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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.

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.

Inclusion Criteria:

1. 18 years or older
2. 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.
3. 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
4. For non-ICU patients or ICU patients without influenza: Meet the EORTC/MSG clinical criterium (appendix 1)
5. For non-ICU patients or ICU patients without influenza: Meet the mycological criterium (appendix 1) or fulfil inclusion criterium 7
6. 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.
7. 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.
8. Written informed consent by patient or legal representative.

Exclusion Criteria:

1. Known history of allergy, hypersensitivity or serious reaction to azole or echinocandin antifungals;
2. 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.
3. 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 (*).
4. Receipt of echinocandin prophylaxis for >96 hours in the preceding 7 days
5. Receipt of systemic antifungal treatment with an echinocandin or an azole for the current episode of invasive aspergillosis for a duration of > 96 hours.
6. 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)
7. 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)
8. ICU patients only: Patients in which weaning from the ventilator or ECMO system is deemed unlikely due to irreversible lung damage
9. 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)
10. Patient previously included in this study