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This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00005860

Trial Description

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Title

Bronchoalveolar Lavage Lateral-Flow Device Test for Invasive Pulmonary Aspergillosis: a Multicenter Study

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

Background Invasive pulmonary aspergillosis (IPA) remains an important cause of morbidity
and mortality among patients with hemato-oncological malignancies. Due to the crude
mortality of >90% in absence of adequate treatment, timely diagnosis and early start of
antifungal therapy are key factors in the successful treatment of IPA. Various studies have
shown that early initiation of antifungal therapy may improve IPA survival to above 70%.
Diagnosis of IPA, however, remains difficult as clinical signs and symptoms as well as
radiological findings are often unspecific and conventional culture methods lack
sensitivity. In recent years antigen testing has therefore become one of the cornerstones of
IPA diagnostics. Brochoalveolar lavage (BAL) Galactomannan (GM) testing is currently the
most promising approach for early detection of pulmonary infections by this fungus. However,
limitations of GM detection are assay turn-around time, which varies widely between centers
(less than a day to several days), and the need for appropriately equipped laboratories that
routinely test for this antigen. These limitations are overcome by the Aspergillus
Lateral-Flow Device (LFD), a novel point-of-care (POC) test for IPA diagnosis developed by
Dr Thornton at the University of Exeter, UK. This simple, rapid (15 min), single-use test
can be performed in rudimentary facilities using BAL specimens. In a retrospective single
centre study we have recently evaluated the LFD test in 39 BAL samples from hematologic
malignancy patients and solid organ transplant recipients. Sensitivities and specificities
of BAL LFD tests for probable IPA were 100% and 81%, respectively. Galactomannan levels in
cases with negative LFD were significantly lower than in patients with positive LFD (P
<0.0001). We concluded that the LFD test of BAL specimens is performed easily and provides
accurate and rapidly available results. Therefore, this new point-of-care test may be a very
promising diagnostic approach for detecting IPA in BAL specimens from haematological
malignancy and SOT patients. For routine clinical use, however, multicenter studies with
larger sample sizes also from other patient collectives are necessary. In this multicenter
study we will evaluate the LFD test in BAL samples.

Study Objectives Primary Objectives To evaluate the Lateral Flow Device test, a rapid (15
min), point-of-care test for IPA diagnosis using bronchoalveolar lavage (BAL) fluids from
patients at risk for IPA.

Secondary Objective To evaluate the potential of BAL Lateral Flow Device test for prognosis
in patients with IPA.

Study Design This is a prospective multi-center study conducted in three centers in Austria
(Graz, Vienna and Innsbruck) and one centre in Germany (Mannheim). In order to meet the
objectives an estimated number of 300 BAL samples from patients at risk for IPA (50 to 100
per centre) will be included in the study cohort. The Lateral Flow Device test will be
performed prospectively in BAL samples from the patients and results will be compared to GM
results, PCR findings, clinical/radiological findings as well as conventional culture
results. In addition, retrospective testing of BAL samples that were previously routinely
tested for GM will be performed in up to three participating centers (Graz, Innsbruck and
Mannheim) to ensure to reach the proposed number of 300 BAL samples. The treating clinicians
will not be informed about BAL Lateral Flow Device test results and the test will therefore
have no impact on patient management / treatment decisions.

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Brief Summary in Scientific Language

Project Outlook Sensitive and specific biomarkers for early diagnosis of IPA are urgently
needed to improve survival. In this multicenter study we will evaluate the potential of the
novel Lateral Flow Device test for early, bedside diagnosis of IPA.

A successful implementation of the studies hypothesis requires a solid background in the
field of IPA. Considering this I am confident that my professional experience combined with
the technical and scientific expertise at my host institute and the associated laboratories
generates a highly competitive and promising setting. The success of the proposed research
will vitally depend on collaborations. Over the last four years I have worked extensively in
the field of IPA among patients with hemato-oncological malignancies, which allowed me to
establish the necessary contacts and cooperations that are vital for the project's success.
The major strength of this multi-center study is therefore the cooperation with three major
centers for IPA diagnosis under the leadership of three outstanding experts (Prof.
Lass-Flörl, Prof. Buchheidt and Prof. Willinger) who have published extensively in the field
of IPA diagnosis over recent years/decades. I am certain that our results will have
far-reaching implementations for the whole field of IPA. Clearly, they will significantly
advance our understanding of the clinical performance of the novel point of care
applications.

