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AzTrials

Invasive AspergillosisPhase 3IA-DUETNCT04876716

Azole-echinocandin Combination Therapy for Invasive Aspergillosis

A Phase 3 study testing Azole and Anidulafungin in people with Invasive Aspergillosis, run by Erasmus Medical Center at 4 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Invasive Aspergillosis
What is being tested?
Azole and Anidulafungin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
66 participants
Where
4 sitesin 2 countries
Study dates
11 May 2021to 1 May 2024
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 18 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 non-ICU patients or ICU patients without influenza: Meet the mycological criterium (appendix 1) or fulfil inclusion criterium 7
  • 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.
  • Please note that patients with AML receiving chemotherapy or patients with ALL receiving or having received corticosteroid therapy within the last 4 weeks in the context of their pre-phase, induction, consolidation, intensification or interphase treatment as well as patients receiving systemic immunosuppressive therapy for GVHD can be included before the mycological criterium is fulfilled on condition that they fulfill the EORTC/MSG lung CT radiology criteria (halo sign, well-described nodule, cavity as described in appendix 1) at the time of inclusion and as long as the mycological test results are expected to become available within 96 and no later than 7 days after inclusion. If these test results turn out to be negative, the patient will be withdrawn from the study and further treatment is at physician's discretion.
  • Written informed consent by patient or legal representative.

Who cannot join

  • 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)
Show all 10Show fewer
  • 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

Trial locations and contacts

4 sites in 2 countries.

4 sites in 2 countries

Belgium2 sites
  • UZ Ghent

    Ghent

  • UZ Leuven

    Leuven

Other trials in Belgium

Netherlands2 sites
  • Radboud Universitair Medisch Centrum

    Nijmegen

  • Erasmus Medical Center (EMC)

    Rotterdam, South Holland, 3000 CA

Other trials in Netherlands

About this study

Official title: Azole-echinocandin Combination Therapy for Invasive Aspergillosis A Randomized Pragmatic Superiority Trial

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.

Read more

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.

Read the detailed description

Background of the study:

Patients with underlying haematological malignancies or immunocompromised for various other reasons, are prone to fungal infections. Invasive aspergillosis (IA) is a common complication during remission inducing chemotherapy for acute leukemia or other hematological malignancies, as well as those who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT).

For more than 15 years voriconazole, a drug of the triazole class, has been the recommended treatment for this life-threatening infection after a pivotal randomized trial showed an improved survival with voriconazole compared with amphotericin B deoxycholate. However, also with voriconazole the overall 6-week mortality is still unacceptably high at 25-30%.

Therefore, a randomized controlled trial assed the efficacy of voriconazole with or without anidulafungin for the treatment of IA in haematology patients to prove that combination therapy can improve outcome.Among the 277 patients with IA in this study, the 6-week mortality with combination therapy was 30% lower (19.3%) than with monotherapy (27.5%), p=0.087. In a post-hoc analysis of the 222 patients with radiographic abnormalities and a positive galactomannan antigen test, a statistically significant difference in mortality was observed (p=0.037). Though, this study did not result in conclusive evidence in favor of combination therapy, it is a credible study which adds to the already existing in vitro and animal studies in support of echinocandin triazole combination therapy for IA and thus paves the way for a second larger and pragmatic clinical trial. Another important and new consideration about the management of IA is the upcoming of infections with triazole-resistant A. fumigatus. This is increasingly becoming a worldwide problem and leads to longer hospital stay, higher costs and is associated with a very high mortality.

It is very likely that the excessive use of antifungals of the triazole class in agriculture has formed the basis of this problem.

Since 2018 the Dutch Working Party on Antibiotic therapy (SWAB) guideline on the management of invasive fungal infections therefore recommends upfront combination therapy (azole plus echinocandins or liposomal-amfotericine B) until resistance can be excluded as one of the treatment options for IA. Given the evidence in favor of voriconazole-echinocandin combination therapy as well as the increasing incidence of voriconazoleresistant A. fumigatus in Belgium and the Netherlands, a large clinical study on the value of combination therapy is urgently needed.

Objective of the study:

Primary objective

  1. Evaluate if the survival in patients with a triazole susceptible IA can be improved when the initial therapy consists of triazole and echinocandin combination therapy instead of triazole monotherapy.

Secondary objectives

  1. Evaluate if a triazole/echinocandin combination therapy improves the overall quality of life and if it is a cost-effective intervention
  2. Evaluate the outcome of patients in which a triazole-resistant A. fumigatus is detected in relation to the initial antifungal therapy patients had received (i.e. triazole monotherapy or combination therapy).
  3. Evaluate the outcome of patients in which resistance testing is unsuccessful in function of the antifungal therapy they received.
  4. Evaluate if the baseline serum galactomannan value and the serum galactomannan kinetics are predictive of overall 6-week survival.

