Azole-echinocandin Combination Therapy for Invasive Aspergillosis

NCT04876716 | Terminated Phase 3

• 2 other identifiers: NL72950.078.202020-000627-40
• Study Type: interventional
• Target: 66
• Locations: 2 countries
• Sites: 4

Brief Summary

The goals of this study are 3-fold: First, the main study and the primary endpoint will evaluate if the overall mortality can be decreased with initial azole-echinocandin combination therapy compared with triazole monotherapy in patients with IA and documented voriconazole susceptibility. Second, the study design described will also allow to study several other subpopulations; Indeed, the outcome of the following subgroups will be evaluated as well; a. Patients starting azole monotherapy but who switch to directed therapy when it has become clear that the infection is caused by an azole resistant A. fumigatus. b. patients in which eventually no resistance data become available in relation to the treatment they received. Third, the study will evaluate what the outcome is of patients that turn out to be infected with a triazole resistant A. fumigatus who started with a triazole-echinocandin combination therapy.

Conditions

Invasive Aspergillosis

Keywords

invasive aspergillosis; azole; echinocandin; combination therapy

Outcome Measures

Primary Outcomes (1)

• Overall survival 42 days

  Overall survival 42 days after the start of antifungal therapy in the MITT population

  42 days after the start of antifungal therapy

Secondary Outcomes (11)

• Overall aspergillus attributable mortality

  12 weeks after the start of antifungal therapy

• Overall survival 12 weeks

  12 weeks after the start of antifungal therapy

• Overall survival 6 weeks (subgroup with positive serum galactomannan at baseline)

  6 weeks after the start of therapy

• Overall survival 6 weeks (subgroup non-ICU patients who fulfill the EORTC/MSG probable or proven definition)

  6 weeks after the start of therapy

• Overall survival 6 weeks (subgroup of non-ICU patients with an underlying haematological disease (MITT population))

  6 weeks after the start of therapy

Study Arms (2)

Azole monotherapy

ACTIVE COMPARATOR

Azole monotherapy Voriconazole or isavuconazole or posaconazole will be dosed according to the SPC and according to the route of administration (IV or orally) that is preferred by the treating physician. However, the dose may be changed based on therapeutic drug monitoring levels according to the local standard of care.

Drug: Azole

Azole + Anidulafungin

EXPERIMENTAL

Azole + Anidulafungin Voriconazole or isavuconazole or posaconazole will be dosed according to the SPC and according to the route of administration (IV or orally) that is preferred by the treating physician. However, the dose may be changed based on therapeutic drug monitoring levels according to the local standard of care. Anidulafungin (Ecalta) is available as an intravenous formulation only. It will be used at the licensed dose of a 200mg loading dose on day 1 and 100mg QD thereafter. No dose adjustment is needed in patients with renal or hepatic insufficiency of any grade.

Drug: Azole; Drug: Anidulafungin

Interventions

Azole DRUG

Dosing according to the SPC

Also known as: Voriconazole, isavuconazole, posaconazole

Azole + Anidulafungin; Azole monotherapy

Anidulafungin DRUG

200mg loading dose on day 1 and 100mg QD thereafter

Also known as: Ecalta

Azole + Anidulafungin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years or older
• Have started or will start voriconazole or isavuconazole (or posaconazole if voriconazole or isavuconazole cannot be given as per treating physician's decision) as antifungal therapy on the baseline visit.
• For all patients: presence of one of the EORTC/MSG host factors as defined in appendix 1 or being admitted to the ICU with influenza
• For non-ICU patients or ICU patients without influenza: Meet the EORTC/MSG clinical criterium (appendix 1)
• For ICU patients with influenza we consider an isolated positive sputum culture for Aspergillus spp. insufficient as amycological criterium. Therefore, in these patients only one of the following mycological criteria are acceptable; Serum galactomannan ≥0.5, BAL galactomannan ≥1.0 or Aspergillus spp. cultured in BAL fluid.
• Written informed consent by patient or legal representative.

You may not qualify if:

• Known history of allergy, hypersensitivity or serious reaction to azole or echinocandin antifungals;
• Patients with chronic invasive aspergillosis or a chronic non-invasive aspergillus infection (e.g. aspergilloma) defined as the clinical or radiological sign of infection being present for \>28 days.
• Receipt of itraconazole, voriconazole, posaconazole or isavuconazole as prophylaxis for at least 7 days in the 14 days preceding the date of the first radiological signs of the Aspergillus infection. Patients in which the most recent serum level of the triazole given as prophylaxis was subtherapeutic can be included (\*).
• Receipt of echinocandin prophylaxis for \>96 hours in the preceding 7 days
• Receipt of systemic antifungal treatment with an echinocandin or an azole for the current episode of invasive aspergillosis for a duration of \> 96 hours.
• For patients in the Netherlands only: Diagnostic testing to exclude azole resistance will not be possible (sputum cultures are negative and BAL sampling will not be performed)
• ICU patients only: Patients with a sequential organ failure assessment (SOFA) score \>11 at the time of screening for the study are excluded. If randomization is done \>24 hours after screening the calculation should be repeated before the patient can be randomized (appendix 3)
• ICU patients only: Patients in which weaning from the ventilator or ECMO system is deemed unlikely due to irreversible lung damage
• Patients with any condition which, in the opinion of the investigator, could affect patient safety, preclude evaluation of response (e.g. because survival beyond 6 weeks is unlikely due to the underlying disease status)
• Patient previously included in this study

Sponsors & Collaborators

• Erasmus Medical Center: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Stichting Hemato-Oncologie voor Volwassenen Nederland: collaborator

Study Sites (4)

UZ Ghent

Ghent, Belgium

Location

UZ Leuven

Leuven, Belgium

Location

Erasmus Medical Center (EMC)

Rotterdam, South Holland, 3000 CA, Netherlands

Location

Radboud Universitair Medisch Centrum

Nijmegen, Netherlands

Location

Related Publications (1)

• Lamberink H, Huygens S, Aerts R, Lagrou K, van Leeuwen-Segarceanu E, Lodewyck T, Nieuwenhuizen L, Corsten MF, Moors I, Servais S, De Greef J, Hites M, Demandt A, Schauwvlieghe A, Maertens J, Rijnders B. Superiority Trials in Invasive Aspergillosis: A Harsh Reality Check With the IA-DUET (HOVON502) Trial. Clin Infect Dis. 2025 Feb 24;80(2):367-370. doi: 10.1093/cid/ciae501.

  PMID: 39378343 DERIVED

MeSH Terms

Interventions

Azoles; Voriconazole; isavuconazole; posaconazole; Anidulafungin

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Triazoles; Echinocandins; Peptides, Cyclic; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Bart Rijnders, MD, PhD

  Erasmus Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 14, 2021
• First Posted: May 6, 2021
• Study Start: May 11, 2021
• Primary Completion: May 1, 2024
• Study Completion: May 1, 2024
• Last Updated: May 7, 2024

Record last verified: 2024-05

Locations

NL (2); BE (2)