The project is expected to have a big impact on patient care. Establishment of the Lateral
Flow Device test may lead to rapidly, frankly on the bedside, available test results and may
therefore enable earlier initiation of appropriate antifungal therapy which may help to save
lives.

1. Background

Invasive fungal infections (IFI) are an important cause of morbidity and mortality
among patients with haemato-oncological malignancies (1-3). Invasive mould infections
(IMI), in particular invasive aspergillosis (IA) are the leading cause of IFI among
these patients, followed by invasive Candida infections (2, 4). Due to the crude
mortality of 80-90% in absence of adequate treatment, timely diagnosis and early start
of antifungal therapy are key factors in the successful treatment of IFI. Various
studies have shown that early initiation of antifungal therapy may improve IFI survival
to above 80% (5, 6). Clinical signs and symptoms of IFI as well as radiological
findings, however, are often unspecific. The inability to consistently make an early
and convincing diagnosis remains, therefore, one central problem. The European
Organization for Research and Treatment of Cancer Invasive Fungal Infections
Cooperative Group (EORTC) and the Mycoses Study Group of the National Institute of
Allergy and Infectious Disease (MSG) had some success in tackling this problem by
establishing consensus definitions for opportunistic IFI (7). However, definitions in
EORTC/MSG guidelines were based not only on review of the literature, but also expert
opinion and subsequent international consensus. The main reason was that studies
evaluating details of the definitions were in part simply not available. In a recent
cohort study our working group proposed some modifications to the criteria (8).

When using EORTC/MSG criteria the prevalence of IFI strongly depends on mycological
evidence which is not easy to get. Culture-based diagnostic approaches do not only
require invasive diagnostic procedures, which are often hindered by the severe medical
condition in patients at risk for IFI, but do also, in fact, frequently result falsely
negative. Antigen testing with rapidly available test results has therefore become
increasingly important to produce a realistic picture of the burden of IFI and enable
early diagnosis and treatment in patients with IFI (1). Antigen testing may not only
facilitate early diagnosis but may also prevent overtreatment which has become
frequent. A recent study by Azoulay and colleagues who evaluated antifungal therapy on
one day in multiple French hospitals confirmed that in fact most of the patients that
received antifungals did in fact not have IFI (9). Overtreatment may not only increase
costs significantly (daily costs for most antifungals 600-1000€) but may also lead to
development of resistance (10). The use of highly sensitive and specific rapidly
available antigen tests/ biomarkers may guide the clinician to initiate antifungal
therapy only in patients that benefit from treatment as they really have IFI. Last but
not least antigen testing may be also useful for early response assessment, therapy
monitoring and treatment stratification including the decision when to stop antifungal
therapy in patients with IA (11-12).

One of the major limitations of the GM test is that time to results varies between
centres (between less than a day and up to several days), mainly depending on the
number of specimens tested in routine (as the test is performed with plates covering 96
tests), and the distance/duration of transport between the clinical setting and the
laboratory where the test is performed. These limitations are overcome by the Lateral
Flow Device Test, a point of care test for IA developed by Prof. Thornton of the
University of Exeter, United Kingdom. This single sample test can be easily performed
in every laboratory using BAL and serum specimens and time to result is approximately
20 minutes. Recent studies have shown the immense potential of the test in human BAL
and serum samples (13-15). In a very recent study our working group retrospectively
evaluated the LFD test by using bronchoalveolar lavage (BAL) samples from patients with
haematological malignancies and patients after solid organ transplantation (SOT).
Thirty-nine BAL samples from 37 patients were included (29 samples haematological
malignancies and 10 samples SOT; 12 probable IPA, 9 possible IPA, 16 no IPA).
Sensitivity and specificity of BAL LFD test for probable IPA were 100% and 81%,
respectively. GM levels in cases with negative LFD were significantly lower than in
patients with positive LFD (P <0.0001). We concluded that the LFD test of BAL specimens
is performed easily and provides accurate and rapidly available results. Therefore,
this new point-of-care test may be a very promising diagnostic approach for detecting
IPA in BAL specimens from haematological malignancy and SOT patients (16). Another
recent study demonstrated in a neutropenic guinea pig model that the LFD assay is
reproducible between different laboratories and studies (17). Multi-center studies are
needed, however, to further evaluate the test (16).

