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

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ClinicalTrials.gov Identifier: NCT03121235
Recruitment Status : Recruiting
First Posted : April 20, 2017
Last Update Posted : March 22, 2018
Sponsor:
Collaborator:
Gilead Sciences
Information provided by (Responsible Party):
Bart Rijnders, Erasmus Medical Center

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.

Condition or disease Intervention/treatment
Aspergillosis, Invasive Pulmonary Diagnostic Test: PCR based detection of azole resistance in A. fumigatus

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
Estimated Enrollment : 280 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: PCR Based Detection of Azole Resistance in A. Fumigatus to Improve Patient Outcome. A Prospective Multicenter Observational Study.
Actual Study Start Date : April 20, 2017
Estimated Primary Completion Date : October 15, 2019
Estimated Study Completion Date : October 15, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Aspergillosis


Intervention Details:
  • Diagnostic Test: PCR based detection of azole resistance in A. fumigatus
    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.


Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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%.

  2. 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.

  3. 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.


Biospecimen Retention:   Samples With DNA
Broncho-alveolar lavage specimens


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes 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).
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03121235


Contacts
Contact: Alexander Schauwvlieghe, MD +31625568885 a.schauwvlieghe@erasmusmc.nl
Contact: Bart Rijnders, MD/PhD b.rijnders@erasmusmc.nl

Locations
Netherlands
Academisch Medisch Centrum Recruiting
Amsterdam, Netherlands
Contact: B.J. Biemond, MD/PhD       b.j.biemond@amc.uva.nl   
VU Medisch Centrum Recruiting
Amsterdam, Netherlands
Contact: J Janssen       j.janssen@vumc.nl   
Universitair Medisch Centrum Groningen Recruiting
Groningen, Netherlands
Contact: L.F.R. Span, MD/PhD       l.f.r.span@umcg.nl   
Leids Universitair Medisch Centrum Recruiting
Leiden, Netherlands
Contact: PA von dem Borne, MD/PhD       P.A.von_dem_Borne@lumc.nl   
Maastricht Universitair Medisch Centrum + Recruiting
Maastricht, Netherlands
Contact: A.M.P. Demandt       a.demandt@mumc.nl   
Radboud Medisch Universitair Centrum Recruiting
Nijmegen, Netherlands
Contact: W.J.F.M. van der Velden       Walter.vanderVelden@Radboudumc.nl   
Erasmus Medical Center Recruiting
Rotterdam, Netherlands, 3000 CA
Contact: Alexander FA Schauwvlieghe       a.schauwvlieghe@erasmusmc.nl   
Contact: Alexander Schauwvlieghe       a.schauwvlieghe@erasmusmc.nl   
Principal Investigator: Bart JA Rijnders, MD, PhD         
Sub-Investigator: Alexander FA Schauwvlieghe, MD         
Universitair Medisch Centrum Utrecht Recruiting
Utrecht, Netherlands
Contact: A.H.W. Bruns       a.h.w.bruns@umcutrecht.nl   
Sponsors and Collaborators
Erasmus Medical Center
Gilead Sciences
Investigators
Principal Investigator: Bart JA Rijnders, MD/PhD Internal Medicine and Infectious Diseases

Publications:

Responsible Party: Bart Rijnders, MD, PhD, Erasmus Medical Center
ClinicalTrials.gov Identifier: NCT03121235     History of Changes
Other Study ID Numbers: MEC-2016-664
First Posted: April 20, 2017    Key Record Dates
Last Update Posted: March 22, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by Bart Rijnders, Erasmus Medical Center:
aspergillosis
mycosis
neutropenia
hematologic diseases
AsperGenius PCR
Ambisome
Voriconazole

Additional relevant MeSH terms:
Aspergillosis
Invasive Pulmonary Aspergillosis
Pulmonary Aspergillosis
Mycoses
Hyalohyphomycosis
Dermatomycoses
Lung Diseases, Fungal
Skin Diseases, Infectious
Skin Diseases
Invasive Fungal Infections
Lung Diseases
Respiratory Tract Diseases