NCT Number: NCT05842681
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.
Interested in participating?
Request Info18 year–80 year
All sexes
Interventional
Not applicable
Assiut university-Faculty of Medicine, Asyut, Egypt
This randomized, open-label controlled trial forms part of the Assiut University IPF Research Program (2022-2026). An initial target of 130 patients with clinically mild or early-moderate acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was specified for enrollment and randomized to receive standard therapy with or without azithromycin.
SCALE-IPF (Severity Classification and Lung Evaluation for Prognosis in IPF; locked April 2023, archived November 2025, digital object identifier [DOI] 10.5281/zenodo.17575973) served as the prespecified baseline severity classification and stratification framework. IPIM (Idiopathic Pulmonary Fibrosis Phenotypes Identification Model; locked April 2023, archived November 2025, DOI 10.5281/zenodo.17576160) was applied as a predefined phenotypic framework integrating clinical, functional, and radiological domains.
Severity and phenotypic frameworks were used exclusively to define eligibility and baseline characterization. They did not influence randomization procedures, treatment allocation, trial conduct, or study endpoints, and were applied to support reproducibility and structured interpretation of therapeutic effects across severity and phenotypic spectra.
Protocol Amendment (September 2025) - Platform Expansion:
To reflect the ongoing institutional clinical ecosystem, the trial was updated via a protocol amendment approved in September 2025 into a multi-arm single-center therapeutic platform. In addition to the original acute exacerbation cohort, the platform expanded to evaluate combination antifibrotic and immunomodulatory therapy targeting the inflammatory phenotype.
Trial enrollment was concurrently expanded to target 250 patients per group. Two additional arms were integrated: Group C (Pirfenidone alone) and Group D (Pirfenidone plus Azithromycin). This expansion allows for two distinct, prespecified therapeutic contrasts from the same institutional infrastructure: an early versus delayed azithromycin intervention (Groups A/B), and a pirfenidone combination therapy concept (Groups C/D).
The platform expansion does not alter the original randomized comparisons, original enrollment chronology, or original study endpoints. SCALE-IPF and IPIM frameworks continue to be utilized for baseline stratification and descriptive phenotyping across all expanded platform arms.
Healthy volunteers accepted: No
Only the study team can determine whether someone qualifies for participation.
Inclusion criteria
Exclusion criteria
A 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.
Other names: azithromycin 500 mg oral tablet
methylprednisolone 500 mg single intra-venous daily dose for three days
Other names: methylprednisolone 500 mg
Pirfenidone 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.
Other names: Pirfenidone 267 mg oral tablet/capsule
Time frame: 5-10 Days ( Days of Hospital admission until improvement and discharge)
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
Time frame: From randomization (Day 1) to Month 3 post-enrollment.
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.
Time frame: Baseline to 12 months post-randomization.
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.
Time frame: Baseline to 12 months post-randomization.
Analysis comparing treatment outcomes across IPIM-defined phenotypic clusters
Time frame: Baseline to 12 months post-randomization.
Compare event-free survival (freedom from recurrent AE, hospitalization, or death) between azithromycin and control groups across SCALE-defined severity categories.
Time frame: Baseline to 12 months post-randomization.
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.
Time frame: Baseline to Month 12 post-randomization.
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.
Time frame: Baseline to Month 12 post-randomization.
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).
Time frame: Baseline to Month 12 post-randomization.
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.
Time frame: Baseline to Month 12 post-randomization.
Comparison of all-cause mortality between the Pirfenidone Therapy arm and the Pirfenidone Plus Azithromycin Therapy arm during longitudinal follow-up. Unit of Measure: Percentage of participants.
Time frame: Baseline to Month 12 post-randomization.
Comparison of event-free survival between the Conventional/Delayed Azithromycin Strategy arm and the Early Azithromycin Strategy arm. Unit of Measure: Time-to-event outcome (days).
Time frame: Baseline to Month 12 post-randomization.
Comparison of longitudinal disease progression between the Conventional/Delayed Azithromycin Strategy arm and the Early Azithromycin Strategy arm. Unit of Measure: Percentage of participants with clinical progression.
Time frame: Baseline to Month 12 post-randomization.
Assessment of clinical outcomes across predefined SCALE-IPF (severity classification and lung evaluation for prognosis in idiopathic pulmonary fibrosis score) severity strata within all therapeutic platform arms. Unit of Measure: Percentage of participants.
