Efficacy of 12-months oral itraconazole versus 6-months oral itraconazole to prevent relapses of chronic pulmonary aspergillosis: an open-label, randomised controlled trial in India

Abstract

Chronic pulmonary aspergillosis has a 5-year mortality of 50-80% globally, and the optimal duration of treatment for chronic pulmonary aspergillosis remains unclear. We aimed to compare the effect of 6-months of oral itraconazole with 12-months of oral itraconazole on chronic pulmonary aspergillosis clinical outcomes. In this single-centre, open-label, randomised controlled trial conducted in one chest clinic in Chandigarh, India, we screened consecutive patients with chronic pulmonary aspergillosis who were naive to antifungal treatment and randomised eligible patients, using block randomisation, to receive a starting dose of 400 mg/day of oral itraconazole for either 6 months or 12 months. There was no masking of participants or investigators. We excluded patients who were unable to provide informed consent; had an intake of any antifungal drugs for more than 3 weeks in the preceding 6 months; had active Mycobacterium tuberculosis or non-tuberculous mycobacterial pulmonary disease; and had allergic, subacute, or invasive forms of aspergillosis. The primary outcome was the proportion of patients having relapse 2 years after treatment initiation. We performed an intention-to-treat analysis for all outcomes. The study is registered with ClinicalTrials.gov, NCT03920527. We recruited participants between July 1, 2019, and Aug 31, 2021. We screened 250 patients, of which 164 were included in the trial. 81 patients were randomised to the 6-month group and 83 patients were randomised to the 12-month group. The study population was 78 (48%) women and 86 (52%) men, and the mean age of participants was 44·3 (SD 13·3) years. The proportion of patients experiencing relapse was significantly lower in the 12-month group, 31 (38%) had a relapse in the 6-month group compared with 8 (10%) in the 12-month group, with an absolute risk reduction of 0.29 [95% CI 0·16-0·40]. The mean time to first relapse was 23 months in the 12-month group, which is significantly longer than the mean of 18 months in the 6-month group (p<0.0001). There were 16 deaths in total, eight in each group. Ten (12%) of 81 patients in the 6-months group and 18 (22%) of 83 patients in the 12-months group had adverse effects, with none requiring treatment modification. Nausea and anorexia were the most common adverse events in both groups. Treatment of chronic pulmonary aspergillosis with 12 months of oral itraconazole was superior to 6 months of oral itraconazole in reducing relapses at 2 years. Itraconazole should be given for at least 12 months for treating chronic pulmonary aspergillosis. None. For the Hindi translation of the abstract see Supplementary Materials section.