This randomized controlled trial evaluates the therapeutic role of azithromycin in acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). Baseline severity classification and stratification were performed using the SCALE-IPF framework (Severity Classification and Lung Evaluation for Prognosis in IPF; locked April 2023) to ensure balanced disease severity across randomized arms. End-of-study analyses included descriptive and stratified phenotyping using the Idiopathic Pulmonary Fibrosis Phenotypes Identification Model (IPIM); locked April 2023).
Following a protocol amendment approved in September 2025, the study expanded into a multi-arm therapeutic platform evaluating both azithromycin timing strategies and combination antifibrotic-immunomodulatory therapy in idiopathic pulmonary fibrosis. Additional treatment arms involving pirfenidone with or without azithromycin were incorporated without altering the original randomized comparisons or baseline study framework.
Both frameworks were developed within the Assiut University IPF Research Program (2022-2026), a coordinated institutional effort investigating clinical, prognostic, and therapeutic dimensions of IPF. Neither framework altered randomization procedures, treatment allocation, or study endpoints; they were applied to improve standardization, reproducibility, and interpretability of results.
Baseline disease severity classified as mild or early-moderate according to the SCALE-IPF (locked April 2023) threshold ≤ 13 points.
Participation within the Assiut University IPF Research Program (2022-2026).
Additional longitudinal therapeutic platform arms involving pirfenidone with or without azithromycin may include clinically stable idiopathic pulmonary fibrosis patients according to protocol-amended eligibility criteria approved in September 2025.
Age: less than 18 years.
Patients with any severity other than mild or early-moderate acute exacerbation of IPF according to SCALE-IPF (locked April 2023).
Patients with multislice computed tomography with a radiological pattern rather than usual interstitial pneumonitis (UIP).
Unstable patients need mechanical ventilation or Respiratory Intensive Care Unit admission.
Parallel
Azithromycin
DrugA single daily oral dose of azithromycin 500 mg for five days during acute exacerbation, followed by azithromycin 500 mg orally three times weekly as maintenance therapy during longitudinal follow-up according to tolerability and standard clinical safety monitoring.
Methylprednisolone
Drugmethylprednisolone 500 mg single intra-venous daily dose for three days
Pirfenidone
DrugPirfenidone will be administered according to the standard full-dose protocol as 801 mg orally three times daily, equivalent to a total daily dose of 2403 mg/day, administered as three 267 mg tablets/capsules three times daily according to tolerability and standard clinical safety monitoring.
Hospital stay
the main aim of the study to assess the hospital stay expressed in days in the Add-on Azithromycin 500 mg single oral daily dose in comparison to the conventional therapy group only
Change in clinical outcome measures stratified by SCALE-IPF severity
Evaluate the treatment response and short-term progression of AE-IPF patients across baseline severity strata as defined by the SCALE-IPF classification (locked April 2023). Outcomes include improvement in oxygenation, radiological resolution, and need for hospitalization. This will assess whether baseline SCALE-IPF strata correlate with therapeutic response and clinical stability.
Association between SCALE-IPF severity and one-year mortality
Determine whether baseline SCALE-IPF severity independently predicts 12-month all-cause mortality following acute exacerbation in both treatment arms. This analysis provides validation of the SCALE-IPF prognostic gradient within a randomized framework.
Correlation between azithromycin response and IPIM phenotypic clusters
Analysis comparing treatment outcomes across IPIM-defined phenotypic clusters
Event-free survival across SCALE-IPF strata
Compare event-free survival (freedom from recurrent AE, hospitalization, or death) between azithromycin and control groups across SCALE-defined severity categories.
Analytical validation of SCALE-IPF and IPIM within the randomized AE-IPF cohort
Evaluate the performance, calibration, and clinical concordance of the two institutional frameworks-SCALE-IPF (randomization classifier) and IPIM (descriptive phenotype model)-within the azithromycin randomized trial population.
Exacerbation frequency in the pirfenidone combination therapy domain
Comparison of acute exacerbation frequency between the Pirfenidone Therapy arm and the Pirfenidone Plus Azithromycin Therapy arm during longitudinal follow-up. Unit of Measure: Number of exacerbation events per participant.
Forced vital capacity decline in the pirfenidone combination therapy domain
Comparison of longitudinal forced vital capacity decline between the Pirfenidone Therapy arm and the Pirfenidone Plus Azithromycin Therapy arm. Unit of Measure: Forced vital capacity (% predicted).
Hospitalization frequency in the pirfenidone combination therapy domain
Comparison of hospitalization frequency related to respiratory deterioration between the Pirfenidone Therapy arm and the Pirfenidone Plus Azithromycin Therapy arm. Unit of Measure: Percentage of participants.
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