A Phase III, Randomized, Double-Blind Trial to Evaluate Efficacy and Safety of Isavuconazole Versus Voriconazole in Patients with Invasive Mold Disease (SECURE): Outcomes in Hematopoietic Stem Cell Transplant Patients with Invasive Aspergillosis

[Graphic][1] Background : Isavuconazole (ISA) is a novel, water-soluble, triazole agent, with broad-spectrum antifungal activity . The SECURE trial ([NCT00412893][2]), a Phase III, randomized, double-blind study, investigated the efficacy and safety of ISA vs. voriconazole (VRC) in patients with invasive fungal disease caused by Aspergillus spp. or other filamentous fungi. Patients undergoing hematopoietic stem cell transplant (HSCT) are at particular risk of developing invasive aspergillosis (IA), which is associated with a high mortality in this population. The outcomes in HSCT patients with IA enrolled in SECURE are presented here. Methods : Patients with proven/probable/possible invasive mold disease were randomized 1:1 to receive ISA or VRC. Patients in the ISA arm received ISA 200mg IV TID for 2 days, followed by 200mg QD (IV or PO) thereafter. Patients in the VRC arm received VRC6mg/kg IV BID on Day 1; 4mg/kg IV BID on Day 2; then either 4mg/kg IV BID or 200mg PO BID. Antifungal therapy was given up to 84 days. The primary endpoint was all-cause mortality on Day 42. Overall treatment success (clinical, mycological, and radiological) at end-of-treatment (EOT), safety, and tolerability were also analyzed in HSCT patients with proven or probable IA who received at least one dose of the study drug (mycological intent-to-treat population [myITT]). All outcomes were assessed by an independent data review committee. Results : Of the 527 patients randomized for the SECURE trial, 67 patients with proven or probable IA had a history of HSCT (ISA: n=38; VRC: n=29). Fifty four (80.6%) patients had received an allogeneic stem cell transplant, 32 (47.8%) were neutropenic, and 26 (38.8%) had graft-vs-host disease (GVHD). Mortality was higher in patients with neutropenia (37.5%) compared with those without neutropenia (14.3%; adjusted difference: 17.8; 95% confidence interval: –0.09, 35.6); and, was higher in patients without GVHD (32.6%) compared with those with GVHD (15.4%; adjusted difference; –13.2; 95% confidence interval: –35.3, 8.9). The highest mortality was observed in HSCT patients with neutropenia (Table 1). Treatment-emergent adverse events (TEAEs) were reported in 94.7% (ISA) and 100% (VRC) of patients, and drug-related TEAEs in 36.8% (ISA) and 62.1% (VRC) of patients (P=0.051). The percentages of TEAEs in most System Organ Classes were lower in the ISA arm, although the difference between arms only reached statistical significance for cardiac disorders (ISA 15.8% vs. VRC 41.4%; difference –0.256, asymptotic 95% confidence interval: –0.47, –0.04; P=0.027). Conclusion : In this large, prospective, randomized study, IA was shown to adversely affect the outcomes of HSCT patients. Patients with neutropenia at the time of diagnosis had the highest rate of mortality. ISA was demonstrated to be efficacious for the primary treatment of IA in HSCT patients. The analyses of adverse events suggest a safety advantage of ISA compared with VRC. | Outcome | ISA arm | VRC arm | Adjusted difference % (95% CI) | Total (ISA+VRC) | | ------------------------------- | ---------------- | ---------------- | ------------------------------ | ----------------------- | ------------------- | | | N | Event (%) | N | Event (%) | | Event/N (%) | | All-cause mortality at Day 42 a | | | | | | | | All HSCT patients | 38 | 8 (21.1) | 29 | 9 (31.0) | –7.5 (–25.8, 10.8) | 17/67 (25.4) | | Allogeneic HSCT | 32 | 7 (21.9) | 22 | 6 (27.3) | –2.1 (–22.8, 18.6) | 13/54 (24.1) | | Non-allogeneic HSCT | 6 | 1 (16.7) | 7 | 3 (42.9) | –38.5 (–72.2, –4.7) | 4/13 (30.8) | | With neutropenia | 21 | 6 (28.6) | 11 | 6 (54.5) | –26.0 (–69.6, 17.6) | 12/32 (37.5) | | With GVHD | 13 | 2 (15.4) | 13 | 2 (15.4) | 0.4 (–23.4, 24.2) | 4/26 (15.4) | | Without GVHD | 26 | 7 (26.9) | 17 | 7 (41.2) | –15.9 (–43.4, 11.5) | 14/43 (32.6) | | Overall success at EOTb | 38 | 10 (26.3) | 29 | 9 (31.0) | 4.5 (–13.5, 22.5) | 19/67 (28.4) | | Clinical response at EOT | 34 | 19 (55.9) | 28 | 13 (46.4) | –5.8 (–27.1, 15.5) | 32/62 (51.6) | | Mycological response at EOT | 38 | 11 (28.9) | 29 | 9 (31.0) | 2.5 (–15.5, 20.4) | 20/67 (29.9) | | Radiological response at EOT | 38 | 8 (21.1) | 29 | 8 (27.6) | 8.0 (–9.4, 25.5) | 16/67 (23.9) | Abstract 1133. Table 1. Efficacy outcomes (myITT population) a Adjusted treatment difference calculated for ISA−VRC b Adjusted treatment difference calculated for VRC−ISA Disclosures Heinz: Astellas, Gilead Science, Janssen-Cilag, MSD Sharp & Dohme/Merck, Pfizer : Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Isavuconazole for the treatment of aspergillosis (Marketing Authorization Application has been submitted by Astellas (FDA ) and Basilea (EMA)). Cornely: Astellas: Consultancy, Honoraria, Research Funding, Speakers Bureau. Franks: Astellas: Employment. Shi: Astellas: Employment. Azie: Astellas: Employment. Maertens: Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. [1]: /embed/inline-graphic-2.gif [2]: /lookup/external-ref? link_type=CLINTRIALGOV&access_num=NCT00412893&atom=%2Fbloodjournal%2F124%2F21%2F1133.atom