PCR Based Detection of Azole Resistance in A. Fumigatus to Improve Patient Outcome.

NCT03121235 | Completed

• 1 other identifier: MEC-2016-664
• Study Type: observational
• Target: 320
• Locations: 1 country
• Sites: 8

Brief Summary

A standard treatment protocol for invasive aspergillosis (IA) will be implemented in several academic hematology centers in the Netherlands in which a diagnostic test demonstrating azole resistance by multiplex real-time polymerase chain reaction will guide the choice of appropriate antifungal treatment. Objectives:

1. 1.Improve the outcome of patients infected with azole resistant A. fumigatus by the early detection of Resistance Associated Mutations (RAMs) and with this the earlier initiation of the most appropriate therapy.
2. 2.Monitor the prevalence of invasive aspergillosis due to strains carrying the TR34/L98H or the TR46/T289A/Y121F resistance associated mutations in the Netherlands.

Conditions

Aspergillosis, Invasive Pulmonary

Keywords

aspergillosis; mycosis; neutropenia; hematologic diseases; AsperGenius PCR; Ambisome; Voriconazole

Outcome Measures

Primary Outcomes (1)

• Incidence of antifungal treatment failure

  Incidence of antifungal treatment failure in patients with the presence of RAM detected by the AsperGenius® resistance PCR. This incidence will be compared with a fixed failure rate set at 75%, based on the observed treatment failure in patients treated with voriconazole that were shown to carry azole resistant A. fumigatus.

  12 weeks

Secondary Outcomes (3)

• Demonstrate that early detection of azole resistance reduces the overall mortality.

  6 weeks

• Demonstrate that a step down to oral posaconazole is a reasonable treatment option in patients that have responded to at least 2 weeks of IV antifungal therapy.

  12 weeks

• Comparison of antifungal treatment failure in patients with the presence of RAM.

  24 weeks

Interventions

PCR based detection of azole resistance in A. fumigatus DIAGNOSTIC_TEST

Diagnosis and treatment of IA will be based on the results of a standardized diagnosis and treatment protocol that includes the use of the AsperGenius® PCR.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with an underlying haematological disease (AML, CLL, CML, stem cell transplant etc.) aged 18 years and older are eligible if they are presenting with a new pulmonary infiltrate on chest CT-scan suspicious for invasive fungal infection and are planned to undergo or have undergone a bronchoscopic alveolar lavage (BAL).

You may qualify if:

• Patient with underlying hematological disease
• Patient will undergo/underwent BAL sampling for suspected invasive fungal infection
• BAL samples should be submitted to the local microbiology lab for fungal culture and for galactomannan detection.
• The treating physician is planning to start voriconazole, isavuconazole or posaconazole after the BAL has been sampled while waiting for the culture or PCR results of the BAL sample or has already started voriconazole or posaconazole before BAL sampling.

You may not qualify if:

• A potential subject who meets any of the following criteria will be excluded from participation in this study:
• Antifungal therapy was started \>120hours prior to BAL sampling (\*)
• Antifungal prophylaxis with posaconazole or voriconazole for \>5 days within the 2 weeks preceding BAL sampling
• Antifungal prophylaxis with itraconazole and at least half of the plasma itraconazole/hydroxy-itraconazole levels that were measured through therapeutic drug monitoring were above the minimum effective plasma concentration of 0.5mg/L (parental compound only, HLPC assay method). The minimum effective plasma concentration of 0.5mg/L for itraconazole has been established by the ECIL 6 meeting with a recommendation AII.
• (\*) Patients that develop new pulmonary infiltrates during antifungal prophylaxis (systemic azoles or aerosolized amphotericin B) can be included.

Sponsors & Collaborators

• Erasmus Medical Center: lead
• Gilead Sciences: collaborator

Study Sites (8)

Academisch Medisch Centrum

Amsterdam, Netherlands

Location

VU Medisch Centrum

Amsterdam, Netherlands

Location

Universitair Medisch Centrum Groningen

Groningen, Netherlands

Location

Leids Universitair Medisch Centrum

Leiden, Netherlands

Location

Maastricht Universitair Medisch Centrum +

Maastricht, Netherlands

Location

Radboud Medisch Universitair Centrum

Nijmegen, Netherlands

Location

Erasmus Medical Center

Rotterdam, 3000 CA, Netherlands

Location

Universitair Medisch Centrum Utrecht

Utrecht, Netherlands

Location

Related Publications (9)

• Verweij PE, Zhang J, Debets AJM, Meis JF, van de Veerdonk FL, Schoustra SE, Zwaan BJ, Melchers WJG. In-host adaptation and acquired triazole resistance in Aspergillus fumigatus: a dilemma for clinical management. Lancet Infect Dis. 2016 Nov;16(11):e251-e260. doi: 10.1016/S1473-3099(16)30138-4. Epub 2016 Sep 13.

