Azithromycin in Idiopathic Pulmonary Fibrosis

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

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.

Study Overview

• Status: Completed
• Conditions: Cough; Idiopathic Pulmonary Fibrosis
• Intervention / Treatment: Drug: azithromycin; Drug: placebo

Detailed Description

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

1. To determine the efficiency after 12 weeks of treatment on subjective and objective cough reduction and increase of QoL
2. To monitor safety by recording severe adverse events, including mortality, organ-specific toxicities and exacerbations requiring hospitalization
3. 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
4. To determine efficiency in clinical course
5. To monitor overall adverse events
6. To determine the influence on cytokines and biomarkers in IPF
7. 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.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland
    • Universitätsspital Basel
  • Berne, Switzerland, 3010
    • University Hospital for Pulmonology
  • St. Gallen, Switzerland
    • Kantonsspital St. Gallen
  • Zürich, Switzerland
    • Universitätsspital Zürich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Azithromycin first, Placebo second; Medication with Azithromycin 500mg/d 3x/week p.o. o.d. for 12 weeks or placebo.	Drug: azithromycin; 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.; Drug: placebo; Placebo will be given 3 times a wek over a period of 3 months.
Active Comparator: Placebo first, Azithromycin second; 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; 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.; Drug: placebo; Placebo will be given 3 times a wek over a period of 3 months.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Collaborators: University of Bern
• Investigators: Principal Investigator: Manuela Funke, MD, University Hospital for Pulmonology, Berne

Publications and helpful links

General Publications

• Guler SA, Clarenbach C, Brutsche M, Hostettler K, Brill AK, Schertel A, Geiser TK, Funke-Chambour M. Azithromycin for the Treatment of Chronic Cough in Idiopathic Pulmonary Fibrosis: A Randomized Controlled Crossover Trial. Ann Am Thorac Soc. 2021 Dec;18(12):2018-2026. doi: 10.1513/AnnalsATS.202103-266OC.
• Rindlisbacher B, Schmid C, Geiser T, Bovet C, Funke-Chambour M. Serum metabolic profiling identified a distinct metabolic signature in patients with idiopathic pulmonary fibrosis - a potential biomarker role for LysoPC. Respir Res. 2018 Jan 10;19(1):7. doi: 10.1186/s12931-018-0714-2.
• Rindlisbacher B, Strebel C, Guler S, Kollar A, Geiser T, Martin Fiedler G, Benedikt Leichtle A, Bovet C, Funke-Chambour M. Exhaled breath condensate as a potential biomarker tool for idiopathic pulmonary fibrosis-a pilot study. J Breath Res. 2017 Nov 29;12(1):016003. doi: 10.1088/1752-7163/aa840a.

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2014
• Primary Completion (Actual): August 16, 2019
• Study Completion (Actual): August 16, 2019

Study Registration Dates

• First Submitted: June 23, 2014
• First Submitted That Met QC Criteria: June 23, 2014
• First Posted (Estimate): June 24, 2014

Study Record Updates

• Last Update Posted (Actual): August 28, 2019
• Last Update Submitted That Met QC Criteria: August 26, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: immunomodulation; idiopathic pulmonary fibrosis; cough; macrolide
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Signs and Symptoms, Respiratory; Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Cough; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: 002/14