Azithromycin for Acute Exacerbations Requiring Hospitalization

NCT02135354 | Terminated Phase 3

• 3 other identifiers: s55829 - BACE trial2013-004420-11IWT-TBM 130233
• Study Type: interventional
• Target: 301
• Locations: 1 country
• Sites: 20

Brief Summary

This project (funded by the IWT-TBM program) will organize a randomized placebo-controlled multicenter intervention trial in 500 COPD patients to study the effectiveness and safety of azithromycin therapy in the acute setting of COPD exacerbations requiring hospital admission. Although long-term use of azithromycin is proven effective to prevent exacerbations, inherent risks outweigh the benefits. By reducing the dose and duration of the azithromycin treatment and by restricting the treatment to acute periods with highest risk for treatment failure, benefits may counterbalance potential side effects, which may result in a new treatment strategy for these acute events. The present study is designed by the services of respiratory medicine of the Leuven and Ghent University hospitals but will run in total in 17 different large hospitals in Belgium, of which 12 are located in Flanders.

Conditions

Chronic Obstructive Pulmonary Disease

Keywords

AECOPD; Chronic Obstructive Pulmonary Disease; Acute exacerbation; Hospitalization; Azithromycin; Macrolides; Randomized Controlled Trial; Placebo

Outcome Measures

Primary Outcomes (1)

• Time to clinical failure

  Clinical failure is a composite endpoint as multiple clinical interventions may indicate that an initiated therapy is failing. Clinical failure is defined as the composite of death, treatment intensification (additional dose of systemic steroids, switch antibiotics for respiratory reasons or new course of systemic steroids and/or antibiotics) and step up in hospital care for respiratory reasons (from ward to ICU during index event, or from home to ward or ICU (new admission) after discharge). Primary outcome measure will also be analysed in following subgroups as an exploratory analysis: * Male vs female * Smoker vs ex-smoker (stopped smoking \> 6 months) * GOLD A, B vs GOLD C vs GOLD D * former GOLD I, II vs III vs IV * High CRP (\> 50 mg/dL) vs low CRP (\< 50 mg/dL) * Age \> 65 years vs ≤ 65 years * Anthonissen I vs Anthonissen II vs Anthonissen III at admission * ICS use vs no ICS use

  Will be assessed between day 1 (from 1 hour after first drug intake) till day 90 (24 hours after last study drug intake)

Secondary Outcomes (22)

• Number of clinical failures up to Day 90 (key secondary #1)

  Will be assessed on day 90 (last day of treatment phase)

• COPD Assessment Test (CAT) score at Day 90 (key secondary #2)

  Will be assessed on day 90 (last day of treatment phase)

• Total days of additional/prolonged systemic steroid use at Day 90 (key secondary #3)

  Will be assessed on day 90 (last day of treatment phase)

• Number of clinical failures up to Day 270

  Will be assessed on day 270 (last day of follow-up phase)

• Time to clinical failure up to Day 90 and up to Day 270

  Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)

Study Arms (2)

Azithromycin

EXPERIMENTAL

N = 250 * From day 1 up to and including day 3: 500 mg azithromycin PO once a day * From day 4 up to and including day 90: 250 mg azithromycin PO once every 2 days

Drug: Azithromycin

Placebo

PLACEBO COMPARATOR

N = 250 * From day 1 up to and including day 3: 500 mg placebo PO once a day * From day 4 up to and including day 90: 250 mg placebo PO once every 2 days

Drug: Placebo

Interventions

Azithromycin DRUG

* From day 1 up to and including day 3: 500 mg azithromycin PO once a day * From day 4 up to and including day 90: 250 mg azithromycin PO once every 2 days

Also known as: Azitromcyine CF, ATC code: J01FA10

Azithromycin

Placebo DRUG

* From day 1 up to and including day 3: 500 mg placebo PO once a day * From day 4 up to and including day 90: 250 mg placebo PO once every 2 days

Also known as: Inactive substance

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Established diagnosis of COPD by medical doctor (based on clinical history OR pulmonary function test)
• Smoking history of at least 10 pack-years (10 pack-years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years, etc.)
• Current hospitalization for potential infectious AECOPD treated with standard therapy
• History of at least one exacerbation during the last year (prior to the current hospital admission) for which systemic steroids and/or antibiotics were taken
• ECG at admission

You may not qualify if:

