Invasive AspergillosisNCT01695512
Diagnostic Study of Combined Biomnarker Testing in Bronchoalveolar Lavage Samples of Immunocompromised Patients
An observational study of Invasive Aspergillosis and Acute Leukemia, run by Heidelberg University at 1 site in Germany.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 100 yearsHealthy volunteers can take part
- Conditions the study is for
- Invasive Aspergillosis, Acute Leukemia, Biomarkers
- How many people
- 200 participants
- Where
- 1 siteGermany
- Study dates
- Aug 2012to Dec 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
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
Who may be able to join
- acute leukemia or after allogeneic stem cell transplantation
- febrile neutropenia
- lung infiltrates suggestive for fungal infection (halo sign. nodules, air-crescent sign)
Who cannot join
- missing informed consent
- other underlying diagnosis
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Diagnostic certainty
After 6 weeks the diagnostic performance of the biomarkers and their combination in relation to diagnostic accuracy will be measured
Measured: 6 Weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Sep 2012 (estimated)
- Study startAug 2012
- Primary completionDec 2020 (estimated)
- Study completionDec 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Invasive AspergillosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Heidelberg University
- Sponsor type
- University, hospital or other
- Collaborators
- Gilead Sciences
- Responsible party
- Principal investigator, Dieter Buchheidt, Heidelberg University
- Investigators
- Dieter Buchheidt, MD, Principal investigator, Medical Faculty Mannheim, University of Heidelberg
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01695512
- Sponsor's protocol ID
- University of Heidelberg
- Other IDs
- Grant Funding number
- Status last verified
- Apr 2020
- First submitted
- 26 Sep 2012
- Last updated
- 20 Apr 2020
- Results posted
- No
- Data monitoring committee
- No
Publications
Reinwald M, Hummel M, Kovalevskaya E, Spiess B, Heinz WJ, Vehreschild JJ, Schultheis B, Krause SW, Claus B, Suedhoff T, Schwerdtfeger R, Reuter S, Kiehl MG, Hofmann WK, Buchheidt D. Therapy with antifungals decreases the diagnostic performance of PCR for diagnosing invasive aspergillosis in bronchoalveolar lavage samples of patients with haematological malignancies. J Antimicrob Chemother. 2012 Sep;67(9):2260-7. doi: 10.1093/jac/dks208. Epub 2012 Jun 27.
PubMed 22740590Reinwald M, Spiess B, Heinz WJ, Vehreschild JJ, Lass-Florl C, Kiehl M, Schultheis B, Krause SW, Wolf HH, Bertz H, Maschmeyer G, Hofmann WK, Buchheidt D. Diagnosing pulmonary aspergillosis in patients with hematological malignancies: a multicenter prospective evaluation of an Aspergillus PCR assay and a galactomannan ELISA in bronchoalveolar lavage samples. Eur J Haematol. 2012 Aug;89(2):120-7. doi: 10.1111/j.1600-0609.2012.01806.x. Epub 2012 Jun 22.
PubMed 22650156Spiess B, Seifarth W, Merker N, Howard SJ, Reinwald M, Dietz A, Hofmann WK, Buchheidt D. Development of novel PCR assays to detect azole resistance-mediating mutations of the Aspergillus fumigatus cyp51A gene in primary clinical samples from neutropenic patients. Antimicrob Agents Chemother. 2012 Jul;56(7):3905-10. doi: 10.1128/AAC.05902-11. Epub 2012 Apr 23.
PubMed 22526309Spiess B, Postina P, Reinwald M, Cornely OA, Hamprecht A, Hoenigl M, Lass-Florl C, Rath PM, Steinmann J, Miethke T, Lauten M, Will S, Merker N, Hofmann WK, Buchheidt D. Incidence of Cyp51 A key mutations in Aspergillus fumigatus-a study on primary clinical samples of immunocompromised patients in the period of 1995-2013. PLoS One. 2014 Jul 29;9(7):e103113. doi: 10.1371/journal.pone.0103113. eCollection 2014.
PubMed 25072733
Study at a glance
From the registry record, last updated by the sponsor on 20 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01695512
- Acronym / sponsor ID
- University of Heidelberg
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- Heidelberg UniversityUniversity, hospital or other
- Collaborators
- Gilead Sciences
- Study start
- Aug 2012
- Primary completion
- Dec 2020 (estimated)
- Study completion
- Dec 2020 (estimated)
- First posted
- 28 Sep 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 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) |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- 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
Key inclusion criteria (3 listed)
- acute leukemia or after allogeneic stem cell transplantation
- febrile neutropenia
- lung infiltrates suggestive for fungal infection (halo sign. nodules, air-crescent sign)
Key exclusion criteria (2 listed)
- missing informed consent
- other underlying diagnosis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Diagnostic certainty
Time frame: 6 Weeks
After 6 weeks the diagnostic performance of the biomarkers and their combination in relation to diagnostic accuracy will be measured
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Apr 2020.
- Background: PubMed 22740590Reinwald M, Hummel M, Kovalevskaya E, Spiess B, Heinz WJ, Vehreschild JJ, Schultheis B, Krause SW, Claus B, Suedhoff T, Schwerdtfeger R, Reuter S, Kiehl MG, Hofmann WK, Buchheidt D. Therapy with antifungals decreases the diagnostic performance of PCR for diagnosing invasive aspergillosis in bronchoalveolar lavage samples of patients with haematological malignancies. J Antimicrob Chemother. 2012 Sep;67(9):2260-7. doi: 10.1093/jac/dks208. Epub 2012 Jun 27.
- Background: PubMed 22650156Reinwald M, Spiess B, Heinz WJ, Vehreschild JJ, Lass-Florl C, Kiehl M, Schultheis B, Krause SW, Wolf HH, Bertz H, Maschmeyer G, Hofmann WK, Buchheidt D. Diagnosing pulmonary aspergillosis in patients with hematological malignancies: a multicenter prospective evaluation of an Aspergillus PCR assay and a galactomannan ELISA in bronchoalveolar lavage samples. Eur J Haematol. 2012 Aug;89(2):120-7. doi: 10.1111/j.1600-0609.2012.01806.x. Epub 2012 Jun 22.
- Background: PubMed 22526309Spiess B, Seifarth W, Merker N, Howard SJ, Reinwald M, Dietz A, Hofmann WK, Buchheidt D. Development of novel PCR assays to detect azole resistance-mediating mutations of the Aspergillus fumigatus cyp51A gene in primary clinical samples from neutropenic patients. Antimicrob Agents Chemother. 2012 Jul;56(7):3905-10. doi: 10.1128/AAC.05902-11. Epub 2012 Apr 23.
- Derived from this study: PubMed 25072733Spiess B, Postina P, Reinwald M, Cornely OA, Hamprecht A, Hoenigl M, Lass-Florl C, Rath PM, Steinmann J, Miethke T, Lauten M, Will S, Merker N, Hofmann WK, Buchheidt D. Incidence of Cyp51 A key mutations in Aspergillus fumigatus-a study on primary clinical samples of immunocompromised patients in the period of 1995-2013. PLoS One. 2014 Jul 29;9(7):e103113. doi: 10.1371/journal.pone.0103113. eCollection 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dieter Buchheidt, MD principal investigator
Medical Faculty Mannheim, University of Heidelberg
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Invasive Aspergillosis and Acute Leukemia, run by Heidelberg University at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 20 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Diagnostic certainty (time frame: 6 Weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01695512, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Apr 2020.