Novel Biomarkers for Invasive Aspergillosis
Primary Purpose
Aspergillosis Invasive
Status
Unknown status
Phase
Not Applicable
Locations
Belgium
Study Type
Interventional
Intervention
blood sample
Sponsored by
About this trial
This is an interventional diagnostic trial for Aspergillosis Invasive focused on measuring bis(methylthio)gliotoxin, lateral flow device, JF5, Galactomannan, Invasive aspergillosis
Eligibility Criteria
Inclusion Criteria:
- Age ≥ 16y at start of study
- One of the following diagnoses:
- De novo, refractory or relapsed AML/MDS receiving intensive chemotherapy
- De novo, refractory or relapsed ALL/T-lymphoblastic lymphoma receiving intensive chemotherapy
- Aplastic anemia requiring ATG therapy
- Any patient admitted for either autologous or allogeneic hematopoietic stem cell transplantation
- Written informed consent obtained from the patient
Exclusion Criteria:
- AML or ALL beyond the specified inclusion criteria
- Directed treatment for possible, probable, or proven invasive aspergillosis, at moment of screening, or with end of treatment < 6 weeks at screening, or no complete response according to EORTC/MSG criteria, or complete response achieved < 6 weeks at time of screening.
Sites / Locations
- University Hospitals LeuvenRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Total cohort
Arm Description
Outcomes
Primary Outcome Measures
Diagnostic accuracy of serum bmGT
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.
Secondary Outcome Measures
Diagnostic accuracy of a combination of serum bmGT and serum GM
Determine diagnostic accuracy of a combination of serum GM and serum bmGT in the diagnosis of invasive aspergillosis.
Prognostic value of serum bmGT
Determine prognostic value (therapy response / mortality) of initial serum bmGT levels.
Prognostic value of serum bmGT kinetics
Evaluate serum bmGT kinetics as surrogate marker of therapeutic response.
Renal and hepatic influence on bmGT
Evaluate the impact of renal and hepatic function on initial bmGT levels and bmGT kinetics.
Compare bmGT-HPTLC to bmGT-LC/MS
Compare bmGT levels as measured by HPTLC to levels as measured by our own in-house developed chromatographic method.
Diagnostic accuracy of BAL bmGT
Determine diagnostic accuracy of bmGT in BAL in the diagnosis of invasive aspergillosis.
Diagnostic accuracy of LFD
Determine diagnostic accuracy of the lateral flow device (LFD) in BAL and serum in the diagnosis of invasive aspergillosis.
Full Information
NCT ID
NCT03004092
First Posted
December 21, 2016
Last Updated
May 2, 2018
Sponsor
Universitaire Ziekenhuizen KU Leuven
1. Study Identification
Unique Protocol Identification Number
NCT03004092
Brief Title
Novel Biomarkers for Invasive Aspergillosis
Official Title
Novel Biomarkers for Invasive Aspergillosis
Study Type
Interventional
2. Study Status
Record Verification Date
May 2018
Overall Recruitment Status
Unknown status
Study Start Date
January 2017 (undefined)
Primary Completion Date
December 2019 (Anticipated)
Study Completion Date
February 2020 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Universitaire Ziekenhuizen KU Leuven
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aspergillosis Invasive
Keywords
bis(methylthio)gliotoxin, lateral flow device, JF5, Galactomannan, Invasive aspergillosis
7. Study Design
Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
226 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Total cohort
Arm Type
Experimental
Intervention Type
Procedure
Intervention Name(s)
blood sample
Intervention Description
Twice weekly blood sample, and at every outpatient visit
Primary Outcome Measure Information:
Title
Diagnostic accuracy of serum bmGT
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.
Time Frame
2 weeks
Secondary Outcome Measure Information:
Title
Diagnostic accuracy of a combination of serum bmGT and serum GM
Description
Determine diagnostic accuracy of a combination of serum GM and serum bmGT in the diagnosis of invasive aspergillosis.
Time Frame
2 weeks
Title
Prognostic value of serum bmGT
Description
Determine prognostic value (therapy response / mortality) of initial serum bmGT levels.
Time Frame
6 weeks
Title
Prognostic value of serum bmGT kinetics
Description
Evaluate serum bmGT kinetics as surrogate marker of therapeutic response.
Time Frame
6 weeks
Title
Renal and hepatic influence on bmGT
Description
Evaluate the impact of renal and hepatic function on initial bmGT levels and bmGT kinetics.
Time Frame
2 weeks
Title
Compare bmGT-HPTLC to bmGT-LC/MS
Description
Compare bmGT levels as measured by HPTLC to levels as measured by our own in-house developed chromatographic method.
Time Frame
Same day
Title
Diagnostic accuracy of BAL bmGT
Description
Determine diagnostic accuracy of bmGT in BAL in the diagnosis of invasive aspergillosis.
Time Frame
2 weeks
Title
Diagnostic accuracy of LFD
Description
Determine diagnostic accuracy of the lateral flow device (LFD) in BAL and serum in the diagnosis of invasive aspergillosis.
Time Frame
2 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age ≥ 16y at start of study
One of the following diagnoses:
De novo, refractory or relapsed AML/MDS receiving intensive chemotherapy
De novo, refractory or relapsed ALL/T-lymphoblastic lymphoma receiving intensive chemotherapy
Aplastic anemia requiring ATG therapy
Any patient admitted for either autologous or allogeneic hematopoietic stem cell transplantation
Written informed consent obtained from the patient
Exclusion Criteria:
AML or ALL beyond the specified inclusion criteria
Directed treatment for possible, probable, or proven invasive aspergillosis, at moment of screening, or with end of treatment < 6 weeks at screening, or no complete response according to EORTC/MSG criteria, or complete response achieved < 6 weeks at time of screening.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Toine Mercier, MD
Phone
+32 16 34 00 04
Email
toine.mercier@uzleuven.be
Facility Information:
Facility Name
University Hospitals Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Toine Mercier, MD
Phone
+32 16 34 00 04
Email
toine.mercier@uzleuven.be
12. IPD Sharing Statement
Citations:
PubMed Identifier
16619154
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.
Results Reference
background
PubMed Identifier
15618207
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.
Results Reference
background
PubMed Identifier
22480566
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.
Results Reference
background
PubMed Identifier
26678078
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.
Results Reference
background
PubMed Identifier
18463222
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.
Results Reference
background
PubMed Identifier
32188971
Citation
Mercier T, Guldentops E, Lagrou K, Maertens J. Prospective Evaluation of the Turbidimetric beta-D-Glucan Assay and 2 Lateral Flow Assays on Serum in Invasive Aspergillosis. Clin Infect Dis. 2021 May 4;72(9):1577-1584. doi: 10.1093/cid/ciaa295.
Results Reference
derived
Learn more about this trial
Novel Biomarkers for Invasive Aspergillosis
We'll reach out to this number within 24 hrs