In the proposed study we will evaluate the BAL Lateral Flow Device Test and compare
results to routinely performed Galactomannan values as well as, culture and PCR
results.

2. Study design and methods 2.1. Study design The study design is exploratory,
retrospective, and multi-centric. The study will start in March 2013 with duration of
13 months.

2.2. Study sites

1. Section of Infectious Diseases, Department of Internal Medicine, Medical
University of Graz, Austria

2. Division of Hygiene and Medical Microbiology, Innsbruck Medical University,
Austria

3. Division of Clinical Microbiology, Medical University of Vienna, Austria

4. Mannheim University Hospital, University of Heidelberg, Germany

2.3. Study population All stored or routinely obtained BAL samples from adult patients
at risk for invasive pulmonary Aspergillosis will be eligible for study inclusion. The
treating clinicians will be blinded to BAL Lateral Flow Device test results and the
test will therefore have no impact on patient management / treatment decisions. The
treating clinicians will be blinded to BAL Lateral Flow Device test results. Test
results will therefore have no impact on clinical / treatment decisions and therefore
not affect the included patients.

Underlying diseases, EORTC status of IFI (both available from the clinical order
accompanying the BAL sample) and other microbiological/mycological test results will be
recorded in an electronic data base. No patient related personal data will be required.

2.3.1 Key Inclusion criteria

1. Patients above 18 years of age.

2. BAL sample obtained in clinical routine.

3. At risk for IFI (according to attending clinicians). Risk factors may include:

- febrile neutropenia

- induction chemotherapy

- allogeneic stem cell transplant/graft versus host disease

- clinical/radiological/mycological findings suspicious for IFI

- Solid Organ transplantation

- ICU patient

- Liver cirrhosis 2.3.2 Key exclusion criteria

1. Under 18 years of age.

2. No BAL sample obtained in clinical routine.

d.) Not at risk for IFI.

2.4. Lateral Flow Device testing The previously described lateral flow device is
evaluated in BALs from patients at risk for invasive aspergillosis. Briefly, an
immunoglobulin G (IgG) monoclonal antibody (JF5) to an epitope on an extracellular
antigen secreted constitutively during active growth of Aspergillus is immobilized to a
capture zone on a porous nitrocellulose membrane. JF5 IgG is also conjugated to
colloidal gold particles to serve as the detection reagent. BAL fluid (100 μl of neat
sample, with no pre-treatment) is added to a release pad containing the antibody-gold
conjugate, which bound the target antigen, and then passed along the porous membrane
and bound to JF5 IgG monoclonal antibody immobilized in the capture zone. Lateral Flow
Device (LFD) Results will be read 15 minutes after loading the sample. Bound
antigen-antibody-gold complexes are observed as a red line (T for test) with an
intensity proportional to the antigen concentration and were classified as negative,
weakly positive, moderately positive, or strongly positive (Fig. 1). Anti-mouse
immunoglobulin immobilized to the membrane in a separate zone (C for control) serves as
an internal control (13, 15). Detailed product information can be found in the attached
publication "Development of an Immunochromatographic Lateral-Flow Device for Rapid
Serodiagnosis of Invasive Aspergillosis" (14).

As the device is in the process of being CE marked for European use as a medical
diagnostic device, one can only view the current results as a multicentre prototype
test comparison (with no clinical implications for patient management).