  PMID: 27638360 BACKGROUND

• Vermeulen E, Maertens J, De Bel A, Nulens E, Boelens J, Surmont I, Mertens A, Boel A, Lagrou K. Nationwide Surveillance of Azole Resistance in Aspergillus Diseases. Antimicrob Agents Chemother. 2015 Aug;59(8):4569-76. doi: 10.1128/AAC.00233-15. Epub 2015 May 18.

  PMID: 25987612 BACKGROUND

• van der Linden JW, Snelders E, Kampinga GA, Rijnders BJ, Mattsson E, Debets-Ossenkopp YJ, Kuijper EJ, Van Tiel FH, Melchers WJ, Verweij PE. Clinical implications of azole resistance in Aspergillus fumigatus, The Netherlands, 2007-2009. Emerg Infect Dis. 2011 Oct;17(10):1846-54. doi: 10.3201/eid1710.110226.

  PMID: 22000354 BACKGROUND

• Chong GL, van de Sande WW, Dingemans GJ, Gaajetaan GR, Vonk AG, Hayette MP, van Tegelen DW, Simons GF, Rijnders BJ. Validation of a new Aspergillus real-time PCR assay for direct detection of Aspergillus and azole resistance of Aspergillus fumigatus on bronchoalveolar lavage fluid. J Clin Microbiol. 2015 Mar;53(3):868-74. doi: 10.1128/JCM.03216-14. Epub 2015 Jan 7.

  PMID: 25568431 BACKGROUND

• Verweij PE, Chowdhary A, Melchers WJ, Meis JF. Azole Resistance in Aspergillus fumigatus: Can We Retain the Clinical Use of Mold-Active Antifungal Azoles? Clin Infect Dis. 2016 Feb 1;62(3):362-8. doi: 10.1093/cid/civ885. Epub 2015 Oct 20.

  PMID: 26486705 BACKGROUND

• Mavridou E, Bruggemann RJ, Melchers WJ, Mouton JW, Verweij PE. Efficacy of posaconazole against three clinical Aspergillus fumigatus isolates with mutations in the cyp51A gene. Antimicrob Agents Chemother. 2010 Feb;54(2):860-5. doi: 10.1128/AAC.00931-09. Epub 2009 Nov 16.

  PMID: 19917751 BACKGROUND

• Verweij PE, Ananda-Rajah M, Andes D, Arendrup MC, Bruggemann RJ, Chowdhary A, Cornely OA, Denning DW, Groll AH, Izumikawa K, Kullberg BJ, Lagrou K, Maertens J, Meis JF, Newton P, Page I, Seyedmousavi S, Sheppard DC, Viscoli C, Warris A, Donnelly JP. International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus. Drug Resist Updat. 2015 Jul-Aug;21-22:30-40. doi: 10.1016/j.drup.2015.08.001. Epub 2015 Aug 7.

  PMID: 26282594 BACKGROUND

• Verweij PE, Lestrade PP, Melchers WJ, Meis JF. Azole resistance surveillance in Aspergillus fumigatus: beneficial or biased? J Antimicrob Chemother. 2016 Aug;71(8):2079-82. doi: 10.1093/jac/dkw259.

  PMID: 27494831 BACKGROUND

• Chong GM, van der Beek MT, von dem Borne PA, Boelens J, Steel E, Kampinga GA, Span LF, Lagrou K, Maertens JA, Dingemans GJ, Gaajetaan GR, van Tegelen DW, Cornelissen JJ, Vonk AG, Rijnders BJ. PCR-based detection of Aspergillus fumigatus Cyp51A mutations on bronchoalveolar lavage: a multicentre validation of the AsperGenius assay(R) in 201 patients with haematological disease suspected for invasive aspergillosis. J Antimicrob Chemother. 2016 Dec;71(12):3528-3535. doi: 10.1093/jac/dkw323. Epub 2016 Aug 15.

  PMID: 27530755 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Broncho-alveolar lavage specimens

MeSH Terms

Conditions

Invasive Pulmonary Aspergillosis; Aspergillosis; Mycoses; Neutropenia; Hematologic Diseases

Condition Hierarchy (Ancestors)

Pulmonary Aspergillosis; Bacterial Infections and Mycoses; Infections; Invasive Fungal Infections; Lung Diseases, Fungal; Lung Diseases; Respiratory Tract Diseases; Agranulocytosis; Leukopenia; Cytopenia; Hemic and Lymphatic Diseases; Leukocyte Disorders

Study Officials

• Bart JA Rijnders, MD/PhD

  Internal Medicine and Infectious Diseases

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: April 14, 2017
• First Posted: April 20, 2017
• Study Start: April 20, 2017
• Primary Completion: December 31, 2021
• Study Completion: March 20, 2022
• Last Updated: March 23, 2022

Record last verified: 2022-03

Locations

NL (8)