Two dose levels of once-weekly fosravuconazole versus daily itraconazole in combination with surgery in patients with eumycetoma in Sudan: a randomised, double-blind, phase 2, proof-of-concept superiority trial.

ABSTRACT

BACKGROUND: Eumycetoma is an implantation mycosis characterised by a large subcutaneous mass in the extremities commonly caused by the fungus Madurella mycetomatis. Despite the long duration of treatment, commonly a minimum of 12 months, treatment failure is frequent and can lead to amputation. We aimed to compare the efficacy of two doses of fosravuconazole, a synthetic antifungal designed for use in onychomycosis and repurposed for mycetoma, with standard-of-care itraconazole, both in combination with surgery. METHODS: This phase 2, randomised, double-blind, active-controlled, superiority trial was conducted in a single centre in Sudan. Patients with eumycetoma caused by M mycetomatis, who were aged 15 years or older, with a set lesion diameter (>2 cm and ≤16 cm) requiring surgery were included. There was a limit of 20 female patients in the initial enrolment, owing to preclinical toxicity concerns. Exclusion criteria included previous surgical or medical treatment for eumycetoma; presence of loco-regional lymphatic extension; osteomyelitis, or other bone involvement; pregnancy or lactation; severe concomitant diseases; a BMI under 16 kg/m2; contraindication to use of the study drugs; pre-existing liver disease; lymphatic extension; osteomyelitis; transaminase levels more than two times the laboratory's upper limit of normal, or elevated levels of alkaline phosphatase or bilirubin; or any history of hypersensitivity to any azole antifungal drug. Patients were randomly allocated in a 111 ratio to 300 mg fosravuconazole weekly for 12 months (group 1); 200 mg fosravuconazole weekly for 12 months (group 2); or 400 mg itraconazole daily for 12 months (group 3) using a random number list with non-disclosed fixed blocks of size 12, with equal allocation to each of the three arms within a block. To ensure masking between groups, placebo pills were used to disguise the difference in dosing schedules. All groups took pills twice daily with meals. In all groups, surgery was performed at 6 months. The primary outcome was complete cure at end of treatment at the month 12 visit, as evidenced by absence of mycetoma mass, sinuses, and discharge; normal ultrasonography or MRI examination of the eumycetoma site; and, if a mass was present, negative fungal culture from the former mycetoma site. The primary outcome was assessed in the modified intention-to-treat (mITT) population (all patients who received one or more treatment dose with one or more primary efficacy assessment). Safety was assessed in all patients who received one or more doses of the study drug. This study is registered with ClinicalTrials.gov (NCT03086226) and is complete. FINDINGS: Between May 9, 2017, and June 10, 2021, 104 patients were randomly allocated (34 in group 1 and 2, respectively, and 36 in group 3). 86 (83%) of 104 patients were male and 18 (17%) patients were female. After an unplanned second interim analysis, the study was terminated early for futility. Complete cure at 12 months in the mITT population was 17 (50%) of 34 (95% CI 32-68) for group 1, 22 (65%) of 34 (47-80) for group 2, and 27 (75%) of 36 (58-88) in group 3. Neither dose of fosravuconazole was superior to itraconazole (p=0·35 for 200 mg fosravuconazole vs p=0·030 for 300 mg fosravuconazole). 83 patients had a total of 205 treatment-emergent adverse events, and two patients had serious adverse events that led to discontinuation, neither related to treatment. INTERPRETATION: Treatment with either dose of fosravuconazole was not superior to itraconazole, and the two doses had a numerically lower efficacy. However, fosravuconazole presented no new safety signals, and its lower pill burden and reduced risk of drug-drug interactions compared with the relatively expensive and inaccessible itraconazole suggests further research into effective treatments with a shorter duration and higher cure rate, without the need for surgery are warranted. FUNDING: Drugs for Neglected Diseases initiative.