Clinical trial NCT00985244: Macrolide Maintenance Therapy in Chronic Obstructive Pulmonary Disease
Official title: Influence of Macrolide Maintenance Therapy and Bacterial Colonisation on Exacerbation Frequency and Progression of COPD, a Randomized Double-blind Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: COPD
Keywords: COPD
COPD exacerbation
macrolide
diseae progression
bacterial colonisation
Lead sponsor: Amphia Hospital
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: Stichting Solong
name: Amphia Hospital
First posted: 2009-09-28
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: To assess whether maintenance treatment with macrolide antibiotics in COPD patients with three or more exacerbations in the preceding year of inclusion can decrease the exacerbation rate in the year of treatment.

Detailed description: COPD is characterized by progressive development of airflow limitation that is poorly reversible. Because of a poor understanding of COPD pathogenesis, treatment is mostly symptomatic and new therapeutic strategies are limited. There is a direct relationship between the severity of the disease and the intensity of the inflammatory response.One of the hypothesis for persistent airway inflammation is that the presence of recurrent infections is responsible for this condition.

Macrolide antibiotics have a bacteriostatic as well as anti-inflammatory properties. This clinical trial will investigate whether maintenance treatment with macrolide antibiotics during 1 year in people with 3 or more exacerbations in the preceding year of inclusion can decrease the exacerbation rate in that same year of treatment.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of COPD according to GOLD criteria (FEV1/FVC\<70%), classification into GOLD I (FEV1 70-100% predicted), GOLD II (FEV1 50-70% predicted), GOLD III (FEV1 30- 50% predicted) or GOLD IV (FEV1 ≤ 30% predicted)
* Age ≥ 18 years
* Three or more exacerbations of COPD in one year for which a course of prednisone and/or antibiotic therapy was started
* Clinically stable during 1 month. Patients have to be free of COPD exacerbation or respiratory tract infection within a month prior to involvement in the study and they should not have received a high dose of systemic glucocorticoids or antibiotics in this period
* Informed consent

Exclusion Criteria:

* Use of antibiotics or high dose of systemic steroids within a month prior to involvement in the study.
* Addition of inhalation steroids to the patient's therapy regimen, shortly before entering the study.
* Pregnant or lactating women.
* Allergy to macrolides.
* Liver disease (alanine transaminase and/or aspartate transaminase levels 2 or more times the upper limit of normal).
* Asthma, defined as episodic symptoms of airflow obstruction which is reversible with bronchodilators, assessed with lung function testing.
* Presence of a malignancy which is clinically active.
* Bronchiectasis.
* Malignancy of any kind for which the subject is under treatment or is being monitored as part of follow up after treatment.
* Heart failure.
* Use of drugs which can adversely interact with macrolides and for which therapeutic monitoring cannot be undertaken.

Primary outcomes:
measure: Reduction in number of exacerbations
timeFrame: 1 year
Secondary outcomes:
measure: Lung function parameters (FEV1 (L), FVC (L), FRC (L), RV (L), TLC(L), IC (L), 6 minute walking distance)
timeFrame: Day 1. Also 3, 6, 9 and 12 months.
measure: Disease specific health related quality of life measured by St. George's Respiratory Questionnaire (SGRQ)
timeFrame: Day 1. Also 3, 6, 9 and 12 months. In case of an exacerbation.
measure: Indication of anxiety and depression by Hospital Anxiety Depression Scale (HADS)
timeFrame: Day 1. Also 3, 6, 9 and 12 months.
measure: Microbiology of sputum (culture and PCR).
timeFrame: Day 1. Also 3, 6, 9 and 12 months. In case of an exacerbation of COPD.
measure: Measurement of inflammatory markers in sputum and serum.
timeFrame: Day 1. Also 3, 6, 9 and 12 months. In case of an exacerbation of COPD.
measure: Adverse events of treatment.
timeFrame: Day 1. Also 3, 6, 9 and 12 months. Whenever adverse events occur.
measure: Length of hospital stay.
timeFrame: Whenever admission to hospital is required for an exacerbation of COPD.
measure: Time till next exacerbation.
timeFrame: Whenever an exacerbation of COPD occurs.
measure: Assess type D personality by DS-14 questionnaire.
timeFrame: Day 1 and month 12.
measure: Generic health status measured by 12-Item Short Form Health Survey (SF-12).
timeFrame: Day 1, month 3, 6, 9 and 12. In case of an exacerbation.
measure: Decrease in percentage of clinical versus outdoor department exacerbations.
timeFrame: Month 12.
measure: Effect of maintenance macrolides on intestinal bacterial restistancy patterns
timeFrame: Day 1, month 6 and month 12
measure: Serology and PCR for atypical microorganisms in serum
timeFrame: day 1. In case of an exacerbation.
measure: Intestinal bacterial resistance patterns
timeFrame: Day 1, month 6 and month 12
Other outcomes:
Locations:
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
state: Noord-Brabant
Study officials:
affiliation: Amphia ziekenhuis
name: Joachim Aerts, MD, PhD
role: STUDY_DIRECTOR
affiliation: Erasmus Medical Center
name: Menno van der Eerdem, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Djamin RS, Talman S, Schrauwen EJA, von Wintersdorff CJH, Wolffs PF, Savelkoul PHM, Uzun S, Kerstens R, van der Eerden MM, Kluytmans JAJW. Prevalence and abundance of selected genes conferring macrolide resistance genes in COPD patients during maintenance treatment with azithromycin. Antimicrob Resist Infect Control. 2020 Jul 28;9(1):116. doi: 10.1186/s13756-020-00783-w.
citation: Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van't Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014 May;2(5):361-8. doi: 10.1016/S2213-2600(14)70019-0. Epub 2014 Apr 15.
citation: Uzun S, Djamin RS, Kluytmans J, Van't Veer NE, Ermens AA, Pelle AJ, Mulder P, van der Eerden MM, Aerts J. Influence of macrolide maintenance therapy and bacterial colonisation on exacerbation frequency and progression of COPD (COLUMBUS): study protocol for a randomised controlled trial. Trials. 2012 Jun 9;13:82. doi: 10.1186/1745-6215-13-82.