<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/NCT03004092</url>
  </required_header>
  <id_info>
    <org_study_id>S59863</org_study_id>
    <nct_id>NCT03004092</nct_id>
  </id_info>
  <brief_title>Novel Biomarkers for Invasive Aspergillosis</brief_title>
  <official_title>Novel Biomarkers for Invasive Aspergillosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universitaire Ziekenhuizen KU Leuven</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Universitaire Ziekenhuizen KU Leuven</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Diagnosis of invasive aspergillosis remains difficult, and is often based on a combination of&#xD;
      patient characteristics, radiological and microbiological findings. To data, galactomannan&#xD;
      (GM) is the only well-validated biomarker available. However, GM still has its shortcomings.&#xD;
      There is therefore a need for new, complementary biomarkers. In this study, two of those&#xD;
      tests, bis(methylthio)gliotoxin (bmGT) and a lateral flow device, will be validated in a&#xD;
      hematological population, and compare it to GM.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Diagnosis of invasive aspergillosis is often difficult to achieve with certainty, as this&#xD;
      requires direct evidence of invasive growth on histopathological examination. A probable&#xD;
      diagnosis can be suspected based on both clinical and mycological evidence of the disease, in&#xD;
      presence of a susceptible patient. The EORTC-MSG guidelines offer a widely accepted basis for&#xD;
      this diagnosis. Under these guidelines, mycological evidence can consist of a positive&#xD;
      culture of aspergillus spp, or of detection of galactomannan (GM) in a relevant body sample.&#xD;
      GM is a part of the Aspergillus mould and can be detected using a commercially available&#xD;
      immunoenzymatic sandwich microplate assay. However, like most biomarkers, galactomannan is&#xD;
      far from a perfect biomarker. Several beta-lactam antibiotics are known to cause false&#xD;
      positives, and anti-mould therapy has been reported to significantly lower the&#xD;
      sensitivity[1]. Additional biomarkers that could circumvent these problems would therefore be&#xD;
      beneficial.&#xD;
&#xD;
      A potential new target is gliotoxin (GT), a secondary metabolite of several fungi, the most&#xD;
      clinically important of which is Aspergillus[2]. GT is released during invasive growth, and&#xD;
      can therefore be used as a biomarker of invasive fungal disease by GT-producing fungi.&#xD;
      However, GT is quickly removed by red blood cells from circulation, making it an unreliable&#xD;
      marker[3]. A degradation product of GT, bis(methylthio)gliotoxin (bmGT), appears to be more&#xD;
      stable as it is not taken up by red blood cells. Serum bmGT or bmGT in bronchoalveolar lavage&#xD;
      (BAL) fluid has already been shown in small studies to be a potential marker of invasive&#xD;
      aspergillosis, especially when used in combination with GM[3-5].&#xD;
&#xD;
      Recently, another highly specific test has become available, based on detection of an&#xD;
      extracellular glycoprotein secreted during the growth of Aspergillus species, using a&#xD;
      monoclonal antibody (JF5) in an immunochromatographic lateral-flow device (LFD)[6,7]. This&#xD;
      test allows fast (&lt;15 minutes) testing using a commercially available device.&#xD;
&#xD;
      In this study, both the LFD and bmGT will be characterized and validated in a hematological&#xD;
      population, and compared to GM.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>January 2017</start_date>
  <completion_date type="Anticipated">February 2020</completion_date>
  <primary_completion_date type="Anticipated">December 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Diagnostic accuracy of serum bmGT</measure>
    <time_frame>2 weeks</time_frame>
    <description>Determine the diagnostic accuracy (specificity, sensitivity predictive values, accuracy and other key diagnostic values) of serum bmGT in the diagnosis of invasive aspergillosis, using the revised EORTC criteria as gold standard.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Diagnostic accuracy of a combination of serum bmGT and serum GM</measure>
    <time_frame>2 weeks</time_frame>
