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

March 22, 2022 updated by: Bart Rijnders, Erasmus Medical Center

PCR Based Detection of Azole Resistance in A. Fumigatus to Improve Patient Outcome. A Prospective Multicenter Observational Study.

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. 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. Monitor the prevalence of invasive aspergillosis due to strains carrying the TR34/L98H or the TR46/T289A/Y121F resistance associated mutations in the Netherlands.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Invasive aspergillosis (IA) is the most common mould infection in immunocompromised haematological patients. A relatively low mortality is observed when diagnosis is made early and treatment with voriconazole, the first choice of treatment, is initiated promptly. However, azole resistance in Aspergillus fumigatus is increasingly reported in Europe. Fungal susceptibility testing is difficult, time consuming and not widely available. Furthermore, cultures remain negative in the majority of the patients with IA. AsperGenius®, is a CE certified multiplex real-time polymerase chain reaction (PCR) assay that allows for a simultaneous detection of the presence of Aspergillus species and identification of the most common mutations in the A. fumigatus CYP51A gene conferring resistance. The use of this PCR results in faster diagnosis of azole resistance and thus the initiation of appropriate therapy at an earlier point in time. A fast diagnosis and correct treatment leads to an improved outcome. After extensive discussions and a face-to-face meeting with 7 of the 8 UMC in the Netherlands a consensus diagnostic and therapeutic protocol was agreed upon. In this protocol, the AsperGenius® PCR will be used for the diagnosis of azole resistance and antifungal treatment will be changed if resistance is detected. This protocol is the current standard diagnostic and treatment approach at Erasmus MC.

Haematological patients suspected of having an invasive fungal pulmonary infection undergo BAL sampling as standard of care. AsperGenius® PCR on BAL sample allows to make a rapid diagnosis of invasive aspergillosis and gives information about azole resistance faster than standard time consuming methods like fungal culture and galactomannan measurement. A standard treatment protocol based on this new diagnostic tool is in place at Erasmus MC and will be implemented in the other study centres. The centres will be asked to send BAL sample of at least 1ml, preferably 2ml.

If RAMs are detected, the treating physician will be advised to switch from voriconazole to 1 of the following options:

  1. Ambisome 3mg/kg IV
  2. In case of treatment limiting toxicity of Ambisome IV, we suggest the use of an echinocandin in combination with posaconazole and aiming at serum Cthrough levels of 3-4mg/L
  3. Step down therapy from IV therapy as described under 1 and 2 to oral therapy with posaconazole is allowed after at least 2 weeks of IV therapy and after a documented clinical and or radiological response. Posaconazole serum Cthrough levels of 3-4mg/L will be aimed for. Step down to posaconazole will not be done if an A. fumigatus strain with an MIC of >0.5 microgram/ml is cultured.
  4. As an alternative to posaconazole step down, IV ambisome 5mg/kg thrice weekly can be given as well.

Study Type

Observational

Enrollment (Actual)

320

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Amsterdam, Netherlands
        • VU medisch centrum
      • Amsterdam, Netherlands
        • Academisch Medisch Centrum
      • Groningen, Netherlands
        • Universitair Medisch Centrum Groningen
      • Leiden, Netherlands
        • Leids Universitair Medisch Centrum
      • Maastricht, Netherlands
        • Maastricht Universitair Medisch Centrum +
      • Nijmegen, Netherlands
        • Radboud Medisch Universitair Centrum
      • Rotterdam, Netherlands, 3000 CA
        • Erasmus Medical Center
      • Utrecht, Netherlands
        • Universitair Medisch Centrum Utrecht

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

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).

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of antifungal treatment failure
Time Frame: 12 weeks
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Demonstrate that early detection of azole resistance reduces the overall mortality.
Time Frame: 6 weeks
This will be compared with a fixed mortality of 50%.
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.
Time Frame: 12 weeks
Posaconazole step down therapy will be considered effective if <35% of the patients treated with posaconazole oral monotherapy show progression of their invasive aspergillosis after documented response after at least 14 days of IV antifungal therapy.
12 weeks
Comparison of antifungal treatment failure in patients with the presence of RAM.
Time Frame: 24 weeks
A group that received appropriate antifungal therapy soon will be compared with a group that received treatment late.
24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Erasmus Medical Center

Collaborators

Gilead Sciences

Investigators

  • Principal Investigator: Bart JA Rijnders, MD/PhD, Internal Medicine and Infectious Diseases

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 20, 2017

Primary Completion (Actual)

December 31, 2021

Study Completion (Actual)

March 20, 2022

Study Registration Dates

First Submitted

April 14, 2017

First Submitted That Met QC Criteria

April 14, 2017

First Posted (Actual)

April 20, 2017

Study Record Updates

Last Update Posted (Actual)

March 23, 2022

Last Update Submitted That Met QC Criteria

March 22, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MEC-2016-664

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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