3. Statistical Considerations Statistical analysis including multivariate analyses will be
performed in cooperation with ao. Univ. Prof. Dipl.-Ing. Dr. tech. Josef Haas from the
Institute for Medical Informatics, Statistics and Documentation, Medical University of
Graz and Univ. Doz. Mag. Dr. Herbert Schwetz, University of Salzburg.

3.1. Sample size calculation Due to the explorative study design statistical sample size
calculation is not possible. The samples size has been calculated by using recent published
epidemiological data from involved centres (3, 16). The proposed number of patients to be
investigated is representative and appropriate to generate data for further studies and has
been considered to be adequate by the statistical advisor.

3.2. Statistical Analysis Statistical analysis will be performed by using SPSS in
cooperation with our specialized co-operators mentioned above.

References

1. Hoenigl M, Valentin T, Salzer HJ, Zollner-Schwetz I, Krause R. Underestimating the real
burden of invasive fungal infections in hematopoietic stem cell transplant recipients?
Clin Infect Dis. 2010 Jul 15;51(2):253,4; author reply 254-5.

2. Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, et al.
Prospective surveillance for invasive fungal infections in hematopoietic stem cell
transplant recipients, 2001-2006: Overview of the transplant-associated infection
surveillance network (TRANSNET) database. Clin Infect Dis. 2010 Apr 15;50(8):1091-100.

3. Hoenigl M, Salzer HJ, Raggam RB, Valentin T, Rohn A, Woelfler A, et al. Impact of
galactomannan testing on the prevalence of invasive aspergillosis in patients with
hematological malignancies. Med Mycol. 2012 Apr;50(3):266-9.

4. Perkhofer S, Lass-Florl C, Hell M, Russ G, Krause R, Honigl M, et al. The nationwide
austrian aspergillus registry: A prospective data collection on epidemiology, therapy
and outcome of invasive mould infections in immunocompromised and/or immunosuppressed
patients. Int J Antimicrob Agents. 2010 Dec;36(6):531-6.

5. Greene RE, Schlamm HT, Oestmann JW, Stark P, Durand C, Lortholary O, et al. Imaging
findings in acute invasive pulmonary aspergillosis: Clinical significance of the halo
sign. Clin Infect Dis. 2007 Feb 1;44(3):373-9.

6. Lass-Florl C, Resch G, Nachbaur D, Mayr A, Gastl G, Auberger J, et al. The value of
computed tomography-guided percutaneous lung biopsy for diagnosis of invasive fungal
infection in immunocompromised patients. Clin Infect Dis. 2007 Oct 1;45(7):e101-4.

7. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised
definitions of invasive fungal disease from the european organization for research and
treatment of Cancer/Invasive fungal infections cooperative group and the national
institute of allergy and infectious diseases mycoses study group (EORTC/MSG) consensus
group. Clin Infect Dis. 2008 Jun 15;46(12):1813-21.

8. Hoenigl M, Strenger V, Buzina W, Valentin T, Koidl C, Wolfler A, et al. European
organization for the research and treatment of Cancer/Mycoses study group (EORTC/MSG)
host factors and invasive fungal infections in patients with haematological
malignancies. J Antimicrob Chemother. 2012 May 7.

9. Azoulay E, Dupont H, Tabah A, Lortholary O, Stahl JP, Francais A, et al. Systemic
antifungal therapy in critically ill patients without invasive fungal infection*. Crit
Care Med. 2012 Mar;40(3):813-22.

10. van der Linden JW, Snelders E, Kampinga GA, Rijnders BJ, Mattsson E, Debets-Ossenkopp
YJ, et al. Clinical implications of azole resistance in aspergillus fumigatus, the
netherlands, 2007-2009. Emerg Infect Dis. 2011 Oct;17(10):1846-54.

11. Seeber K, Duettmann W, Krause R, Hoenigl M. Usefulness of the serum galactomannan assay
for early response assessment and treatment stratifications of invasive aspergillosis.
Curr Fungal Infect Rep [DOI: 10.1007/s12281-012-0099-5]. 2012 Online First™, 29 Juni
2012;DOI: 10.1007/s12281-012-0099-5.

