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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Conventional therapy group | Active Comparator | Patients will receive conventional treatment for acute exacerbation of IPF, including pulse corticosteroid therapy and supportive treatment, and oxygen therapy. |
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| Add-on Azithromycin | Experimental | Patients will receive conventional therapy and Add-on Azithromycin 500 mg single daily dose for five days then Patients will receive conventional treatment and early adjunctive azithromycin according to the study treatment protocol. Azithromycin will be administered as a 500 mg oral dose three times weekly during longitudinal follow-up according to tolerability and standard clinical safety monitoring. This arm represents the early inflammatory intervention strategy targeting inflammatory disease behavior in idiopathic pulmonary fibrosis. |
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| Pirfenidone Therapy | Active Comparator | Pirfenidone will be administered according to the standard full-dose protocol as 801 mg orally three times daily, corresponding to a total daily dose of 2403 mg/day. This regimen is equivalent to nine 267 mg tablets/capsules per day, given as three tablets/capsules three times daily, according to tolerability and standard safety monitoring. |
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| Pirfenidone Plus Azithromycin Therapy | Experimental | Patients will receive pirfenidone therapy according to the standard full-dose protocol: 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, combined with adjunctive azithromycin administered as a 500 mg oral dose three times weekly according to the study treatment protocol and standard safety monitoring. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Azithromycin | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 5-10 Days ( Days of Hospital admission until improvement and discharge) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline to 12 months post-randomization. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| ahmad M shaddad, MD | Contact | 01111171930 | shaddad_ahmad@yahoo.com |
| Name | Affiliation | Role |
|---|---|---|
| ahmad M shaddad | Assiut university-Faculty of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Assiut university-Faculty of Medicine | Recruiting | Asyut | 71515 | Egypt |
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| ID | Term |
|---|---|
| D054990 | Idiopathic Pulmonary Fibrosis |
| ID | Term |
|---|---|
| D011658 | Pulmonary Fibrosis |
| D017563 | Lung Diseases, Interstitial |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D017963 | Azithromycin |
| D008775 | Methylprednisolone |
| C093844 | pirfenidone |
| D013607 | Tablets |
| D002214 | Capsules |
| ID | Term |
|---|---|
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 |
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Randomized controlled trial
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| Methylprednisolone | Drug | methylprednisolone 500 mg single intra-venous daily dose for three days |
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| Pirfenidone | Drug | 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. |
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| From randomization (Day 1) to Month 3 post-enrollment. |
| 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. | Baseline to 12 months post-randomization. |
| Correlation between azithromycin response and IPIM phenotypic clusters | Analysis comparing treatment outcomes across IPIM-defined phenotypic clusters | Baseline to 12 months post-randomization. |
| 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. | Baseline to 12 months post-randomization. |
| 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. | Baseline to Month 12 post-randomization. |
| 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). | Baseline to Month 12 post-randomization. |
| 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. | Baseline to Month 12 post-randomization. |
| Mortality in the pirfenidone combination therapy domain | 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. | Baseline to Month 12 post-randomization. |
| Event-free survival in the azithromycin timing intervention domain | 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). | Baseline to Month 12 post-randomization. |
| Disease progression in the azithromycin timing intervention domain | 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. | Baseline to Month 12 post-randomization. |
| SCALE-IPF stratified clinical outcomes across therapeutic platform arms | 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. | Baseline to Month 12 post-randomization. |
| IPIM phenotype-treatment interaction across therapeutic platform arms | Assessment of treatment-response variation across IPIM-defined phenotypic groups within all therapeutic platform arms. Unit of Measure: Percentage of participants. | Baseline to Month 12 post-randomization. |
| C-reactive protein levels in the pirfenidone combination therapy domain | 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). | Baseline to Month 12 post-randomization. |
| Indirect mediation effect of C-reactive protein on azithromycin-associated clinical progression across platform arms | 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. | Baseline to Month 12 post-randomization. |
| Joint modeling of forced vital capacity decline and acute exacerbation risk across platform arms | 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. | Baseline to Month 12 post-randomization. |
| Joint modeling of oxygen saturation decline and acute exacerbation risk across platform arms | 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. | Baseline to Month 12 post-randomization. |
| Joint modeling of C-reactive protein change and acute exacerbation risk across platform arms | 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. | Baseline to Month 12 post-randomization. |
| Effect size of azithromycin exposure on clinical progression across platform arms | 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. | Baseline to Month 12 post-randomization. |
| Change-point analysis of azithromycin-associated clinical progression across platform arms | 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). | Baseline to Month 12 post-randomization. |
| Longitudinal modeling of clinical progression across therapeutic platform arms | Assessment of longitudinal clinical progression trajectories across therapeutic platform arms using repeated-measures longitudinal modeling. Unit of Measure: Longitudinal trajectory model estimate. | Baseline to Month 12 post-randomization. |
| Regression analysis of predictors of clinical progression across platform arms | Assessment of clinical, physiological, and inflammatory predictors of longitudinal clinical progression across therapeutic platform arms using regression analysis. Unit of Measure: Regression coefficient estimate. | Baseline to Month 12 post-randomization. |
| Correlation analysis of C-reactive protein change and forced vital capacity decline across platform arms | Assessment of the correlation between longitudinal C-reactive protein change and forced vital capacity decline across therapeutic platform arms. Unit of Measure: Correlation coefficient. | Baseline to Month 12 post-randomization. |
| Longitudinal oxygen saturation change in the pirfenidone combination therapy domain | 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 (%). | Baseline to Month 12 post-randomization. |
| Treatment tolerability in the pirfenidone combination therapy domain | 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. | Baseline to Month 12 post-randomization. |
| Health-related quality of life change across therapeutic platform arms | 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). | Baseline to Month 12 post-randomization. |
| Faculty of Medicine Assuit University | Active, not recruiting | Asyut | Egypt |
| Organic Chemicals |
| D011239 | Prednisolone |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |