Chronic Pulmonary Aspergillosis
Conditions
Keywords
Aspergillosis, Triazoles, Posaconazole, Itraconazole, Aspergilloma
Brief summary
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
Detailed description
Chronic pulmonary aspergillosis (CPA) is a progressive fungal lung disease associated with substantial morbidity and mortality. India bears one of the largest global burdens of CPA owing to the high prevalence of post-tuberculosis lung disease (PTLD), the principal predisposing condition for CPA in low- and middle-income countries (Expert Rev Anti Infect Ther 2026;1-21; Mycoses 2025;68:e70060). Despite increasing recognition of CPA as a major public health problem, several critical gaps remain in the optimization of antifungal therapy, particularly with respect to azole selection, pharmacokinetic variability, and the emergence of antifungal resistance during prolonged treatment. Oral itraconazole remains the recommended first-line therapy for CPA (Expert Rev Anti Infect Ther 2026;1-21; Mycoses 2025;68:e70060; Lancet Infect Dis 2026;26:239-249; Curr Opin Pulm Med 2024;30:156-166; Lancet Infect Dis 2022;22:1052-1061). Our group, in a randomized controlled trial, previously showed that extending itraconazole therapy from 6 to 12 months significantly improves treatment outcomes (Lancet Infect Dis 2022;22:1052-1061). However, itraconazole exhibits considerable inter-individual variability in systemic drug exposure, requires therapeutic drug monitoring, and may fail to achieve adequate systemic exposure in a subset of patients (J Antimicrob Chemother 2014;69:1162-1176). Furthermore, prolonged azole exposure may contribute to the development of antifungal resistance, an emerging challenge with important implications for long-term disease control (Expert Rev Anti Infect Ther 2026;1-21). More recently, we showed that voriconazole was not superior to itraconazole in treating CPA; moreover, it was associated with a higher incidence of adverse events (Lancet Infect Dis 2026;26:239-249). Posaconazole is an attractive alternative to itraconazole and voriconazole owing to its favourable pharmacokinetic profile, predictable systemic exposure, improved tolerability, and potent activity against Aspergillus species. However, its role as primary therapy for CPA has not been evaluated in a randomized clinical trial (Expert Rev Anti Infect Ther 2026;1-21). In addition, prospective data on the emergence of azole resistance during prolonged therapy and its relationship with treatment outcomes remain limited. This prospective, randomized, open-label comparative study will evaluate oral itraconazole and oral posaconazole in 220 treatment-naïve patients with CPA, with treatment for 12 months. The study will compare clinical effectiveness and safety of the study drugs. By integrating clinical, microbiological, and azole exposure data, the proposed study seeks to identify determinants of treatment success and failure, define exposure-response relationships for azole therapy, and characterize the emergence of resistance during prolonged treatment. 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
Interventions
Posaconazole 300 mg will be given once daily
Itraconazole suprabioavailable will be given 130 mg twice daily
Sponsors
Post Graduate Institute of Medical Education and Research, Chandigarh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The outcome assessor and the radiologist will be blinded to the treatment allocation
Eligibility
Sex/Gender
ALL
Age
12 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* 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)
Exclusion criteria
* 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 * Other forms of pulmonary aspergillosis (subacute or acute invasive aspergillosis) * Pregnancy or lactation * Significant hepatic dysfunction (ALT/AST ≥3× upper limit of normal at baseline) * Known hypersensitivity to azole antifungals
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall favorable treatment response at 12 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall favorable treatment response at 6 months | 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. |
| Significant treatment-emergent adverse events | 12 months | Adverse events requiring discontinuation of study medication |
| CPA relapse | 18 months | Relapse after treatment cessation (assessed at 18 months from randomization) |
| Unfavourable treatment response or CPA relapse | 18 months | Unfavorable response or a CPA relapse anytime during study |
| Time to first CPA relapse | 18 months | Time to CPA relapse by survival curve analysis |
| Drug discontinuation rates | 12 months | Discontinuation rate in either arm |
| Comparative adverse event profile of itraconazole and posaconazole | 12 months | Treatment emergent adverse events in either arm graded according to CTCAE version 5.0. |
| Quality of life assessment by SGRQ | 12 months | Change in St. George's Respiratory Questionnaire (SGRQ) score at 6 and 12 months |
| QoL life change with treatment | 12 months | Proportion of patients achieving a clinically meaningful improvement in SGRQ (delta SGRQ ≥7) at 6 and 12 months |
| All-cause and CPA-related mortality during follow-up | 18 months | Any death during study |
| Other longitudinal clinical outcomes | 12 months | Changes in clinical (VAS symptoms scores (0 to 100 mm, 100 being worse), |
| Change in body weight | 12 months | Absolute and percentage change in body weight at 6 and 12 months compared to baseline weight |
| Change in serum A. fumigatus-IgG | 12 months | Change in serum A. fumigatus-IgG at 6 and 12 months compared to baseline |
| Imaging features (qualitatively) | 12 months | Imaging features will be collected repeatedly during follow-up will be summarized at each assessment. |
Countries
India
Contacts
CONTACTInderpaul S Sehgal, MD, DM
Outcome results
None listed