12. Chamilos G, Luna M, Lewis RE, Bodey GP, Chemaly R, Tarrand JJ, et al. Invasive fungal
infections in patients with hematologic malignancies in a tertiary care cancer center:
An autopsy study over a 15-year period (1989-2003). Haematologica. 2006
Jul;91(7):986-9.

13. Thornton C, Johnson G, Agrawal S. Detection of invasive pulmonary aspergillosis in
haematological malignancy patients by using lateral-flow technology. J Vis Exp. 2012
Mar 22;(61). pii: 3721. doi(61):10.3791/3721.

14. Thornton CR. Development of an immunochromatographic lateral-flow device for rapid
serodiagnosis of invasive aspergillosis. Clin Vaccine Immunol. 2008 Jul;15(7):1095-105.

15. Wiederhold NP, Thornton CR, Najvar LK, Kirkpatrick WR, Bocanegra R, Patterson TF.
Comparison of lateral flow technology and galactomannan and (1->3)-beta-D-glucan assays
for detection of invasive pulmonary aspergillosis. Clin Vaccine Immunol. 2009
Dec;16(12):1844-6.

16. Hoenigl M, Koidl C, Duettmann W, Seeber K, Wagner J, Buzina W, et al. Bronchoalveolar
lavage lateral-flow device test for invasive pulmonary aspergillosis diagnosis in
haematological malignancy and solid organ transplant patients. J Infect.
2012;65(6):588-91.

17. Wiederhold NP, Najvar LK, Bocanegra R, Kirkpatrick WR, Patterson TF, Thornton CR.
Inter-Laboratory and Inter-Study Reproducibility of a Novel Lateral-Flow Device and the
Influence of Antifungal Therapy on the Detection of Invasive Pulmonary Aspergillosis. J
Clin Microbiol. 2013; epup ahead of print

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Organizational Data

  •   DRKS00005860
  •   2014/08/22
  •   2014/01/20
  •   yes
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Secondary IDs

  •   NCT02058316  (ClinicalTrials.gov)
  •   25-221  (Medical University of Graz)
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Health Condition or Problem studied

  •   Invasive Pulmonary Aspergillosis
  •   B44.0 -  Invasive pulmonary aspergillosis
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Interventions/Observational Groups

  •   Device: Lateral Flow Device Test
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Characteristics

  •   Non-interventional
  •   Observational study
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  •   N/A
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Primary Outcome

- Performance of the Lateral Flow Device Test for diagnosisng of invasive pulmonary aspergillosis in BAL fluids; time frame: Day 1; BAL fluid s of included patients will be tested with the LFD. Results will be compared to other diagnostics.

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Secondary Outcome

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Countries of Recruitment

  •   Austria
  •   Germany
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Locations of Recruitment

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Recruitment

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  •   2013/02/27
  •   300
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

- a.) Patients above 18 years of age. b.) BAL sample obtained in clinical routine. c.)
At risk for IFI (according to attending clinicians). Risk factors may include:

- febrile neutropenia

- induction chemotherapy

- allogeneic stem cell transplant/graft versus host disease

- clinical/radiological/mycological findings suspicious for IFI

- Solid Organ transplantation

- ICU patient

- Liver cirrhosis

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Exclusion Criteria

- a.) Under 18 years of age. b.) No BAL sample obtained in clinical routine. d.) Not at
risk for IFI.

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Addresses

  • start of 1:1-Block address primary-sponsor
    • Medical University of Graz
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    • Medical University of Vienna
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    • Medical University Innsbruck
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    • Universitätsmedizin Mannheim
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  • start of 1:1-Block address scientific-contact
    • Martin Hoenigl, MD, PD 
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    end of 1:1-Block address contact scientific-contact
  • start of 1:1-Block address public-contact
    • Martin Hoenigl, MD, PD 
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   2
  •   2014/11/27
* This entry means the parameter is not applicable or has not been set.