1210A Phase 3, Randomized, Double-Blind, Non-inferiority Trial to Evaluate Efficacy and Safety of Isavuconazole versus Voriconazole in Patients with Invasive Mold Disease (SECURE): Outcomes in Neutropenic Patients
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SUBMITTER: Patterson T
PROVIDER: S-EPMC5782025 | biostudies-literature | 2014 Dec
REPOSITORIES: biostudies-literature
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| S-EPMC5781392 | biostudies-literature
Project description:This pooled analysis evaluated the relationship of isavuconazole and voriconazole MICs of Aspergillus pathogens at baseline with all-cause mortality and clinical outcomes following treatment with either drug in the SECURE and VITAL trials. Isavuconazole and voriconazole may have had reduced efficacy against pathogens with drug MICs of ≥16 µg/ml, but there was no relationship with clinical outcomes in cases where the MIC was <16 µg/ml for either drug.
| S-EPMC6325202 | biostudies-literature
Project description:BackgroundVoriconazole is well established as standard treatment for invasive aspergillosis (IA). In 2017, isavuconazole, a new antifungal from the azole class, with a broader pathogen spectrum, was introduced in Sweden. A model has therefore been developed to compare the cost-effectiveness of isavuconazole and voriconazole in the treatment of possible IA in adults in Sweden.MethodsThe cost-effectiveness of isavuconazole versus voriconazole was evaluated using a decision-tree model. Patients with possible IA entered the model, with 6% assumed to actually have mucormycosis. It was also assumed that pathogen information would become available during the course of treatment for only 50% of patients, with differential diagnosis unavailable for the remainder. Patients who were considered unresponsive to first-line treatment were switched to second-line treatment with liposomal amphotericin-B. Data and clinical definitions included in the model were taken from the published randomised clinical trial comparing isavuconazole with voriconazole for the treatment of IA and other filamentous fungi (SECURE) and the single-arm, open-label trial and case-control analysis of isavuconazole for the treatment of mucormycosis (VITAL). A probabilistic sensitivity analysis was used to estimate the combined parameter uncertainty, and a deterministic sensitivity analysis and a scenario analysis were performed to test the robustness of the model assumptions. The model followed a Swedish healthcare payer perspective, therefore only considering direct medical costs.ResultsThe base case analysis showed that isavuconazole resulted in an incremental cost-effectiveness ratio (ICER) of 174,890 Swedish krona (SEK) per additional quality adjusted life-year (QALY) gained. This was mainly due to the efficacy of isavuconazole against IA and mucormycosis, as opposed to voriconazole, which is only effective against IA. Sensitivity and scenario analyses of the data showed that the average ICER consistently fell below the willingness to pay (WTP) threshold of 1,000,000 SEK. The probability of isavuconazole being cost-effective at a WTP of 170,000 SEK per QALY gained was 50% and at a WTP of 500,000 SEK per QALY gained was 100%.ConclusionsThis model suggests that the treatment of possible IA with isavuconazole is cost-effective compared with treatment with voriconazole from a Swedish healthcare payer perspective.
| S-EPMC6371439 | biostudies-literature
Project description:IntroductionInvasive aspergillosis (IA) is associated with a significant clinical and economic burden. The phase III SECURE trial demonstrated non-inferiority in clinical efficacy between isavuconazole and voriconazole. No studies have evaluated the cost-effectiveness of isavuconazole compared to voriconazole. The objective of this study was to evaluate the costs and cost-effectiveness of isavuconazole vs. voriconazole for the first-line treatment of IA from the US hospital perspective.MethodsAn economic model was developed to assess the costs and cost-effectiveness of isavuconazole vs. voriconazole in hospitalized patients with IA. The time horizon was the duration of hospitalization. Length of stay for the initial admission, incidence of readmission, clinical response, overall survival rates, and experience of adverse events (AEs) came from the SECURE trial. Unit costs were from the literature. Total costs per patient were estimated, composed of drug costs, costs of AEs, and costs of hospitalizations. Incremental costs per death avoided and per additional clinical responders were reported. Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted.ResultsBase case analysis showed that isavuconazole was associated with a $7418 lower total cost per patient than voriconazole. In both incremental costs per death avoided and incremental costs per additional clinical responder, isavuconazole dominated voriconazole. Results were robust in sensitivity analysis. Isavuconazole was cost saving and dominant vs. voriconazole in most DSA. In PSA, isavuconazole was cost saving in 80.2% of the simulations and cost-effective in 82.0% of the simulations at the $50,000 willingness to pay threshold per additional outcome.ConclusionIsavuconazole is a cost-effective option for the treatment of IA among hospitalized patients.FundingAstellas Pharma Global Development, Inc.
