Novel Biomarkers for Invasive Aspergillosis

Aspergillosis Invasive Clinical Trial

Official title:

Novel Biomarkers for Invasive Aspergillosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03004092
• Other study ID #: S59863
• Status: Recruiting
• Phase: N/A
• Start date: January 2017
• Est. completion date: February 2020

Study information

• Verified date: May 2018
• Source: Universitaire Ziekenhuizen Leuven
• Contact: Toine Mercier, MD
• Phone: +32 16 34 00 04
• Email: toine.mercier[@]uzleuven.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 226
• Est. completion date: February 2020
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Aspergillosis
• Aspergillosis Invasive

Intervention

Procedure:
• blood sample
Twice weekly blood sample, and at every outpatient visit

Locations

Country	Name	City	State
Belgium	University Hospitals Leuven	Leuven

Sponsors (1)

Lead Sponsor	Collaborator
Universitaire Ziekenhuizen Leuven

Country where clinical trial is conducted

Belgium, 

References & Publications (5)

Domingo MP, Colmenarejo C, Martínez-Lostao L, Müllbacher A, Jarne C, Revillo MJ, Delgado P, Roc L, Meis JF, Rezusta A, Pardo J, Gálvez 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. — View 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. — View 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. Epub 2006 Apr 14. — View 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. — View Citation

Vidal-García M, Domingo MP, De Rueda B, Roc L, Delgado MP, Revillo MJ, Pardo J, Gálvez 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	2 weeks
Secondary	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.	2 weeks
Secondary	Prognostic value of serum bmGT	Determine prognostic value (therapy response / mortality) of initial serum bmGT levels.	6 weeks
Secondary	Prognostic value of serum bmGT kinetics	Evaluate serum bmGT kinetics as surrogate marker of therapeutic response.	6 weeks
Secondary	Renal and hepatic influence on bmGT	Evaluate the impact of renal and hepatic function on initial bmGT levels and bmGT kinetics.	2 weeks
Secondary	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.	Same day
Secondary	Diagnostic accuracy of BAL bmGT	Determine diagnostic accuracy of bmGT in BAL in the diagnosis of invasive aspergillosis.	2 weeks
Secondary	Diagnostic accuracy of LFD	Determine diagnostic accuracy of the lateral flow device (LFD) in BAL and serum in the diagnosis of invasive aspergillosis.	2 weeks