Chronic Airway Disease, Mucus Rheology and Exacerbations (COPD-CARhE)

Chronic Airway Disease, Mucus Rheology and Exacerbations: a Randomized Controlled Trial of COPD Patients

The main objective of this trial is to compare the exacerbation number over 12 months of follow-up between a group of patients with COPD treated according to standardized management (azithromycin prescribed in the event of severe sputum according to the CASA-Q score , standardized comparator arm) and a similar group in which azithromycin is prescribed based on mucus rheology (experimental arm) or CASA-Q.

The secondary objectives are to compare between the 2 arms: exacerbation number according to their severity (observed throughout the duration of the study); the evolution of the symptoms, the rheology of the sputum, and the pulmonary function (measurements repeated every three months); medication consumption and adverse events (monitored throughout the duration of the study); patient trajectories during follow-up; the overall clinical improvement at the end of the study and the evolution of the quality of life (measurements repeated every 3 months); the change in biomarkers of interest (baseline versus end of study).

CASA-Q scoring is performed by the patient and then sealed away from investigator-view. Similarly, mucus rheology results are blinded. The patient does not know what arm he/she is in, as so does not know exactly why the prescription was made or not. Similarly, investigators/outcome assessors are blinded to both CASA-Q scores and sputum rheology. The prescription strategy is determined according to an algorithm, and investigators/outcome assessors do not know what arm the patient is in nor exactly why a prescription was made or not.

Patients randomized to this arm will be prescribed azithromycin in function of their sputum rheology.

Patients randomized to the "standardized comparator arm" will benefit from the standard treatment for COPD, including with regard to the prescription of azithromycin in case of severe sputum complaints (here defined by a CASA-Q sputum symptoms score <70 to homogenize practices between centers). CASA-Q will be evaluated every 3 months. If the patient has a sputum symptoms score <70, a prescription for 3 months of azithromycin treatment will be initiated. This prescription can be renewed every 3 months during the 12 months of follow-up planned in this study, if the patient continues to obtain a sputum symptoms score <70. If the patient has a sputum symptoms score> 70, management is not changed.

Treatment according to standard COPD management, except for the prescription of azithromycin, which will be prescribed in function of mucus rheology or as a function of sputum complaints (here defined by a CASA-Q sputum symptoms score <70). The rheology of mucus will be quantified every 3 months. If the patient has spontaneous or induced sputum, and this sputum has a critical constraint (tau-C) > 39, a prescription for 3 months of azithromycin treatment will be initiated. This prescription may be renewed every 3 months during the 12 months of follow-up planned in this study. If the patient has a sputum symptoms score <70, a prescription for 3 months of azithromycin treatment will be initiated. This prescription can be renewed every 3 months during the 12 months of follow-up planned in this study, if the patient continues to obtain a sputum symptoms score <70. If the patient has a sputum symptoms score> 70, management is not changed.

An exacerbation is defined according to French recommendations as an "acute event characterized by worsening of respiratory symptoms (notably cough, sputum and dyspnea) beyond [normal] daily variation and leading to a modification of treatment: either a simple increase in bronchodilators (in this case, a duration greater than 24 hours is required to define an exacerbation) or the addition of another treatment (antibiotic therapy and / or oral corticosteroid therapy)."

The 22-question SNOT-22 is scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110 (higher scores indicate poorer outcomes).

The 22-question SNOT-22 is scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110 (higher scores indicate poorer outcomes).

The 22-question SNOT-22 is scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110 (higher scores indicate poorer outcomes).

The 22-question SNOT-22 is scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110 (higher scores indicate poorer outcomes).

The 22-question SNOT-22 is scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110 (higher scores indicate poorer outcomes).

The four domains of the CASA-Q (cough/sputum symptom and impact) use scales from 0 to 100, with lower scores indicating higher symptom/impact levels. The 20-item questionnaire with a 7-day recall assesses the frequency and severity of cough and sputum and their impact on everyday life in clinical (trial) settings.

The four domains of the CASA-Q (cough/sputum symptom and impact) use scales from 0 to 100, with lower scores indicating higher symptom/impact levels. The 20-item questionnaire with a 7-day recall assesses the frequency and severity of cough and sputum and their impact on everyday life in clinical (trial) settings.

The four domains of the CASA-Q (cough/sputum symptom and impact) use scales from 0 to 100, with lower scores indicating higher symptom/impact levels. The 20-item questionnaire with a 7-day recall assesses the frequency and severity of cough and sputum and their impact on everyday life in clinical (trial) settings.

The four domains of the CASA-Q (cough/sputum symptom and impact) use scales from 0 to 100, with lower scores indicating higher symptom/impact levels. The 20-item questionnaire with a 7-day recall assesses the frequency and severity of cough and sputum and their impact on everyday life in clinical (trial) settings.

The four domains of the CASA-Q (cough/sputum symptom and impact) use scales from 0 to 100, with lower scores indicating higher symptom/impact levels. The 20-item questionnaire with a 7-day recall assesses the frequency and severity of cough and sputum and their impact on everyday life in clinical (trial) settings.

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of dyspnea possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of dyspnea possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of dyspnea possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of dyspnea possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of dyspnea possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of coughing possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of coughing possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of coughing possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of coughing possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of coughing possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of sputum production possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of sputum production possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of sputum production possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of sputum production possible).