    <description>Determine diagnostic accuracy of a combination of serum GM and serum bmGT in the diagnosis of invasive aspergillosis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prognostic value of serum bmGT</measure>
    <time_frame>6 weeks</time_frame>
    <description>Determine prognostic value (therapy response / mortality) of initial serum bmGT levels.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prognostic value of serum bmGT kinetics</measure>
    <time_frame>6 weeks</time_frame>
    <description>Evaluate serum bmGT kinetics as surrogate marker of therapeutic response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal and hepatic influence on bmGT</measure>
    <time_frame>2 weeks</time_frame>
    <description>Evaluate the impact of renal and hepatic function on initial bmGT levels and bmGT kinetics.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare bmGT-HPTLC to bmGT-LC/MS</measure>
    <time_frame>Same day</time_frame>
    <description>Compare bmGT levels as measured by HPTLC to levels as measured by our own in-house developed chromatographic method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diagnostic accuracy of BAL bmGT</measure>
    <time_frame>2 weeks</time_frame>
    <description>Determine diagnostic accuracy of bmGT in BAL in the diagnosis of invasive aspergillosis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diagnostic accuracy of LFD</measure>
    <time_frame>2 weeks</time_frame>
    <description>Determine diagnostic accuracy of the lateral flow device (LFD) in BAL and serum in the diagnosis of invasive aspergillosis.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">226</enrollment>
  <condition>Aspergillosis Invasive</condition>
  <arm_group>
    <arm_group_label>Total cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>blood sample</intervention_name>
    <description>Twice weekly blood sample, and at every outpatient visit</description>
    <arm_group_label>Total cohort</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 16y at start of study&#xD;
&#xD;
          -  One of the following diagnoses:&#xD;
&#xD;
          -  De novo, refractory or relapsed AML/MDS receiving intensive chemotherapy&#xD;
&#xD;
          -  De novo, refractory or relapsed ALL/T-lymphoblastic lymphoma receiving intensive&#xD;
             chemotherapy&#xD;
&#xD;
          -  Aplastic anemia requiring ATG therapy&#xD;
&#xD;
          -  Any patient admitted for either autologous or allogeneic hematopoietic stem cell&#xD;
             transplantation&#xD;
&#xD;
          -  Written informed consent obtained from the patient&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  AML or ALL beyond the specified inclusion criteria&#xD;
&#xD;
          -  Directed treatment for possible, probable, or proven invasive aspergillosis, at moment&#xD;
             of screening, or with end of treatment &lt; 6 weeks at screening, or no complete response&#xD;
             according to EORTC/MSG criteria, or complete response achieved &lt; 6 weeks at time of&#xD;
             screening.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Toine Mercier, MD</last_name>
    <phone>+32 16 34 00 04</phone>
    <email>toine.mercier@uzleuven.be</email>
  </overall_contact>
  <location>
    <facility>
      <name>University Hospitals Leuven</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Toine Mercier, MD</last_name>
      <phone>+32 16 34 00 04</phone>
      <email>toine.mercier@uzleuven.be</email>
    </contact>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <reference>
    <citation>Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis. 2006 May 15;42(10):1417-27. doi: 10.1086/503427. Epub 2006 Apr 14.</citation>
    <PMID>16619154</PMID>
  </reference>
  <reference>
    <citation>Lewis RE, Wiederhold NP, Chi J, Han XY, Komanduri KV, Kontoyiannis DP, Prince RA. Detection of gliotoxin in experimental and human aspergillosis. Infect Immun. 2005 Jan;73(1):635-7. doi: 10.1128/IAI.73.1.635-637.2005.</citation>
    <PMID>15618207</PMID>
  </reference>
  <reference>
    <citation>Domingo MP, Colmenarejo C, Martinez-Lostao L, Mullbacher A, Jarne C, Revillo MJ, Delgado P, Roc L, Meis JF, Rezusta A, Pardo J, Galvez EM. Bis(methyl)gliotoxin proves to be a more stable and reliable marker for invasive aspergillosis than gliotoxin and suitable for use in diagnosis. Diagn Microbiol Infect Dis. 2012 May;73(1):57-64. doi: 10.1016/j.diagmicrobio.2012.01.012. Epub 2012 Apr 4.</citation>
