Randomized Controlled Trial of Azithromycin Dihydrate in Chronic Obstructive Pulmonary Disease Patients: Evaluating Mucus Rheology and Exacerbation Frequency

The primary objective of this study is to compare the **exacerbation** number over a 12-month follow-up period between two groups of patients with **Chronic Obstructive Pulmonary Disease** (COPD). One group will receive treatment according to standardized management, where **azithromycin** is prescribed in the event of severe sputum as determined by the CASA-Q score (standardized comparator arm). The other group will have azithromycin prescribed based on mucus rheology (experimental arm) or CASA-Q. This comparison is clinically relevant as it aims to determine the most effective method for managing exacerbations in COPD patients, potentially leading to improved patient outcomes and optimized treatment protocols.

Secondary objectives include:

• Comparing the exacerbation number according to their severity throughout the study duration.
• Assessing the evolution of symptoms, sputum rheology, and pulmonary function with measurements every three months.
• Evaluating medication consumption and adverse events monitored throughout the study.
• Analyzing patient trajectories during follow-up.
• Comparing overall clinical improvement at the study's end and the evolution of quality of life, with measurements every three months.
• Examining changes in biomarkers of interest from baseline to the study's end.
• Comparing exacerbation numbers between experimental and comparator arms with and without azithromycin prescription.
• Estimating the rate of patients in the experimental arm who would have had different care using CASA-Q versus rheology.

The clinical trial involves participants diagnosed with **Chronic Obstructive Pulmonary Disease** (COPD), aged between 40 and 85 years. Both male and female subjects are included, and the study does not involve a vulnerable population. Participants are required to have had COPD for at least one year, with a history of at least three exacerbations or one severe exacerbation requiring hospitalization in the past 12 months. The trial population was selected based on their ability to produce spontaneous or induced sputum and their compliance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Participants must have a normal audiogram for their age or no contraindication to azithromycin as determined by an Oto-Rhino-Laryngological specialist. The sponsor has not provided the total number of participants involved in the study. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **azithromycin dihydrate** in managing exacerbations in patients with **Chronic Obstructive Pulmonary Disease (COPD)**. This is a randomized, controlled trial with a double-blind design, ensuring that neither the participants nor the investigators are aware of the treatment allocations. The trial is set to span a duration of 12 months, with the primary objective being the comparison of exacerbation numbers between two groups: one receiving azithromycin based on standardized management and the other based on mucus rheology or CASA-Q score.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age, COPD diagnosis, and ability to comply with study procedures. Follow-up visits are scheduled at 3, 6, 9, and 12 months to assess primary and secondary endpoints, including the number of exacerbations, symptom evolution, and pulmonary function. The end-of-study visit will conclude the trial, evaluating the overall clinical improvement and quality of life changes.

The expected length of participant involvement is 12 months, with conditions for early termination including non-compliance with study procedures or the occurrence of adverse events. The trial aims to provide comprehensive data on the impact of azithromycin on COPD exacerbations, contributing valuable insights into its therapeutic potential.

The clinical trial involves the use of **azithromycin dihydrate** as the experimental medication. Azithromycin dihydrate is administered in the form of a **tablet**. The active substance, azithromycin dihydrate, is of chemical origin. The medication is intended for **oral use**. The maximum daily dose is 500 mg, with a total maximum dose of 78 g over the course of the treatment. The treatment period is set for a maximum of 12 months. Azithromycin is classified as an anti-infective agent and is not formulated specifically for pediatric use. The administration of azithromycin in this trial is based on the severity of sputum as assessed by the CASA-Q score in the standardized comparator arm, or based on mucus rheology in the experimental arm.

In addition to the experimental treatment, the study includes a standardized management approach for patients with Chronic Obstructive Pulmonary Disease (COPD). This involves the prescription of azithromycin in the event of severe sputum production, as determined by the CASA-Q score. This serves as the comparator treatment in the trial. The study aims to compare the number of exacerbations over a 12-month follow-up period between the experimental arm and the standardized comparator arm. Compliance with the dosing schedule and administration is monitored throughout the trial to ensure adherence to the protocol.

Efficacy in the clinical trial titled "COPD-CARhE - Chronic Airway Disease, Mucus Rheology and Exacerbations: a Randomized Controlled Trial of COPD Patients" will be assessed through a series of primary and secondary endpoints. The primary endpoint is the number of **exacerbations** over a 12-month follow-up period. Secondary endpoints include the number of mild, moderate, and severe exacerbations throughout the follow-up, with severity defined by the need for additional medication or hospitalization.

Symptom evolution will be evaluated using several validated tools, including the COPD Assessment Test (CAT) questionnaire, the Cough and Sputum Assessment Questionnaire (CASA-Q), and the Visual Analogue Scale (VAS) for dyspnea, coughing, and sputum production. These assessments will occur at 3, 6, 9, and 12 months. Sputum rheology will be measured using the Rheomuco device, focusing on parameters such as modulus of elasticity (G'), viscous module (G''), and critical constraint (tau-C) at the same timepoints.

Pulmonary function will be assessed through spirometry and plethysmography, measuring forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and other related parameters at baseline and various intervals. Quality of life will be evaluated using the EQ-5D-5L and St-George’s Respiratory questionnaires. Additional assessments include changes in complete blood counts and serum Club cell secretory protein levels from baseline to the end of the study.

Data collection will be conducted at specified intervals, and the analysis will compare the experimental and comparator arms, particularly focusing on the prescription of azithromycin based on CASA-Q scores. The trial aims to provide a comprehensive evaluation of treatment efficacy in managing chronic obstructive pulmonary disease (COPD) exacerbations and related symptoms.