| S-EPMC5216061 | biostudies-literature
Project description:Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at high risk for invasive mold infections (IMI). The goal of the study is to describe the incidence and outcome of IMI in patients after allo-HSCT in a large cohort of patients receiving anti-mold prophylaxis. We conducted a retrospective review of 988 consecutive adults who underwent allo-HSCT in our center from 2008 through 2014. Standard prophylaxis consisted of micafungin 150 mg IV daily from admission to day +7 ± 3 followed by voriconazole until day +75 to +100. Cases meeting criteria for proven or probable IMI according to EORTC-MSG criteria were included. Median age at HSCT was 54 years. The most common diagnoses were acute myeloid leukemia (n = 351, 36%) and lymphoid malignancies (n = 248, 25%). Matched related or unrelated donors (URD) were used in 686 (69%) patients, mismatched URD in 142 (14%) and cord blood units in 154 (16%). Twenty-one patients were diagnosed with IMI after allo-HSCT, 19 probable and 2 proven, and one patient was diagnosed postmortem. Microbiological diagnosis was established in 9 cases, 5 of them being Aspergillus. One-year cumulative incidence (CI) of IMI was 1.6% (95% CI 0.9-2.5) while 12-week overall survival after IMI was 39% (95% CI 24-65) Analyzed by disease, there was a trend for a higher 1-year CI of IMI in patients with ALL (5% [95% CI 1.6-11.4]) when compared with AML (1.4%), MDS (1.5%) and lymphoma (1.2%), P = .06. The 1-year CI of IMI after transplantation is low in patients receiving anti-mold prophylaxis with micafungin bridged to voriconazole, although these infections are associated with a higher risk of mortality.
| S-EPMC6913888 | biostudies-literature
Project description:ObjectivesThis analysis evaluated the variability of isavuconazole plasma concentrations between subjects and between sampling times, and assessed their relationship to outcomes for subjects with invasive fungal disease (IFD) in the SECURE trial.MethodsIsavuconazole-treated subjects received 372 mg of isavuconazonium sulphate (corresponding to 200 mg of isavuconazole) three times daily for 2 days, then once daily. Plasma samples were collected after day 4 and analysis sets were constructed as follows: analysis set 1 included all samples from subjects with proven/probable/possible IFD who received ≥1 dose of isavuconazole; analysis set 2 included samples from subjects in analysis set 1 who had provided >1 sample; and analysis set 3 included samples from subjects in analysis set 1 with proven/probable invasive aspergillosis. Assessments included overall distributions of plasma concentrations and variability between samples (analysis sets 1 and 2) as well as relationships to outcomes [all-cause mortality (day 42), overall response (end of treatment) and treatment-emergent adverse events; analysis sets 1 and 3].ResultsAnalysis sets 1, 2 and 3 included samples from 160, 97 and 98 subjects, respectively. Trough concentrations for each were distributed similarly [mean (SD): 3406.6 (1511.5), 3495.6 (1503.3) and 3368.1 (1523.2) ng/mL, respectively]. The mean coefficient of variation between samples in analysis set 2 was 23.2%; differences between concentrations in first samples and subsequent samples were <2-fold for 85/97 subjects. In quartiles of subject data, no concentration-dependent relationships were observed for efficacy or safety.ConclusionsPlasma concentrations of isavuconazole were reasonably consistent between subjects and sampling times, and were not associated with differences in outcomes.
| S-EPMC6376854 | biostudies-literature
Project description:Background.The ability to make early therapeutic decisions when treating invasive aspergillosis using changes in biomarkers as a surrogate for therapeutic response could significantly improve patient outcome.Methods.Cox proportional hazards model and logistic regression were used to correlate early changes in galactomannan index (GMI) to mortality and overall response, respectively, from patients with positive baseline GMI (≥0.5) and serial GMI during treatment from a phase 3 clinical trial for the treatment of invasive mold disease. Pharmacokinetic/pharmacodynamic (PK/PD) analysis in patients with isavuconazole plasma concentrations was conducted to establish the exposure necessary for GMI negativity at the end of therapy.Results.The study included 158 patients overall and 78 isavuconazole patients in the PK/PD modeling. By day 7, GMI increases of >0.25 units from baseline (3/130 survivors; 9/28 who died) significantly increased the risk of death compared to those with no increase or increases <0.25 (hazard ratio, 9.766; 95% confidence interval [CI], 4.356-21.9; P < .0001). For each unit decrease by day 7 from baseline, the odds of successful therapy doubled (odds ratio, 2.154; 95% CI, 1.173-3.955). An area under the concentration-versus-time curve over half-maximal effective concentration (AUC:EC50) of 108.6 is estimated to result in a negative GMI at the end of isavuconazole therapy.Conclusions.Early trends in GMI are highly predictive of patient outcome. GMI increases by day 7 could be considered in context of clinical signs to trigger changes in treatment, once validated. Our data suggest that this improves survival by 10-fold and positive outcome by 3-fold. These data have important implications for individualized therapy for patients and clinical trials.Clinical trials registration.NCT00412893.
