By Richard R. Watkins, MD, MS, FACP, FIDSA

Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports no financial relationships relevant to this field of study.

SYNOPSIS: In a large, randomized, double-blind, multicenter clinical trial, researchers found that isavuconazole did not meet the primary endpoint of noninferiority compared to caspofungin for candidemia and invasive candidiasis.

SOURCE: Kullberg BJ, Viscoli C, Pappas PG, et al. Isavuconazole versus caspofungin in the treatment of candidemia and other invasive candida infections: The ACTIVE Trial. Clin Infect Dis 2019;68:1981-1989.

Isavuconazole, the newest triazole, offers a number of advantages over some older agents, including broad antifungal activity, fewer drug-drug interactions, availability of IV and oral formulations with excellent bioavailability, and less toxicity and side effects. Investigators conducted a clinical trial to determine the role of isavuconazole in treating invasive candidiasis.

The study was a multicenter, randomized, double-blind trial that compared IV isavuconazole followed by oral isavuconazole to IV caspofungin followed by oral voriconazole. Patients were eligible who were at least 18 years of age and had candidemia with a positive blood culture or tissue culture within 96 hours before randomization, along with signs and symptoms of infection. Exclusion criteria included hepatic dysfunction, Candida endocarditis, Candida osteomyelitis, Candida meningitis, severe immunodeficiency, or systemic antifungal therapy for more than 48 hours before randomization. Patients in the trial were randomized in a 1:1 ratio to receive isavuconazole or caspofungin.

Patients without neutropenia could be switched from IV therapy to oral therapy after day 10. Therapy was continued for a minimum of 14 days after the last positive blood culture and could be extended up to 56 days. Venous catheters were removed for all patients with candidemia. Investigators followed patients for six weeks after the end of therapy (EOT). The primary endpoint was the overall response at the end of IV therapy (EOIVT) in patients who had proven Candida infections who received one dose or more of the study drug (modified-intent-to-treat [mITT] population).

Of the 450 patients randomized, 400 (199 in the isavuconazole group and 201 in the caspofungin group) were included in the mITT population. Patient demographics were comparable in both groups, including baseline neutropenia (12% in each). A successful outcome at EOIVT was achieved in 120/199 (60.3%) in the isavuconazole group and 143/201 (71.1%) in the caspofungin group (adjusted difference, -10.8%; 95% confidence interval [CI], -19.9% to -1.8%).

Because the lower limit of the 95% CI for the treatment difference (-19.9%) was lower than the -15% prespecified noninferiority margin, the study results did not demonstrate noninferiority of isavuconazole to caspofungin. Secondary endpoints were comparable between the two groups, including overall response rates at two weeks after EOT and survival at days 14 and 56. For the patients with only candidemia, 110/170 (64.7%) exhibited a successful overall response at EOIVT in the isavuconazole group vs. 118/163 (72.4%) in the caspofungin group (adjusted difference, -7.7%; 95% CI, -18.3% to -2.9%). For those with invasive candidiasis, the response rates were 34.5% (10/29) for isavuconazole and 65.8% (25/38) for caspofungin (adjusted difference, -31.3%; 95% CI, -57.7% to -5.0%).

A body mass index ≥ 25 resulted in a lower response rate, with a trend toward a worse outcome with isavuconazole compared to caspofungin. Five patients in the isavuconazole group and 11 in the caspofungin group had either breakthrough, emergent, or recurrent Candida infection during the study. Finally, safety profiles were comparable for the isavuconazole recipients and the caspofungin-voriconazole recipients.

COMMENTARY

This was a large, multinational clinical trial that included sites in the United States, Europe, Israel, and Thailand. It identified a significant difference in treatment arms for the primary endpoint, with isavuconazole failing to demonstrate noninferiority to caspofungin for candidemia and invasive candidiasis. Previous studies comparing echinocandins to azoles have been criticized for methodological shortcomings, such as imbalances in treatment arms. However, that was not an issue in the current study, as both groups were similar in terms of species of Candida, minimum inhibitory concentrations of the drugs, severity of illness, and removal of vascular catheters. The trial also was larger than others that compared an azole to an echinocandin, which likely allowed for the detection of differences with more precision.

Furthermore, the sponsor of the trial should be commended for publishing the results despite the finding that the study drug did not meet the threshold for noninferiority. Indeed, many negative clinical trials are never published, to the detriment of science and patient care.

Although it was a well-designed and well-conducted study, there are a few limitations to mention. First, it did not include children, so the findings might not be generalizable to this population. Second, the number of patients with neutropenia was relatively small.

Finally, investigators did not perform therapeutic drug monitoring, which may have affected the results, especially for overweight patients.

How do the results of this trial affect clinical practice? The findings strengthen the recommendation from the current guidelines for using echinocandins as empiric first-line therapy.1 Also, isavuconazole seems to be a reasonable choice (along with voriconazole) for oral step-down therapy for fluconazole-resistant strains once clinical improvement and clearance of fungemia have been achieved.

Further investigation of isavuconazole in other settings and patient populations (e.g., prophylaxis, pediatric patients, and neutropenic patients) may help clarify its place in the antifungal armamentarium.

REFERENCE

  1. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;62:e1-50.