame: Day 180
description: 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.
arm group label: high-risk PTX3 SNPs
arm group type: Other
description: risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): homozygous for rs230561 and/or rs381652
arm group label: low-risk PTX3 SNPs
arm group type: Other
description: risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): other than homozygous for rs230561 and/or rs381652
intervention type: Drug
intervention name: Posaconazole
description: 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.
arm group label: high-risk PTX3 SNPs
arm group label: low-risk PTX3 SNPs
other name: Noxafil
intervention type: Drug
intervention name: Fluconazole
description: 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.
arm group label: high-risk PTX3 SNPs
arm group label: low-risk PTX3 SNPs
other name: Diflucan
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Pierre-Yves Bochud, MD
role: Principal Investigator
affiliation: Centre Hospitalier Universitaire Vaudois
last name: Pierre-Yves Bochud, MD
phone: 0041 213144379
email: Pierre-Yves.Bochud@chuv.ch
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Belgium
country: France
country: Switzerland
responsible party type: Sponsor-Investigator
investigator affiliation: Centre Hospitalier Universitaire Vaudois
investigator full name: Bochud Pierre-Yves
investigator title: Associate Professor
mesh term: Candidiasis
mesh term: Mycoses
mesh term: Aspergillosis
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Genetic Predisposition to Disease
mesh term: Fluconazole
mesh term: Posaconazole