Azithromycin in the Management of Patients With Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Assiut University

Status: Enrolling

Conditions: Idiopathic Pulmonary Fibrosis

Treatments: Drug: Pirfenidone; Drug: Methylprednisolone; Drug: Azithromycin

Study type: Interventional

Funder types: Other

Identifiers

NCT05842681

2516771716

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 1,000 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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.

Exclusion criteria

• 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.
• Patients with end-organ failure.
• Patients with known hypersensitivity or contraindication to pirfenidone or azithromycin, significant hepatic impairment, severe drug intolerance, or other contraindications to study medications according to standard clinical judgment.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,000 participants in 4 patient groups

Conventional therapy group

Active Comparator group

Description:

Patients will receive conventional treatment for acute exacerbation of IPF, including pulse corticosteroid therapy and supportive treatment, and oxygen therapy.

Treatment:

Drug: Methylprednisolone

Add-on Azithromycin

Experimental group

Description:

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.

Treatment:

Drug: Azithromycin

Drug: Methylprednisolone

Pirfenidone Therapy

Active Comparator group

Description:

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.

Treatment:

Drug: Pirfenidone

Pirfenidone Plus Azithromycin Therapy

Experimental group

Description:

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.

Treatment:

Drug: Azithromycin

Drug: Pirfenidone