Time frame: Baseline to Month 12 post-randomization.
Assessment of treatment-response variation across IPIM-defined phenotypic groups within all therapeutic platform arms. Unit of Measure: Percentage of participants.
Time frame: Baseline to Month 12 post-randomization.
Comparison of longitudinal C-reactive protein levels between the Pirfenidone Therapy arm and the Pirfenidone Plus Azithromycin Therapy arm during follow-up. Unit of Measure: C-reactive protein (mg/L).
Time frame: Baseline to Month 12 post-randomization.
Assessment of the indirect mediation effect of longitudinal C-reactive protein change on the association between azithromycin exposure and clinical progression across therapeutic platform arms using mediation analysis. Unit of Measure: Standardized indirect mediation effect estimate.
Time frame: Baseline to Month 12 post-randomization.
Assessment of the association between longitudinal forced vital capacity decline and acute exacerbation risk across therapeutic platform arms using joint longitudinal-event modeling. Unit of Measure: Joint model association estimate.
Time frame: Baseline to Month 12 post-randomization.
Assessment of the association between longitudinal oxygen saturation decline and acute exacerbation risk across therapeutic platform arms using joint longitudinal-event modeling. Unit of Measure: Joint model association estimate.
Time frame: Baseline to Month 12 post-randomization.
Assessment of the association between longitudinal C-reactive protein change and acute exacerbation risk across therapeutic platform arms using joint longitudinal-event modeling. Unit of Measure: Joint model association estimate.
Time frame: Baseline to Month 12 post-randomization.
Estimation of the standardized effect size for the association between azithromycin exposure and clinical progression across therapeutic platform arms. Unit of Measure: Standardized effect size.
Time frame: Baseline to Month 12 post-randomization.
Assessment of temporal change-points in clinical progression patterns associated with azithromycin exposure across therapeutic platform arms using longitudinal change-point analysis. Unit of Measure: Estimated temporal change-point (days).
Time frame: Baseline to Month 12 post-randomization.
Assessment of longitudinal clinical progression trajectories across therapeutic platform arms using repeated-measures longitudinal modeling. Unit of Measure: Longitudinal trajectory model estimate.
Time frame: Baseline to Month 12 post-randomization.
Assessment of clinical, physiological, and inflammatory predictors of longitudinal clinical progression across therapeutic platform arms using regression analysis. Unit of Measure: Regression coefficient estimate.
Time frame: Baseline to Month 12 post-randomization.
Assessment of the correlation between longitudinal C-reactive protein change and forced vital capacity decline across therapeutic platform arms. Unit of Measure: Correlation coefficient.
Time frame: Baseline to Month 12 post-randomization.
Comparison of longitudinal oxygen saturation change between the Pirfenidone Therapy arm and the Pirfenidone Plus Azithromycin Therapy arm during follow-up. Unit of Measure: Oxygen saturation (%).
Time frame: Baseline to Month 12 post-randomization.
Comparison of treatment tolerability and drug-related adverse effects between the Pirfenidone Therapy arm and the Pirfenidone Plus Azithromycin Therapy arm during follow-up. Unit of Measure: Percentage of participants with treatment-related adverse events.
Time frame: Baseline to Month 12 post-randomization.
Assessment of longitudinal change in King's Brief Interstitial Lung Disease (K-BILD) questionnaire scores across therapeutic platform arms. The K-BILD score ranges from 0 to 100, with higher scores indicating better health-related quality of life. Unit of Measure: K-BILD score (0-100 scale).
Contact information is provided by the study sponsor or research team.
Assiut University
Other
Role of Add-on Azithromycin in the Management of Patients With Acute Exacerbation of Idiopathic Pulmonary Fibrosis
OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.
View the official ClinicalTrials.gov record (opens in a new tab)This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.
Published trials that share one or more normalized conditions with this study.
NCT07036523
Idiopathic Pulmonary Fibrosis, Lung Diseases
Birmingham, Alabama, United States
View Trial DetailsNCT06325696
Fibrosis, Idiopathic Pulmonary Fibrosis
Research Triangle Park, North Carolina, United States
View Trial DetailsNCT07284459
Fibrosis, Idiopathic Pulmonary Fibrosis
Rosario, Santa Fe Province, Argentina
View Trial DetailsNCT07679893
Fibrosis, Idiopathic Pulmonary Fibrosis
Windsor, Ontario, Canada
View Trial Details