Clinical trial NCT03121235: PCR Based Detection of Azole Resistance in A. Fumigatus to Improve Patient Outcome.
Official title: PCR Based Detection of Azole Resistance in A. Fumigatus to Improve Patient Outcome. A Prospective Multicenter Observational Study.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Aspergillosis, Invasive Pulmonary
Keywords: aspergillosis
mycosis
neutropenia
hematologic diseases
AsperGenius PCR
Ambisome
Voriconazole
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: Gilead Sciences
First posted: 2017-04-20
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
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).

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. 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of antifungal treatment failure
timeFrame: 12 weeks
Secondary outcomes:
measure: Demonstrate that early detection of azole resistance reduces the overall mortality.
timeFrame: 6 weeks
measure: 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.
timeFrame: 12 weeks
measure: Comparison of antifungal treatment failure in patients with the presence of RAM.
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Maastricht
country: Netherlands
facility: Maastricht Universitair Medisch Centrum +
city: Nijmegen
country: Netherlands
facility: Radboud Medisch Universitair Centrum
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
Study officials:
affiliation: Internal Medicine and Infectious Diseases
name: Bart JA Rijnders, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References:
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