Azole-echinocandin Combination Therapy for Invasive Aspergillosis

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.