    <PMID>22480566</PMID>
  </reference>
  <reference>
    <citation>Vidal-Garcia M, Domingo MP, De Rueda B, Roc L, Delgado MP, Revillo MJ, Pardo J, Galvez EM, Rezusta A. Clinical validity of bis(methylthio)gliotoxin for the diagnosis of invasive aspergillosis. Appl Microbiol Biotechnol. 2016 Mar;100(5):2327-34. doi: 10.1007/s00253-015-7209-6. Epub 2015 Dec 17.</citation>
    <PMID>26678078</PMID>
  </reference>
  <reference>
    <citation>Thornton CR. Development of an immunochromatographic lateral-flow device for rapid serodiagnosis of invasive aspergillosis. Clin Vaccine Immunol. 2008 Jul;15(7):1095-105. doi: 10.1128/CVI.00068-08. Epub 2008 May 7.</citation>
    <PMID>18463222</PMID>
  </reference>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>December 21, 2016</study_first_submitted>
  <study_first_submitted_qc>December 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 28, 2016</study_first_posted>
  <last_update_submitted>May 2, 2018</last_update_submitted>
  <last_update_submitted_qc>May 2, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">May 3, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>bis(methylthio)gliotoxin</keyword>
  <keyword>lateral flow device</keyword>
  <keyword>JF5</keyword>
  <keyword>Galactomannan</keyword>
  <keyword>Invasive aspergillosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspergillosis</mesh_term>
  </condition_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/NCT03004092
org study id: S59863
nct id: NCT03004092
lead sponsor: 
has dmc: No
Diagnosis of invasive aspergillosis remains difficult, and is often based on a combination of
      patient characteristics, radiological and microbiological findings. To data, galactomannan
      (GM) is the only well-validated biomarker available. However, GM still has its shortcomings.
      There is therefore a need for new, complementary biomarkers. In this study, two of those
      tests, bis(methylthio)gliotoxin (bmGT) and a lateral flow device, will be validated in a
      hematological population, and compare it to GM.
Diagnosis of invasive aspergillosis is often difficult to achieve with certainty, as this
      requires direct evidence of invasive growth on histopathological examination. A probable
      diagnosis can be suspected based on both clinical and mycological evidence of the disease, in
      presence of a susceptible patient. The EORTC-MSG guidelines offer a widely accepted basis for
      this diagnosis. Under these guidelines, mycological evidence can consist of a positive
      culture of aspergillus spp, or of detection of galactomannan (GM) in a relevant body sample.
      GM is a part of the Aspergillus mould and can be detected using a commercially available
      immunoenzymatic sandwich microplate assay. However, like most biomarkers, galactomannan is
      far from a perfect biomarker. Several beta-lactam antibiotics are known to cause false
      positives, and anti-mould therapy has been reported to significantly lower the
      sensitivity[1]. Additional biomarkers that could circumvent these problems would therefore be
      beneficial.

      A potential new target is gliotoxin (GT), a secondary metabolite of several fungi, the most
      clinically important of which is Aspergillus[2]. GT is released during invasive growth, and
      can therefore be used as a biomarker of invasive fungal disease by GT-producing fungi.
      However, GT is quickly removed by red blood cells from circulation, making it an unreliable
      marker[3]. A degradation product of GT, bis(methylthio)gliotoxin (bmGT), appears to be more
      stable as it is not taken up by red blood cells. Serum bmGT or bmGT in bronchoalveolar lavage
      (BAL) fluid has already been shown in small studies to be a potential marker of invasive
      aspergillosis, especially when used in combination with GM[3-5].

      Recently, another highly specific test has become available, based on detection of an
      extracellular glycoprotein secreted during the growth of Aspergillus species, using a
      monoclonal antibody (JF5) in an immunochromatographic lateral-flow device (LFD)[6,7]. This
      test allows fast (<15 minutes) testing using a commercially available device.

