Non‑inferiority of Azithromycin Withdrawal vs Continuation in Stable Non‑Cystic Fibrosis Bronchiectasis after ≥1 Year of Therapy: Multicenter Randomized Controlled Trial

The primary objective is to demonstrate the non-inferiority of withdrawing low‑dose macrolides after at least one year of therapy compared with continued treatment in patients with stable bronchiectasis unrelated to cystic fibrosis. Secondary objectives are to compare the withdrawal and continuation arms with respect to:

• time to first exacerbation;
• annual number of severe pulmonary exacerbations;
• quality‑of‑life assessments at baseline, 12 and 24 months;
• emergence of macrolide‑resistant bacterial and mycobacterial strains;
• respiratory symptom burden and lung‑function parameters;
• identification of prognostic factors for failure of macrolide discontinuation;
• time to loss of disease control, defined by the need to initiate additional preventive therapy.

The trial enrolled adult patients (≥18 years) of both sexes who had a diagnosis of bronchiectasis unrelated to cystic fibrosis confirmed by thoracic CT, were receiving long‑term azithromycin for at least 12 months, and had experienced ≤1 pulmonary exacerbation and no severe exacerbation requiring hospitalization in the preceding year. All participants were affiliated with the French health‑care system and were capable of providing informed consent. The sponsor did not provide the total number of participants. Selection was based on the stated inclusion criteria; no specific dietary, physical‑activity, or habit requirements were detailed. Vulnerable individuals were not excluded.

The study is a multicenter randomized controlled trial designed to assess the non‑inferiority of withdrawing long‑term azithromycin therapy in patients with stable non‑cystic fibrosis bronchiectasis who have received the drug for at least 12 months. Eligible participants (≥18 years, confirmed bronchiectasis on CT, ≤1 pulmonary exacerbation in the previous year, and continuous azithromycin use) undergo a screening visit to verify inclusion criteria and provide informed consent, after which they are randomized to either continue low‑dose azithromycin or discontinue it. Follow‑up assessments occur at 12 and 24 months post‑randomization and include evaluation of pulmonary exacerbations, lung function, quality‑of‑life questionnaires, and microbiological monitoring for macrolide‑resistant organisms; the final visit marks the end‑of‑study. The primary efficacy endpoint is the annualized number of adjudicated pulmonary exacerbations, with secondary endpoints encompassing time to first exacerbation, severe exacerbation rate, lung function parameters, quality‑of‑life scores, emergence of resistance, and exploratory prognostic analyses. Participant involvement spans approximately 24 months from randomization, and the overall trial recruitment period is planned from September 2026 to September 2030.

The investigational product consists of Azithromycin 250 mg and 500 mg film‑coated tablets, supplied in oral dosage form. Each tablet contains the specified amount of azithromycin and is intended for administration by the oral route. The 250 mg tablets are provided for participants requiring a lower dose, while the 500 mg tablets are available for those assigned to the higher dose regimen.

Participants assigned to the continuation arm receive the low‑dose macrolide regimen as described above, administered orally at the allocated dose throughout the study period. Participants in the withdrawal arm discontinue the study medication and receive no active macrolide; standard of care for non‑cystic fibrosis bronchiectasis is otherwise maintained according to local practice.

Study medication is dispensed in blister packs to facilitate dosing adherence. Administration occurs in accordance with the study schedule, and compliance is assessed by pill count at each study visit and documented in the trial’s electronic case report form. Any deviations from the prescribed dosing schedule are recorded and reported per protocol requirements.

The primary efficacy assessment is the annualized number of PE confirmed through a blinded event adjudication process. All exacerbation events reported by participants are documented continuously and reviewed by an independent committee to verify eligibility according to predefined criteria.

Secondary efficacy parameters include Time (days) to first exacerbation, which is calculated from the date of randomization to the onset of the first documented exacerbation; the annual count of severe exacerbations requiring hospitalization for respiratory failure; and the Quality-of-life score measured with the Quality of Life‑Bronchiectasis (QOL‑B) and Bronchiectasis Impact Measure (BIM) questionnaires at baseline, 12 months, and 24 months. Emergence of macrolide‑resistant strains of bacteria or mycobacteria is assessed by microbiological cultures obtained at screening, 12 months, and 24 months. Pulmonary function is evaluated using spirometry to obtain Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at the same three time points. The interval between randomization and initiation of any new preventive therapy for exacerbations is recorded in days. Prognostic factors for macrolide discontinuation failure, including age, disease severity, Pseudomonas colonization, and prior macrolide exposure, are explored using univariable and multivariable logistic regression models.