PCR Based Detection of Azole Resistance in A. Fumigatus to Improve Patient Outcome. (AzorMan)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03121235|
Recruitment Status : Recruiting
First Posted : April 20, 2017
Last Update Posted : March 22, 2018
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.
- 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.
- 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|
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:
- Ambisome 3mg/kg IV
- 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
- 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.
- 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|
|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|
Diagnostic Test: PCR based detection of azole resistance in A. fumigatus
- 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.
- 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%.
- 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.
- 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
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03121235
|Contact: Alexander Schauwvlieghe, MDfirstname.lastname@example.org|
|Contact: Bart Rijnders, MD/PhDemail@example.com|
|Academisch Medisch Centrum||Recruiting|
|Contact: B.J. Biemond, MD/PhD firstname.lastname@example.org|
|VU Medisch Centrum||Recruiting|
|Contact: J Janssen email@example.com|
|Universitair Medisch Centrum Groningen||Recruiting|
|Contact: L.F.R. Span, MD/PhD firstname.lastname@example.org|
|Leids Universitair Medisch Centrum||Recruiting|
|Contact: PA von dem Borne, MD/PhD P.A.von_dem_Borne@lumc.nl|
|Maastricht Universitair Medisch Centrum +||Recruiting|
|Contact: A.M.P. Demandt email@example.com|
|Radboud Medisch Universitair Centrum||Recruiting|
|Contact: W.J.F.M. van der Velden Walter.vanderVelden@Radboudumc.nl|
|Erasmus Medical Center||Recruiting|
|Rotterdam, Netherlands, 3000 CA|
|Contact: Alexander FA Schauwvlieghe firstname.lastname@example.org|
|Contact: Alexander Schauwvlieghe email@example.com|
|Principal Investigator: Bart JA Rijnders, MD, PhD|
|Sub-Investigator: Alexander FA Schauwvlieghe, MD|
|Universitair Medisch Centrum Utrecht||Recruiting|
|Contact: A.H.W. Bruns firstname.lastname@example.org|
|Principal Investigator:||Bart JA Rijnders, MD/PhD||Internal Medicine and Infectious Diseases|