• Mechanical or non-invasive ventilation at moment of randomization (D1)
• Long QT interval on ECG (QTc \> 450msec for males or \> 470msec for females)
• History of life-threatening arrhythmias
• Myocardial infarction (NSTEMI or STEMI) less than 6 weeks before start of study drug
• Unstable angina pectoris or acute myocardial infarction (NSTEMI or STEMI) at admission
• Drugs with high risk for long QT interval and torsade de pointes (amiodarone, flecainide, procainamide, sotalol, droperidol, haldol, citalopram, other macrolides)
• Documented uncorrected severe hypokalemia (K+ \< 3.0 mmol/L) or hypomagnesemia (Mg2+ \< 0.5 mmol/L)
• Chronic systemic steroids (\> 4 mg methylprednisolone /day for ≥ 2 months)
• Actual use of macrolides for at least 2 weeks
• Allergy to macrolides
• Active cancer treatment
• Life expectancy \< 3 months
• Pregnant or breast-feeding subjects. Woman of childbearing potential must have a pregnancy test performed and a negative result must be documented before start of treatment

Sponsors & Collaborators

• Wim Janssens: lead
• Agentschap voor Innovatie door Wetenschap en Technologie: collaborator

Study Sites (20)

UZ Brussel

Brussels, Brussel Hoofdstedelijk Gewest, 1090, Belgium

Location

St. Pieterziekenhuis

Brussels, Brussels Capital, 1000, Belgium

Location

ZNA Middelheim

Antwerp, Flanders, 2020, Belgium

Location

St. Augustinus Ziekenhuis

Antwerp, Flanders, 2610, Belgium

Location

Imelda Ziekenhuis

Bonheiden, Flanders, 2820, Belgium

Location

St. Jan Brugge Ziekenhuis

Bruges, Flanders, 8000, Belgium

Location

Maria Middelaresziekenhuis

Ghent, Flanders, 9000, Belgium

Location

UZ Gent

Ghent, Flanders, 9000, Belgium

Location

Jessa Ziekenhuis

Hasselt, Flanders, 3500, Belgium

Location

AZ Groeninge Ziekenhuis

Kortrijk, Flanders, 8500, Belgium

Location

UZ Gasthuisberg

Leuven, Flanders, 3000, Belgium

Location

Heilig Hart Ziekenhuis

Roeselare, Flanders, 8800, Belgium

Location

St. Andriesziekenhuis

Tielt, Flanders, 8700, Belgium

Location

CHU Charleroi

Charleroi, Wallonia, 6110, Belgium

Location

Grand Hôpital de Charleroi

Gilly, Wallonia, 6060, Belgium

Location

CHU Liège

Liège, Wallonia, 4000, Belgium

Location

CHU Mont-Godinne

Yvoir, Wallonia, 5530, Belgium

Location

Onze-Lieve-Vrouwziekenhuis

Aalst, 9300, Belgium

Location

Clinique Reine Astrid

Malmedy, 4960, Belgium

Location

Clinique Sainte-Elisabeth

Namur, 5000, Belgium

Location

Related Publications (2)

• Vermeersch K, Belmans A, Bogaerts K, Gyselinck I, Cardinaels N, Gabrovska M, Aumann J, Demedts IK, Corhay JL, Marchand E, Slabbynck H, Haenebalcke C, Vermeersch S, Verleden GM, Troosters T, Ninane V, Brusselle GG, Janssens W; BACE trial investigators. Treatment failure and hospital readmissions in severe COPD exacerbations treated with azithromycin versus placebo - a post-hoc analysis of the BACE randomized controlled trial. Respir Res. 2019 Oct 29;20(1):237. doi: 10.1186/s12931-019-1208-6.

  PMID: 31665017 DERIVED

• Vermeersch K, Gabrovska M, Deslypere G, Demedts IK, Slabbynck H, Aumann J, Ninane V, Verleden GM, Troosters T, Bogaerts K, Brusselle GG, Janssens W. 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. Int J Chron Obstruct Pulmon Dis. 2016 Mar 31;11:687-96. doi: 10.2147/COPD.S95501. eCollection 2016.

  PMID: 27099485 DERIVED

Related Links

• Protocol paper

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Azithromycin

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Officials

• Wim Janssens, MD. PhD

  KU Leuven - UZ Leuven

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: * The identity of the study drug will be concealed by the use of a format that is identical in packaging, labelling, schedule of administration and appearance. * Patients will be randomly assigned in a 1:1 ratio to receive either azithromycin or placebo, with a permuted block size of ten and sequential assignment, stratified by the center. * Randomization of the study drug is based on an online generated randomization schedule (http://www.randomization.com). Unique randomization codes are locally obtained through a secured Web-based program. * At all times, randomization codes are kept strictly confidential during the study, with the exception of an ad hoc independent safety committee adjudicating cardiovascular side effects and mortality after 300 patients. * Nevertheless, code breaks will be available at the site and un-blinding may occur in the case of an emergency which will require knowledge of the treatment assignment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD. PhD

Study Record Dates

• First Submitted: May 8, 2014
• First Posted: May 9, 2014
• Study Start: August 1, 2014
• Primary Completion: October 1, 2017
• Study Completion: April 1, 2018
• Last Updated: September 5, 2018

Record last verified: 2018-09

Data Sharing

• IPD Sharing: Will not share

Locations

BE (20)