A patient-reported visual analogue scale (VAS) starting at 0 (no symptoms) and ending at 100 (the worst possible level of sputum production possible).

Clinical improvement is scored via a point system from 0 to 3 at the end of the study. The points are added-up as follows: 1 point: no more than one exacerbation without hospitalization during the 52 weeks of follow-up; 1 point: gain > 100mL in pre-bronchodilator FEV1 at the 52nd week compared to the baseline state; 1 point: variation of the CAT score during the 52 weeks of observation > 2.

The SF-36 taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. A score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

The SF-36 taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. A score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

The SF-36 taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. A score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

The SF-36 taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. A score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

The SF-36 taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. A score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

In its original version, this self-administered questionnaire consists of two pages: the first contains the EQ-5D descriptive system and the second a visual analogue scale. The descriptive system has five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each described by five levels of intensity ("no problems", "slight problems", "moderate problems", "severe problems" and "extreme problems or complete inability"). The respondent must indicate one intensity level for each dimension.

In its original version, this self-administered questionnaire consists of two pages: the first contains the EQ-5D descriptive system and the second a visual analogue scale. The descriptive system has five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each described by five levels of intensity ("no problems", "slight problems", "moderate problems", "severe problems" and "extreme problems or complete inability"). The respondent must indicate one intensity level for each dimension.

In its original version, this self-administered questionnaire consists of two pages: the first contains the EQ-5D descriptive system and the second a visual analogue scale. The descriptive system has five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each described by five levels of intensity ("no problems", "slight problems", "moderate problems", "severe problems" and "extreme problems or complete inability"). The respondent must indicate one intensity level for each dimension.

In its original version, this self-administered questionnaire consists of two pages: the first contains the EQ-5D descriptive system and the second a visual analogue scale. The descriptive system has five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each described by five levels of intensity ("no problems", "slight problems", "moderate problems", "severe problems" and "extreme problems or complete inability"). The respondent must indicate one intensity level for each dimension.

In its original version, this self-administered questionnaire consists of two pages: the first contains the EQ-5D descriptive system and the second a visual analogue scale. The descriptive system has five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each described by five levels of intensity ("no problems", "slight problems", "moderate problems", "severe problems" and "extreme problems or complete inability"). The respondent must indicate one intensity level for each dimension.

Inclusion Criteria: Subjets between 40 - 85 years (included) Written and signed informed consent form Subjects must be able to attend all planned visits and comply with all test procedures Beneficiary of or affiliated with the French social security system Man or woman with chronic obstructive pulmonary disease for at least 1 year defined according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and validated by the clinical investigator Optimal treatment according to GOLD class severity C or D recommendations >=3 exacerbation (regardless of severity: mild-moderate-severe) or ≥ 1 severe exacerbations (requiring hospitalization) in the past 12 months Spontaneous or induced sputum production Electrocardiogram: corrected distance between Q and T waves (QTC) <450 ms in men, QTC <470 ms in women Normal audiogram for age or absence of contraindication to azithromycin for long course according to Oto-Rhino-Laryngological specialist opinion Exclusion Criteria: Pregnancy or breastfeeding Patients who are prisoners or under other forms of judicial protection Patients under any form of guardianship Participation in another interventional protocol, (current or during the month preceding inclusion) Received azithromycin in the past 3 months Patient whose primary diagnosis is bronchial dilation based on CT scan documentation Known hypersensitivity to azithromycin, erythromycin, any other macrolide, ketolide or any of the excipients of the azithromycin-based specialty used Concomitant use of medication contraindicated with azithromycin (dihydroergotamine, ergotamine, cisapride, colchicine) Other respiratory diseases or associated lung infections Severe hepatic insufficiency and severe cholestasis (a liver biological test will be carried out if clinical suspicion) Renal impairment with creatinine clearance < 40 mL/min Patients with hematological malignancies who have undergone allogeneic hematopoietic stem cell transplantation Patients with galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary disease) due to the presence of lactose in the specialty Zithromax.

The general goal is to make the study data available to interested researchers as well as to provide proof of transparency for the study. Data (and an accompanying data dictionary) will be de-identified and potentially further cleaned or aggregated as the investigators deem necessary to protect participant anonymity. Data will be made available to persons who address a reasonable request to the study director and fulfil the requirements stipulated by the French CNIL (Commission Nationale de l'Informatique et des Libertés : https://www.cnil.fr/professionnel).

As close to "real time" as possible, the following supporting information will be made public: Study Protocol (to be published in an appropriate journal). Statistical Analysis Plan Participant Information materials Analytic code These will be posted and registered on osf.io and/or clinicaltrials.gov (if not published). Datasets can be requested after the publication process has been completed.

The conditions under which members of the public will be granted access to datasets are: The data will be used/examined in a not-for-profit manner; The data will not be used in an attempt to identify a participant or group of participants; The user does not work for a private insurance company; The data will not be used in support of any kind of private insurance policy or health penalties; The data will be used/examined for the advancement of science/teaching while respecting participant/patient privacy and rights; The user will state why they wish to access the data. The appropriate CNIL approval has been obtained by the user.