Diagnostic Study of Combined Biomnarker Testing in Bronchoalveolar Lavage Samples of Immunocompromised Patients

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Heidelberg University
Sponsor:
Collaborator:
Gilead Sciences
Information provided by (Responsible Party):
Dieter Buchheidt, University of Heidelberg
ClinicalTrials.gov Identifier:
NCT01695512
First received: September 26, 2012
Last updated: March 27, 2014
Last verified: March 2014
  Purpose

The aim of our prospective and multicentre diagnostic study is therefore to elucidate on the sensitivity and specificity rates of these serologic markers in combination with molecular tools (both an Aspergillus specific and a multifungal PCR based assay), as serologic mark-ers are not pathogen-specific, and furthermore to define species-specific cut-off values for BDG in BAL samples.

Additionally, if genomic material of Aspergillus fumigatus is detected by PCR in a clinical sample, we investigate fungal DNA for point mutations in the cyp51A gene mediating resis-tance against common mould-active triazoles with novel rapid, sensitive and specific, non-culture-based PCR-assays and sequencing to optimize antifungal treatment as early as pos-sible.


Condition
Invasive Aspergillosis
Acute Leukemia
Biomarkers
Stem Cell Transplantation

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Open, Prospective, Multicenter Trial to Evaluate the Clinical Significance of Combined Serological (Galactomannan ELISA, 1->3-β-D Glucan Assay) and Molecular (Nested Aspergillus PCR Assay, Multifungal DNA Microarray) Diagnostic Assays to Detect and Characterize Fungal Pathogens in Bronchoalveolar Lavage (BAL) and Blood Samples of Hematological High Risk Patients and to Detect Point Mutations Conferring Azole Resistance

Resource links provided by NLM:


Further study details as provided by Heidelberg University:

Primary Outcome Measures:
  • Diagnostic certainty [ Time Frame: 6 Weeks ] [ Designated as safety issue: No ]
    After 6 weeks the diagnostic performance of the biomarkers and their combination in relation to diagnostic accuracy will be measured


Biospecimen Retention:   Samples With DNA

Only fungal DNA is retained and investigated


Estimated Enrollment: 200
Study Start Date: August 2012
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts
Immunocompromised Patients
Patients with acute leukemia undergoing induction chemotherapy or undergoing allogeneic stem cell transplantation
Control Group
Patients underdoing bronchoscopy and diagnostic BAL without immunosuppression and without signs of infection (Sarcoidosis, Lung Cancer)

Detailed Description:

The major problem in managing life threatening invasive fungal infections in patients (pts) with acute leukemia and pts after allogeneic hematopoietic stem cell transplantation is the lack of sensitive and specific diagnostic tools to identify fungal pathogens reliably and early in the course of the disease. Because of deep neutropenia and low platelet count, invasive diagnostic procedures are rarely feasible in time, therefore bronchoscopy with BAL is the method of choice in diagnosing pulmonary infections, as the sensitivity of culture-based methods from blood is low, especially in mould infections. Indirect methods, so-called surrogate markers, are becoming increasingly important in this clinical setting. These serologic markers, mainly galactomannan (GM) and recently 1(1,3)-β-D-glucan (BDG), have been validated in clinical trials for blood samples, however the clinical significance of testing BAL samples is up to now only based on retrospective data for GM and has not been reported yet for BDG.

The aim of our prospective and multicentre diagnostic study is therefore to elucidate on the sensitivity and specificity rates of these serologic markers in combination with molecular tools (both an Aspergillus specific and a multifungal PCR based assay), as serologic markers are not pathogen-specific, and furthermore to define species-specific cut-off values for BDG in BAL samples.

Additionally, if genomic material of Aspergillus fumigatus is detected by PCR in a clinical sample, we investigate fungal DNA for point mutations in the cyp51A gene mediating resistance against common mould-active triazoles with novel rapid, sensitive and specific, non-culture-based PCR-assays and sequencing to optimize antifungal treatment as early as possible.

This study aims to improve the early, sensitive and specific diagnosis of invasive pulmonary fungal infections and detect azole resistance patterns, it might impact on the prognosis in hematologic patients; therefore antifungal treatment data and clinical outcome will be recorded.

Clinical samples (BAL and blood) from approximately 100 pts suffering from acute leukemia and pts after allogeneic stem cell transplantation with febrile neutropenia and lung infiltrates diagnosed in a chest CT scan suggestive for fungal infection will be investigated after pts`s informed consent in a multicentre, prospective trial. Pts will undergo standardized diagnostic imaging and microbiological procedures for identification of the underlying infectious pathogen. BAL and blood samples will be tested additionally for GM, BDG and with a diagnostic nested Aspergillus PCR assay, a multifungal DNA-Microarray and an azole resistance PCR assay. The molecular assays were established by our group and encompass the detection of Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Candida albicans, Candida dubliniensis, Candida glabrata, Candida lusitaniae, Candida tropicalis, Fusarium oxysporum, Fusarium solani, Mucor racemosus, Rhizopus microsporus, Scedosporium prolificans, Trichosporon asahii and identify the three most common point mutations that confer resistance to triazoles like voriconazole or posaconazole.

Results of other diagnostic means including culture findings as well as patients` clinical data (e.g. duration of neutropenia, underlying disease and outcome including follow-up data concerning antifungal treatment and mortality attributable to fungal infections) will be documented, pseudonomyzed and included in our data bank.

BAL and blood aliquots of 20 control pts without immunosuppression (suffering from lung diseases) will be collected and tested identically.

Case definitions will be made according to 2008 EORTC/MSG criteria. The duration of the study will be approximately 24 months

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population

Patients suffering from acute leukemia and pts after allogeneic stem cell transplantation with febrile neutropenia and lung infiltrates diagnosed in a chest CT scan suggestive for fungal infection will be investigated after pts`s informed consent in a multicentre, prospective trial

Criteria

Inclusion Criteria:

  • acute leukemia or after allogeneic stem cell transplantation
  • febrile neutropenia
  • lung infiltrates suggestive for fungal infection (halo sign. nodules, air-crescent sign)

Exclusion Criteria:

  • missing informed consent
  • other underlying diagnosis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01695512

Contacts
Contact: Dieter Buchheidt, MD +49.621.383.4115 dieter.buchheidt@umm.de
Contact: Mark Reinwald, MD +49.621.383.4115 mark.reinwald@umm.de

Locations
Germany
University Hospital Mannheim Recruiting
Mannheim, Germany, 68167
Contact: Dieter Buchheidt, MD    +49.621.383.4115    dieter.buchheidt@umm.de   
Contact: Mark Reinwald, MD    +49.621.383.4115    mark.reinwald@umm.de   
Principal Investigator: Dieter Buchheidt, MD         
Sub-Investigator: Mark Reinwald, MD         
Sponsors and Collaborators
Heidelberg University
Gilead Sciences
Investigators
Principal Investigator: Dieter Buchheidt, MD Medical Faculty Mannheim, University of Heidelberg
  More Information

Publications:
Responsible Party: Dieter Buchheidt, Professor Dr. Dieter Buchheidt, University of Heidelberg
ClinicalTrials.gov Identifier: NCT01695512     History of Changes
Other Study ID Numbers: University of Heidelberg, Grant Funding number
Study First Received: September 26, 2012
Last Updated: March 27, 2014
Health Authority: Germany: University of Heidelberg

Additional relevant MeSH terms:
Aspergillosis
Leukemia
Mycoses
Neoplasms by Histologic Type
Neoplasms

ClinicalTrials.gov processed this record on July 23, 2014