Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: phase 3, randomised, controlled, non-inferiority trial Mihaela Sava JA Maertens et al. Jounal Club The Lancet Klinik für Infektiologie und Spitalhygiene February 2021 15.02.2021 Volume 397 Issue 10273 Pages 499-509 DOI: 10.1016/S0140-6736(21)00219-1 Background • Invasive Aspergillosis is a severe disease, often fatal in immunocompromised patients • Voriconazole is the recommended primary treatment invasive aspergillosis • Concerns about short and long term adverse events, pharmacokinetic variability, and interactions with other medication • Posaconazole, a broad-spectrum triazole, is mostly used for prevention of invasive fungal infections in haematological patients, or as salvage therapy • Activity against Aspergillus spp. other than A. fumigatus, and importantly, against Zygomycetes 2 Methods • randomised, double-blind, double-dummy, controlled trial of posaconazole vs. voriconazole for the primary treatment of invasive aspergillosis • 91 study sites : 26 countries : 4 continents • Participants Inclusion Criteria : Exclusion Criteria : • 13 years or older • chronic aspergillosis (>1-month duration) • weight >40 kg and ≤150 kg • relapsed or recurrent aspergillosis • Neutropenia of any duration • invasive aspergillosis not responding to past • proven, probable, or possible invasive aspergillosis antifungal therapy (2008 EORTC/MSG definition) • mixed invasive mold fungal infection including • Acute invasive aspergillosis (clinical syndrome start Zygomycetes <30d) • clinically significant liver dysfunction • severe renal insufficiency (GFR <20 mL/min)/haemodialysis • receipt of systemic mould-active antifungal therapy for 96 h or more before randomisation • Randomisation POS : VOR 1 : 1 • By risk status (high risk vs. Non high risk) • High risk : allo HSCT, relapsed leukaemia undergoing salvage chemotherapy and liver tranplanted patients 3 Methods • Treatment : *50% reduction in voriconazole dosing was made for hepatic insufficiency • Study visits: 4 Outcomes • Primary Outcome • all-cause mortality up until study day 42 (6 weeks) in the ITT population • Secondary Outcomes • all-cause mortality up until day 84 (12 weeks) in the ITT population • all-cause mortality up until day 42 and day 84 in the FAS population • global clinical response for pos vs. vor at weeks 6 and 12 in the FAS population • time to death (all causes) in the FAS population • death from IA up until days 42 and 84 in the FAS population • Treatment safety in the ITT population ITT=intention-to-treat. FAS=full analysis set (ITT with proven or probable invasive aspergillosis) 5 Statistical • Sample size calculation: 600 paticipants non-inferiority of POS vs. VOR • 10% margin and assuming a mortality of 23% up until day 42 in the ITT population • Hypothesis: • all-cause mortality up until day 42 in the POS group was non-inferior to that in the VOR group in the ITT population • non-inferiority of posaconazole was declared if the upper limit of the CI was less than 10% 6 Results Oct 2013 - Sept 2019 575 participants = ITT population 281 participants completed study treatment 7 Baseline characteristics (with proven or probable invasive aspergillosis) 8 Outcomes: Efficacy 9 All-cause mortality up until day 42 10 Treatment-related adverse events Most frequent treatment- related AE: Posaconazol Voriconazol • Transaminases (6 - • Eyes disorders (10%) 8%) • Blurred vision (3%) • Hypokalaemia (4%) • Transaminases • Nausea (4%) (6%), GGT (4%), AP • Vomiting (3%) (6%) • Hallucination (4%) • Nausea (4%) 11 Conclusions/limitations • posaconazole was non-inferior to voriconazole for the treatment of IA • patients receiving posaconazole had significantly fewer treatment- related adverse events • No pharmacokinetic data (will be reported in another publication) • No dose adjustments for voriconazole • Limited data on longer treatment periods/outpatients 12.