Oral itraconazole versus oral voriconazole for treatment-naive patients with chronic pulmonary aspergillosis in India (VICTOR-CPA trial): a single-centre, open-label, randomised, controlled, superiority trial.

Abstract

Both itraconazole and voriconazole are used to treat chronic pulmonary aspergillosis. However, treatment success with itraconazole is only around 65-70%. Voriconazole, with its lower minimum inhibitory concentrations and better oral bioavailability, might offer improved outcomes, but no head-to-head comparison has been conducted to date. We aimed to evaluate whether oral voriconazole is superior to itraconazole in treating chronic pulmonary aspergillosis. This single-centre, prospective, open-label, superiority trial was conducted at the chest clinic of a tertiary care hospital in Chandigarh, India. We enrolled treatment-naive adults aged 18 years or older with chronic cavitary pulmonary aspergillosis or chronic fibrosing pulmonary aspergillosis. We excluded those who denied consent, received any antifungal azoles for more than 3 weeks in the previous 6 months, or had other forms of aspergillosis. Participants were randomly assigned 1:1 to receive 200 mg twice daily of oral itraconazole or oral voriconazole for 6 months, using a computer-generated randomisation sequence with variable block sizes (4-8). Participants, staff administering the interventions, clinical outcome assessors, and data analysts were not masked to treatment assignment; a radiologist masked to clinical details and treatment allocation evaluated chest images. The primary outcome was the proportion of participants achieving a favourable response (clinical and radiological stability or improvement) at 6 months in the modified intention-to-treat population, which included all participants who received at least one dose of the allocated treatment. The safety analyses (a secondary outcome) were also performed in the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT04824417) and is complete. Between April 15, 2021, and May 31, 2024, 150 individuals were screened, and 116 were randomly assigned to receive itraconazole (n=58) or voriconazole (n=58). Of the 116 participants, 74 (64%) were men, 42 (36%) were women, and the mean age was 45·9 years (SD 14·4). All participants received at least one dose of the study drug and were included in the primary analysis. The proportion of participants achieving a favourable response at 6 months was similar in both groups (69% [40 of 58] receiving voriconazole vs 67% [39 of 58] receiving itraconazole; absolute risk reduction -0·02 [95% CI -0·2 to 0·15], p=0·84). Voriconazole was associated with significantly more treatment-related adverse events than itraconazole (55% [32 of 58] of participants receiving voriconazole vs 34% [20 of 58] receiving itraconazole, p=0·025). There were four deaths, all in the voriconazole group; none were directly attributable to the treatment. Voriconazole was not superior to itraconazole for treating chronic pulmonary aspergillosis and was associated with a significantly higher incidence of adverse events. Our findings support the continued use of itraconazole as the preferred therapy for chronic pulmonary aspergillosis, although voriconazole remains a reasonable alternative. The choice between the two agents should be guided by factors such as patient tolerance, drug availability, and cost considerations. Cipla Pharmaceuticals, India.