Azithromycin in Idiopathic Pulmonary Fibrosis

Study Overview
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Brief Summary
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Idiopathic pulmonary fibrosis (IPF) is a devastating disease with no cure available. Patients suffer from respiratory symptoms including dyspnea and cough. To improve life quality the investigators will test the effects of immunomodulation of macrolides specifically on cough in IPF patients. The investigators hypothesize that immunomodulatory treatment reduces cough frequency and might improve lung function.

Detailed Description
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Background Idiopathic pulmonary fibrosis is a progressive interstitial lung disease, which ultimately leads to respiratory failure and death. The median survival is 2-3 years and thus comparable to the survival of a malignant disease. Today, there is no cure available. Improvement of quality of life (QoL) is thus a major goal in IPF patients. Cough is a common distressing and debilitating symptom in IPF. Increased cough in IPF patients may be linked to functional upregulation of lung sensory neurones. In addition, cough independently predicts disease progression in IPF patients. Symptomatic treatment options for cough in IPF are limited. Dysregulation of the immune system has been suggested to cause IPF associated cough and treatment trials with immunomodulating agents have been promising. Unfortunately the recently studied medication thalidomide is famous for its side effects and might be apprehensively received by some patients. Immunomodulatory effects of macrolide treatment in chronic inflammatory diseases as well as reduced cough reflex in animal studies suggest a possible reduction in cough in IPF patients. In addition, in animal in vivo models azithromycin also showed anti-fibrotic properties. The investigators hypothesize that immunomodulatory treatment of IPF patients with AZT reduces cough frequency and might improve lung function. Objective The purpose of this protocol is to determine the effect of azithromycin (AZT) on subjective and objective cough, QoL and lung function, its effects on biomarkers as well as its safety in patients with idiopathic pulmonary fibrosis.Specific Objectives To determine the efficiency after 12 weeks of treatment on subjective and objective cough reduction and increase of QoL To monitor safety by recording severe adverse events, including mortality, organ-specific toxicities and exacerbations requiring hospitalization To test efficiency at 12 weeks with overall response measured by changes in FEV1, FVC, TLC, DLCO, oxygen desaturation on exertion and 6-min walking distance To determine efficiency in clinical course To monitor overall adverse events To determine the influence on cytokines and biomarkers in IPF To determine the impact on oro-pharyngeal flora and antibiotical resistance Methods Single center, prospective, randomized, double blind, 2 treatments, 2 period crossover study with two 12-week treatment periods separated by a 4-week drug-free washout period and a 4 week follow-up period performed at the University Hospital Berne. All patients will be treated with both AZT and placebo. Individual changes in clinical symptoms with focus on cough frequency, life quality, lung function and adverse events will be monitored.

Official Title
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Azithromycin for the Treatment of Cough in Idiopathic Pulmonary Fibrosis- a Clinical Trial

Conditions
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Cough, Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: azithromycin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Idiopathic pulmonary fibrosis; new diagnosis, or known. Diagnosis according to the current guidelines from ATS/ERS for IPF diagnosis, other differential diagnoses ruled out. Clinical symptoms of cough Written informed consent for study participation Exclusion Criteria Previous history of an adverse reaction or allergy on azithromycin or other macrolide or ketolide antibiotics or any other ingredient (e.g. lactose) Evidence of respiratory infection or systemic infection one month before randomisation Known rhythmogenic heart disease Pregnancy or lactation History of non-compliance to medical treatment Current alcohol or drug abuse Active hepatitis, history of hepatitis, other significant liver disease Serum bilirubin > 50 μmol/L Transaminases or alkaline phosphatase elevated > 3x upper limit of normal at baseline Severe renal insufficiency with GFR <10ml/min Concomitant treatment with ergotamines Concomitant treatment with ciclosporin Concomitant treatment with ributin Concomitant treatment with digoxin Change of medication until 4 weeks before randomisation Pirfenidone <3 Mo

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azithromycin first, Placebo second<br>Medication with Azithromycin 500mg/d 3x/week p.o. o.d. for 12 weeks or placebo. | Drug: azithromycin<br>* Azithromycin is a macrolide antibiotic. 500mg Azithromycin will be given p.o. 3 times a week for 3 months. Azithromycin will be compared to placebo.<br>Drug: placebo<br>* Placebo will be given 3 times a wek over a period of 3 months.<br>|
| Active Comparator: Placebo first, Azithromycin second<br>Medication with Azithromycin 500mg/d 3x/week p.o. o.d. for 12 weeks or placebo. Placebo will be capsulated similar to verum and given 3 times a week. | Drug: azithromycin<br>* Azithromycin is a macrolide antibiotic. 500mg Azithromycin will be given p.o. 3 times a week for 3 months. Azithromycin will be compared to placebo.<br>Drug: placebo<br>* Placebo will be given 3 times a wek over a period of 3 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with a subjective response to treatment | Subjective response is defined as a 1.3 unit reduction of cough as measured with the Leicester Cough Score from treatment start to 12 weeks of treatment. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with an objective response to treatment | Objective response is defined as the Overall response in the measured cough frequency by respiratory Polygraph (Resmed, Nox T3®). | 3 months | 
| Number of patients with a change in lung function | Measured by FEV1, FVC, TLC, & DLCO | 3 months | 
| Number of patients with a change in oxygen saturation | Measured by oxygen desaturation on exertion | 3 months | 
| Number of patients with a change in quality of life | Measured by quality of life questionnaires | 3 months | 
| Number of patients with changes in oropharyngeal flora |  | 3 months | 
| Number of patients with a change in 6 min walking distance | Measured by oxygen desaturation on 6-min walking distance | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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idiopathic pulmonary fibrosis, cough, immunomodulation, macrolide