A prospective, randomized, open-label comparative study evaluating oral itraconazole and oral posaconazole in treatment-naïve patients with CPA, with treatment for 12 months is proposed. The study will compare clinical effectiveness and safety of the study drugs.
The findings will generate evidence to guide individualized antifungal therapy, inform antifungal stewardship strategies, and strengthen resistance surveillance frameworks for CPA. As the first randomized evaluation of posaconazole in CPA, the study has the potential to directly influence clinical practice and international treatment recommendations for this neglected fungal disease
One or more clinical symptoms (persistent cough, recurrent haemoptysis, weight loss, malaise, fever, dyspnoea) for ≥3 months
Slowly progressive or persistent radiological findings on CT thorax including one or more cavities with or without a fungal ball, fibrosis, pericavitary infiltrates, consolidation, nodules, or pleural thickening
Serum A. fumigatus-IgG ≥27 milligrams of antibody/litre (mgA/L), or growth of Aspergillus in respiratory secretions (twice in sputum or once in bronchoalveolar lavage fluid [BALF]) or serum galactomannan index (GMI) ≥1.7 or BALF GMI ≥2.6.
Exclusion of other pulmonary disorders with similar presentation (active pulmonary TB, malignancy, other infections)
Failure or refusal to provide written informed consent
Patients on immunosuppressive drugs, receiving prednisolone (or equivalent) ≥10 mg/day for ≥3 weeks, or known HIV infection
Intake of antifungal triazoles for ≥3 weeks in the preceding 3 months (prior azole therapy)
Active pulmonary infection due to Mycobacterium tuberculosis or non-tuberculous mycobacteria
Parallel
Posaconazole Delayed Release Oral Tablet
DrugPosaconazole 300 mg will be given once daily
Itraconazole (ITZ)
DrugItraconazole suprabioavailable will be given 130 mg twice daily
Overall favorable treatment response at 12 months
Defined by: (1) Clinical improvement or stability; (2) Radiological improvement or stability on chest CT; and (3) No requirement for antifungal modification because of treatment failure.
Significant treatment-emergent adverse events
Adverse events requiring discontinuation of study medication
CPA relapse
Relapse after treatment cessation (assessed at 18 months from randomization)
Time to first CPA relapse
Time to CPA relapse by survival curve analysis
Quality of life assessment by SGRQ
Change in St. George's Respiratory Questionnaire (SGRQ) score at 6 and 12 months
Subgroup analyses
Prespecified exploratory subgroup analyses will be performed for unfavourable treatment response and CPA relapse according to: (1) sex (men vs women); (2) baseline serum A. fumigatus-IgG concentration (≥100 vs \<100 mgA/L); (3) presence or absence of a fungal ball on baseline chest CT; (4) number of cavities on baseline chest CT (≥2 vs \<2); (5) extent of disease on baseline chest CT (unilateral vs bilateral); (6) age (≥60 vs \<60 years); and (7) baseline overall VAS symptom score (\>50 vs ≤50 mm).
Overall favorable treatment response at 6 months
Defined by: (1) Clinical improvement or stability; (2) Radiological improvement or stability on chest CT; and (3) No requirement for antifungal modification because of treatment failure.
Unfavourable treatment response or CPA relapse
Unfavorable response or a CPA relapse anytime during study
Drug discontinuation rates
Discontinuation rate in either arm
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