| S-EPMC5434340 | biostudies-literature
Project description:Isavuconazole is a triazole with broad-spectrum antifungal activity. In this post-hoc analysis of two prospective clinical trials (VITAL and SECURE), the safety and efficacy of isavuconazole in patients aged ≥ 65 years with invasive fungal diseases were evaluated. Patients were divided into two subgroups (≥ 65 and < 65 years). Adverse events (AEs); all-cause mortality; and overall, clinical, mycological, and radiological response were assessed. A total of 155 patients ≥ 65 years were enrolled in both trials. Most patients reported AEs. In the isavuconazole arm of both studies, serious AEs (SAEs) were greater in patients ≥ 65 versus < 65 years: 76.7% versus 56.9% (VITAL); 61.9% versus 49.0% (SECURE). In SECURE, SAE rates were similar in the ≥ 65 years subgroup of both treatment arms (61.9% vs 58.1%), while in the < 65 years subgroup the SAE rate was lower in the isavuconazole arm (49.0% vs 57.4%). In VITAL, all-cause mortality through day 42 (30.0% vs 13.8%) was higher, and overall response at end of treatment (27.6% vs 46.8%) was lower in patients ≥ 65 years versus < 65 years. In SECURE, all-cause mortality was similar between both subgroups, and isavuconazole (20.6% vs 17.9%) and voriconazole (22.6% vs 19.4%) treatment arms. The overall response was lower in the ≥ 65 years than the < 65 years subgroup in the isavuconazole (23.7% vs 39.0%) and voriconazole (32.0% vs 37.5%) arms. The safety and efficacy of isavuconazole were better in patients < 65 versus ≥ 65 years, and the safety profile was more favorable than that of voriconazole in both subgroups.Clinicaltrials.gov identifier NCT00634049 and NCT00412893.
| S-EPMC10127179 | biostudies-literature
Project description:BackgroundIsavuconazole has been used to treat invasive fungal infections, however, it is unclear whether the efficacy of isavuconazole is superior to that of voriconazole. The purpose of this meta-analysis was to assess the efficacy and safety of isavuconazole compared to voriconazole in treating invasive fungal infections.MethodsElectronic databases, including PubMed, EMBASE, Cochrane Library, and Web of Science, were searched to identify relevant studies. Studies evaluating the effect of isavuconazole in the treatment of patients with invasive fungal infections were included. Pooled rates of overall response, all-cause mortality, drug-related adverse events (AEs), and discontinuation due to drug-related AEs were calculated.ResultsSeven studies involving 890 patients were included. Meta-analysis showed that there was no significant difference between isavuconazole and voriconazole in overall response (risk ratio [RR]: 1.02, 95% confidence interval [CI]: 0.83 to 1.25, p = 0.86) and all-cause mortality (RR: 0.95, 95% CI: 0.78 to 1.16, p = 0.61). However, isavuconazole had a significantly lower incidence of drug-related AEs (RR: 0.70, 95% CI: 0.61 to 0.81, p < 0.001) and discontinuation due to drug-related AEs (RR: 0.56, 95% CI: 0.39 to 0.82, p = 0.003) compared with voriconazole. Trial sequential analysis (TSA) confirmed that the difference between isavuconazole and voriconazole in discontinuation due to drug-related AEs need further valiadation, but the results of other outcomes were conclusive. < 0.001) and discontinuation due to drug-related AEs (RR: 0.56, 95% CI: 0.39 to 0.82, p = 0.003) compared with voriconazole. Trial sequential analysis (TSA) confirmed that the difference between isavuconazole and voriconazole in discontinuation due to drug-related AEs needs further validation, but the results of other outcomes were conclusive.ConclusionsOur findings support the use of isavuconazole as the primary therapy for invasive fungal infections. More research is needed to compare the discontinuation rates of isavuconazole and voriconazole.
| S-EPMC11834645 | biostudies-literature
Project description:Triazoles are first-line agents for treating aspergillosis. The prevalence of azole resistance in Aspergillus fumigatus is increasing, and cross-resistance is a growing concern. In this study, the susceptibilities of 40 A. fumigatus clinical isolates were tested by using the CLSI method with amphotericin B, itraconazole, voriconazole, posaconazole, and the new triazole isavuconazole. Isavuconazole MICs were higher in strains with reduced susceptibilities to other triazoles, mirroring changes in voriconazole susceptibility. Isavuconazole MICs differed depending on the Cyp51A substitution.
| S-EPMC3811286 | biostudies-literature