      In this study, both the LFD and bmGT will be characterized and validated in a hematological
      population, and compared to GM.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Diagnostic accuracy of serum bmGT
time frame: 2 weeks
description: Determine the diagnostic accuracy (specificity, sensitivity predictive values, accuracy and other key diagnostic values) of serum bmGT in the diagnosis of invasive aspergillosis, using the revised EORTC criteria as gold standard.
measure: Diagnostic accuracy of a combination of serum bmGT and serum GM
time frame: 2 weeks
description: Determine diagnostic accuracy of a combination of serum GM and serum bmGT in the diagnosis of invasive aspergillosis.
measure: Prognostic value of serum bmGT
time frame: 6 weeks
description: Determine prognostic value (therapy response / mortality) of initial serum bmGT levels.
measure: Prognostic value of serum bmGT kinetics
time frame: 6 weeks
description: Evaluate serum bmGT kinetics as surrogate marker of therapeutic response.
measure: Renal and hepatic influence on bmGT
time frame: 2 weeks
description: Evaluate the impact of renal and hepatic function on initial bmGT levels and bmGT kinetics.
measure: Compare bmGT-HPTLC to bmGT-LC/MS
time frame: Same day
description: Compare bmGT levels as measured by HPTLC to levels as measured by our own in-house developed chromatographic method.
measure: Diagnostic accuracy of BAL bmGT
time frame: 2 weeks
description: Determine diagnostic accuracy of bmGT in BAL in the diagnosis of invasive aspergillosis.
measure: Diagnostic accuracy of LFD
time frame: 2 weeks
description: Determine diagnostic accuracy of the lateral flow device (LFD) in BAL and serum in the diagnosis of invasive aspergillosis.
arm group label: Total cohort
arm group type: Experimental
intervention type: Procedure
intervention name: blood sample
description: Twice weekly blood sample, and at every outpatient visit
arm group label: Total cohort
criteria: 
gender: All
minimum age: 16 Years
maximum age: N/A
healthy volunteers: No
last name: Toine Mercier, MD
phone: +32 16 34 00 04
email: toine.mercier@uzleuven.be
facility: 
status: Recruiting
contact: 
country: Belgium
citation: Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis. 2006 May 15;42(10):1417-27. doi: 10.1086/503427. Epub 2006 Apr 14.
PMID: 16619154
citation: Lewis RE, Wiederhold NP, Chi J, Han XY, Komanduri KV, Kontoyiannis DP, Prince RA. Detection of gliotoxin in experimental and human aspergillosis. Infect Immun. 2005 Jan;73(1):635-7. doi: 10.1128/IAI.73.1.635-637.2005.
PMID: 15618207
citation: Domingo MP, Colmenarejo C, Martinez-Lostao L, Mullbacher A, Jarne C, Revillo MJ, Delgado P, Roc L, Meis JF, Rezusta A, Pardo J, Galvez EM. Bis(methyl)gliotoxin proves to be a more stable and reliable marker for invasive aspergillosis than gliotoxin and suitable for use in diagnosis. Diagn Microbiol Infect Dis. 2012 May;73(1):57-64. doi: 10.1016/j.diagmicrobio.2012.01.012. Epub 2012 Apr 4.
PMID: 22480566
citation: Vidal-Garcia M, Domingo MP, De Rueda B, Roc L, Delgado MP, Revillo MJ, Pardo J, Galvez EM, Rezusta A. Clinical validity of bis(methylthio)gliotoxin for the diagnosis of invasive aspergillosis. Appl Microbiol Biotechnol. 2016 Mar;100(5):2327-34. doi: 10.1007/s00253-015-7209-6. Epub 2015 Dec 17.
PMID: 26678078
citation: Thornton CR. Development of an immunochromatographic lateral-flow device for rapid serodiagnosis of invasive aspergillosis. Clin Vaccine Immunol. 2008 Jul;15(7):1095-105. doi: 10.1128/CVI.00068-08. Epub 2008 May 7.
PMID: 18463222
responsible party type: Sponsor
mesh term: Aspergillosis