A Phase 2, Randomized, Double-Blind, Multicenter Trial To Evaluate the Safety and Efficacy of Three Dosing Regimens of Isavuconazole Compared with Fluconazole in Patients with Uncomplicated Esophageal Candidiasis

Abstract

Esophageal candidiasis is a frequent cause of morbidity in immunocompromised patients. Isavuconazole is a novel, broad-spectrum antifungal developed for the treatment of opportunistic fungal infections. This phase 2 trial compared the efficacy and safety of three oral dosing regimens of isavuconazole with an oral fluconazole regimen in the primary treatment of uncomplicated esophageal candidiasis. The isavuconazole regimens were as follows: 200 mg on day 1 and then 50 mg once daily (arm A), 400 mg on day 1 and then 400 mg once-weekly (arm B), and 400 mg on day 1 and then 100 mg once daily (arm C). Patients in arm D received fluconazole at 200 mg on day 1 and then 100 mg once daily. The minimum treatment duration was 14 days. The primary endpoint was the rate of endoscopically confirmed clinical response at end of therapy. Safety and tolerability were also assessed. Efficacy was evaluated in 153 of 160 enrolled patients. Overall, 146 (95.4%) achieved endoscopically confirmed clinical success. Each of the isavuconazole regimens was shown to be not inferior to fluconazole, i.e., arm A versus D, ؊0.5% (95% confidence interval [CI] ؊10.0 to 9.4), arm B versus D, 3.5% (95% CI, ؊5.6 to 12.7), and arm C versus D, ؊0.2% (95% CI, ؊9.8 to 9.4). The frequency of adverse events was similar in arm A (n ‫؍‬ 22; 55%), arm B (n ‫؍‬ 18; 45%), and arm D (n ‫؍‬ 22; 58%), but higher in arm C (n ‫؍‬ 29; 71%). In summary, efficacy and safety of once-daily and once-weekly isavuconazole were comparable with once-daily fluconazole in the primary treatment of uncomplicated esophageal candidiasis. E sophageal candidiasis is an opportunistic fungal infection that commonly occurs in immunocompromised patients. Individuals with HIV infection are particularly at risk (1), even in the era of antiretroviral therapy (2). Infections are predominantly caused by Candida albicans; however, infections with other non-albicans Candida species such as C. glabrata, C. krusei, and C. parapsilosis have also been reported (3-6). Although seldom fatal, esophageal candidiasis is associated with significant morbidity, causing dysphagia, odynophagia, and retrosternal pain (1).Current guidelines recommend fluconazole, an echinocandin, or amphotericin B for the primary treatment of esophageal candidiasis (7). Recommended alternatives include itraconazole, posaconazole, and voriconazole (7). Candida albicans is usually susceptible to these commonly used antifungal agents; however, extended periods of antifungal treatment may lead to the development of microbiological resistance (7). Resistance to currently approved triazole medications, particularly fluconazole, is now well described in patients with HIV (8-12). Resistance to the echinocandins, such as caspofungin, is also starting to emerge (13). In addition, prolonged treatment may give rise to unwanted safety and tolerability effects. Thus, there is a therapeutic need for more, well-tolerated antifungal agents that are effective against emerging resistant Candida spp.Isavuconazole is a novel, broad-spectrum, tri...

Isavuconazole: Pharmacology, Pharmacodynamics, and Current Clinical Experience with a New Triazole Antifungal Agent

“…These results agree with those of a previous study investigating the pharmacodynamics of posaconazole in the treatment of invasive pulmonary aspergillosis. 37 Among the same collection of A. fumigatus isolates, the posaconazole fAUC:MIC required for stasis was 0.7 and 1.2 for wild-type and mutant Erg11p isolates, respectively.…”

“…Nine clinical isolates of A. fumigatus , including six with known Erg11p mutations associated with decreased triazole susceptibility, and one laboratory isolate with a mutation in the gene coding for the target of the echinocandins ( Fks1 ) were studied. A model previously shown to produce invasive pulmonary aspergillosis and mortality in 90–100% of untreated control mice was used by the investigators . Suspensions of Aspergillus conidia were instilled into the nares of sedated mice positioned to facilitate aspiration into the lungs.…”

“…A model previously shown to produce invasive pulmonary aspergillosis and mortality in 90-100% of untreated control mice was used by the investigators. 37 Suspensions of Aspergillus conidia were instilled into the nares of sedated mice positioned to facilitate aspiration into the lungs. Initiation of antifungal therapy followed 2 hours later.…”

Pharmacokinetic Evaluation of CYP3A4‐Mediated Drug‐Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults

“…In the rifampin study, an isavuconazole 100 mg once daily (QD) maintenance dose was used based on data obtained in an early phase 2 trial. 12 As more trial data were made available, a maintenance dose of isavuconazole 200 mg QD was selected for the remainder of the phase 1 study program.…”

“…Blood samples were collected for PK analysis of rifampin on day 43 at predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, and 48 hours postdose. Blood samples were collected for PK analysis of isavuconazole on days 14 and 57 at predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6,8,10,12,14,16,24,48,72,96,144,192,240,288, and 336 hours postdose.…”