The Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization: an investigator-initiated study protocol for a multicenter, randomized, double-blind, placebo-controlled trial

Abstract

Background

Long-term use of macrolide antibiotics is effective to prevent exacerbations in chronic obstructive pulmonary disease (COPD). As risks and side effects of long-term intervention outweigh the benefits in the general COPD population, the optimal dose, duration of treatment, and target population are yet to be defined. Hospitalization for an acute exacerbation (AE) of COPD may offer a targeted risk group and an obvious risk period for studying macrolide interventions.

Methods/design

Patients with COPD, hospitalized for an AE, who have a smoking history of ≥10 pack-years and had ≥1 exacerbation in the previous year will be enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (NCT2135354). On top of a standardized treatment of systemic corticosteroids and antibiotics, subjects will be randomized to receive either azithromycin or placebo during 3 months, at an uploading dose of 500 mg once a day for 3 days, followed by a maintenance dose of 250 mg once every 2 days. The primary endpoint is the time-to-treatment failure during the treatment phase (ie, from the moment of randomization until the end of intervention). Treatment failure is a novel composite endpoint defined as either death, the admission to intensive care or the requirement of additional systemic steroids or new antibiotics for respiratory reasons, or the diagnosis of a new AE after discharge.

Discussion

We investigate whether azithromycin initiated at the onset of a severe exacerbation, with a limited duration and at a low dose, might be effective and safe in the highest risk period during and immediately after the acute event. If proven effective and safe, this targeted approach may improve the treatment of severe AEs and redirect the preventive use of azithromycin in COPD to a temporary intervention in the subgroup with the highest unmet needs.

Keywords:

• COPD
• acute exacerbation
• macrolide antibiotics
• azithromycin
• physical activity
• RCT

Acknowledgments

The BACE trial is funded by a grant from the Agentschap voor Innovatie door Wetenschap en Technologie (IWT) through the Toegepast Biomedisch onderzoek met een primair Maatschappelijke finaliteit (TBM) program: IWT–TBM number: 130233. KV is supported by the IWT. Financial support for study logistics is also received from Teva Pharma Belgium. Neither IWT nor Teva Pharma Belgium is involved in the study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication. The trial is also approved and supported by the Belgian Thoracic Society which provided logistic support for the organization of the investigators’ meetings. Special thanks goes to the Clinical Trial Center of UZ Leuven and the contract unit of KU Leuven Research and Development in supporting the financial contracts and legal aspects of the trial organization. Finally, the BACE trial investigators are acknowledged for their participation and the inclusion of the study patients: Vincent Ninane (CHU Saint-Pierre, Brussels, Belgium), Joseph Aumann (Jessa Ziekenhuis, Hasselt, Belgium), Ingel K Demedts (AZ Delta Roeselare-Menen, Roeselare, Belgium), Hans Slabbynck (ZNA Middelheim, Antwerpen, Belgium), Eric Marchand (CHU de Mont-Godinne, Yvoir, Belgium), Christel Haenebalcke (AZ Sint-Jan, Brugge-Oostende, Belgium), Rudi Peché (CHU de Charleroi, Charleroi, Belgium), Guy G Brusselle (UZ Gent, Gent, Belgium), Walter Vincken and Shane Hanon (UZ Brussel, Brussels, Belgium), Jean-Louis Corhay (CHU de Liège, Luik, Belgium), Michiel Haerens (AZ Groeninge, Kortrijk, Belgium), Antoine Fremault (Grand Hôpital de Charleroi, Charleroi, Belgium), Tine Lauwerier (Imeldaziekenhuis, Bonheiden, Belgium), Alix Debrock (Sint Augustinus Ziekenhuis, Antwerpen, Belgium), Jan Lamont (Maria Middelares Ziekenhuis, Gent, Belgium), Geert Tits (Sint-Andriesziekenhuis, Tielt, Belgium), Paul Jordens (Onze-Lieve-Vrouwziekenhuis, Aalst, Belgium), Alain Delobbe (Clinique Reine Astrid, Malmedy, Belgium), Jean-Benoît Martinot (Clinique Sainte-Elisabeth, Namur, Belgium).

Author contributions

Conception and design: WJ and GGB. All authors contributed toward data analysis, drafting and critically revising the paper, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.