Study design:

A non-blinded phase 3 randomized pragmatic clinical trial.

Study population:

Immunocompromised patients who fulfill the EORTC/MSG host factor and mycological criteria of invasive aspergillosis ICU patients with influenza who fulfill a definition of IA specific for this population

Intervention:

Treatment with a triazole (voriconazole or isavuconazole or posaconazole) + anidulafungin IV. The triazole is administered for at least 6 weeks while anidulafungin is given for at least 7 and a maximum of 28 days.

Comparator:

Treatment with a triazole (voriconazole or isavuconazole or posaconazole) for at least 6 weeks.

Being tested
Azole, Anidulafungin
Keywords
invasive aspergillosis, azole, echinocandin, combination therapy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AzoleDrug

    Also called Voriconazole, isavuconazole, posaconazole

    Dosing according to the SPC

  • AnidulafunginDrug

    Also called Ecalta

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

Study groups in NCT04876716
Study groupRoleWhat they receive
Azole monotherapyActive comparatorAzole 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.
Receives: Drug: Azole
Azole + AnidulafunginExperimentalAzole + 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.
Receives: Drug: Azole; Drug: Anidulafungin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall survival 42 days

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

    Measured: 42 days after the start of antifungal therapy

Secondary outcomes (11)
  1. Overall aspergillus attributable mortality

    Overall aspergillus attributable mortality 12 weeks after the start of antifungal therapy.

    Measured: 12 weeks after the start of antifungal therapy

  2. Overall survival 12 weeks

    Overall survival 12 weeks after the start of antifungal therapy in the MITT population

    Measured: 12 weeks after the start of antifungal therapy

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

    Overall survival 6 weeks after the start of therapy in the subgroup of patients in the MITT population with a positive serum galactomannan test at baseline.

    Measured: 6 weeks after the start of therapy

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

    Overall survival 6 weeks after the start of therapy in the subgroup of non-ICU patients who fulfill the EORTC/MSG probable or proven definition (MITT population).

    Measured: 6 weeks after the start of therapy

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

    Overall survival 6 weeks after the start of therapy in the subgroup of non-ICU patients with an underlying haematological disease (MITT population)

    Measured: 6 weeks after the start of therapy

  6. Overall survival 6 weeks (subgroup of non-ICU patients without an underlying haematological disease (MITT population))

    Overall survival 6 weeks after the start of therapy in the subgroup of non-ICU patients without an underlying haematological disease (MITT population)

    Measured: 6 weeks after the start of therapy

  7. Overall survival 6 weeks in patients that started with triazole monotherapy and in which triazole resistance is detected during follow-up (MITT population)

    Overall survival 6 weeks after the start of therapy in patients that started with triazole monotherapy and in which triazole resistance is detected during follow-up (MITT population)

    Measured: 6 weeks after the start of therapy

  8. Overall survival 6 weeks after the start of therapy in patients that started with triazole-anidulafungin combination therapy and in which triazole resistance is detected during follow-up (MITT population)

    Overall survival 6 weeks after the start of therapy in patients that started with triazole-anidulafungin combination therapy and in which triazole resistance is detected during follow-up (MITT population)

    Measured: 6 weeks after the start of therapy

  9. Kinetics of serum galactomannan levels

    In the subgroup of patients with a positive serum galactomannan; Kinetics of serum galactomannan levels with combination versus monotherapy

    Measured: 6 weeks after the start of therapy

  10. Mortality of patients in which resistance testing was unsuccessful

    Mortality of patients in which resistance testing was unsuccessful

    Measured: 12 weeks after the start of therapy

  11. Time to hospital discharge

    Time to hospital discharge (in the MITT subgroup of patients admitted to the hospital at baseline)

    Measured: 24 weeks after the start of therapy

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 May 2021
  2. Study start11 May 2021
  3. Primary completion1 May 2024
  4. Study completion1 May 2024

Why it stopped: futility

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
66 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04876716
Sponsor's protocol ID
NL72950.078.20
Other IDs
2020-000627-40
Acronym
IA-DUET
Status last verified
May 2024
First submitted
14 Apr 2021
Last updated
7 May 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • 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.

    PubMed 39378343

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Azole and Anidulafungin in people with Invasive Aspergillosis, run by Erasmus Medical Center at 4 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 7 May 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Belgium, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: futility). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall survival 42 days (time frame: 42 days after the start of antifungal therapy). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04876716, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 May 2024.

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