Isavuconazole treatment for rare fungal diseases and for invasive aspergillosis in patients with renal impairment: Challenges and lessons of the VITAL trial

Abstract

Invasive fungal disease (IFD) confers a substantial risk for morbidity and mortality to immunocompromised patients. Invasive aspergillosis (IA) is the most common IFD caused by moulds but the prevalence of other rare mould diseases, such as mucormycosis, hyalohyphomycosis and phaeohyphomycosis, may be increasing. Treatments are available for IA, but evidence to support efficacy and safety of antifungal agents for rare IFDs, or for IFDs in special patient populations, is limited or lacking. The VITAL trial was conducted to assess the efficacy and safety of isavuconazole for the treatment of patients with IA and renal impairment, or with IFDs caused by rare moulds, yeasts or dimorphic fungi. These patients stand to benefit most from a new treatment option but are unlikely to be included in a randomised, controlled trial. In this article, we review the challenges faced in the design and conduct of the VITAL trial. We also review the findings of VITAL, which included evidence of the efficacy and safety of isavuconazole. Finally, we consider the importance of trials such as VITAL to inform therapeutic decision making for clinicians faced with the challenge of treating patients with rare IFDs and as one paradigm of how to determine efficacy and safety of new drugs for rare and resistant infections without a suitable comparator.

Isavuconazole for treatment of invasive fungal diseases caused by more than one fungal species

“…The VITAL trial was a Phase III, international, single‐arm, multicentre, open‐label study to evaluate the efficacy and safety of isavuconazole in the treatment of invasive aspergillosis in patients with renal impairment and of rare fungal infections (ClinicalTrials.gov identifier: NCT00634049). Additional details regarding methods are presented in an accompanying article and details of methods and other results from VITAL have been reported elsewhere . The subset of patients with IFD caused by multiple fungal species is presented here.…”

“…The primary endpoint was the overall response to treatment at Day 42 as assessed by the DRC. Overall success was defined as complete or partial responses; treatment failure was defined as stable or progressive disease, following prespecified criteria . Briefly, success required resolution (complete or partial) of clinical symptoms and physical findings associated with IFD; resolution (complete) or improvement (partial) of radiological abnormalities (where relevant), and presumed or documented eradication.…”

EQUAL Aspergillosis Score 2018: An ECMM score derived from current guidelines to measure QUALity of the clinical management of invasive pulmonary aspergillosis

“…For targeted first line treatment of invasive pulmonary aspergillosis isavuconazole or voriconazole with therapeutic drug monitoring (TDM) is recommended (five points) . Voriconazole target plasma trough range is 1‐5.5 mg/L .…”

Treatment outcomes in patients with proven/probable vs possible invasive mould disease in a phase III trial comparing isavuconazole vs voriconazole

“…Isavuconazole also has demonstrated efficacy in the treatment of mucormycosis and evidence of activity against a variety of other rare fungal spp. and mixed fungal infections …”

“…and mixed fungal infections. [18][19][20][21] In 2008, the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) revised its 2002 criteria for the classification of cases of IMD into proven, probable and possible cases based on a combination of host, clinico-radiological, and mycological factors 22 to harmonise clinical and epidemiological research. For the EORTC/MSG mycological criteria, a "threshold recommended by the manufacturer" was applied for galactomannan (GM) and other biological tests.…”