Azithromycin for Acute Exacerbations Requiring Hospitalization

Chronic Obstructive Pulmonary Disease Clinical Trial

— BACE  

Official title:

Belgian Trial With Azithromycin During Acute COPD Exacerbations

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02135354
• Other study ID #: s55829 - BACE trial
• Secondary ID: 2013-004420-11IW
• Status: Terminated
• Phase: Phase 3
• Start date: August 1, 2014
• Est. completion date: April 2018

Study information

• Verified date: September 2018
• Source: KU Leuven
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

In this 9 month, randomized, placebo-controlled, parallel-group, multicenter intervention trial, 500 patients will be randomly assigned (1:1 ratio) to receive either azithromycin or placebo on top of standard therapy in the acute treatment of COPD exacerbations requiring hospitalization. The study drug (azithromycin or placebo) will be initiated and uploaded within 48 hours after hospital admission (500mg once a day for 3 days) and subsequently administered for a prolonged period of 3 months at a lower maintenance dose (250mg every 2 days). An additional follow-up period of 6 months without study drug will be foreseen to study relapse after study drug withdrawal.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 301
• Est. completion date: April 2018
• Est. primary completion date: October 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Azithromycin
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
• Placebo
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

Locations

Country	Name	City	State
Belgium	Onze-Lieve-Vrouwziekenhuis	Aalst
Belgium	St. Augustinus Ziekenhuis	Antwerpen	Vlaanderen
Belgium	ZNA Middelheim	Antwerpen	Vlaanderen
Belgium	Imelda Ziekenhuis	Bonheiden	Vlaanderen
Belgium	St. Jan Brugge Ziekenhuis	Brugge	Vlaanderen
Belgium	St. Pieterziekenhuis	Brussel	Brussels Hoofdstedelijk Gewest
Belgium	UZ Brussel	Brussel	Brussel Hoofdstedelijk Gewest
Belgium	CHU Charleroi	Charleroi	Wallonië
Belgium	Maria Middelaresziekenhuis	Gent	Vlaanderen
Belgium	UZ Gent	Gent	Vlaanderen
Belgium	Grand Hôpital de Charleroi	Gilly	Wallonië
Belgium	Jessa Ziekenhuis	Hasselt	Vlaanderen
Belgium	AZ Groeninge Ziekenhuis	Kortrijk	Vlaanderen
Belgium	UZ Gasthuisberg	Leuven	Vlaanderen
Belgium	CHU Liège	Liège	Wallonië
Belgium	Clinique Reine Astrid	Malmedy
Belgium	Clinique Sainte-Elisabeth	Namur
Belgium	Heilig Hart Ziekenhuis	Roeselare	Vlaanderen
Belgium	St. Andriesziekenhuis	Tielt	Vlaanderen
Belgium	CHU Mont-Godinne	Yvoir	Wallonië

Sponsors (2)

Lead Sponsor	Collaborator
Wim Janssens	Agentschap voor Innovatie door Wetenschap en Technologie

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Number of clinical failures up to Day 90 (key secondary #1)	Secondary outcome measure will also be analysed in following subgroups as 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; ICS use vs no ICS use	Will be assessed on day 90 (last day of treatment phase)
Secondary	COPD Assessment Test (CAT) score at Day 90 (key secondary #2)	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase)
Secondary	Total days of additional/prolonged systemic steroid use at Day 90 (key secondary #3)	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase)
Secondary	Number of clinical failures up to Day 270	Secondary outcome measure will also be analysed in following subgroups as 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; ICS use vs no ICS use	Will be assessed on day 270 (last day of follow-up phase)
Secondary	Time to clinical failure up to Day 90 and up to Day 270	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Time to new exacerbation within 90 and within 270 days	A new exacerbation is defined as the composite of new course of systemic steroids and/or antibiotics, and hospitalization for respiratory reasons, all after the index event.; Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Number of new exacerbations up to 90 days and up to 270 days	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Total days of hospital days within 90 and within 270 days	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Total days in intensive care within 90 and within 270 days	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Quality of Life - 5 Dimensions (EQ5D) score at Day 90 and at Day 270	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	COPD Assessment Test (CAT) score at Day 270	Secondary outcome measure will also be analysed in following subgroups as 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 on day 270 (last day of follow-up phase)
Secondary	Modified Medical Research Council (mMRC) score at Day 90 and Day 270	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Speech, Spatial and Qualities of Hearing (SSQ5) score at Day 90 and Day 270	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Pre-bronchodilator forced expiratory volume in 1 second (FEV1) at Day 90 and Day 270	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Total dose of additional/prolonged systemic steroids at Day 270	Secondary outcome measure will also be analysed in following subgroups as 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 on day 270 (last day of follow-up phase)
Secondary	Total days of additional/prolonged systemic steroid use at Day 270	Secondary outcome measure will also be analysed in following subgroups as 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 on day 270 (last day of follow-up phase)
Secondary	Total days of non-study antibiotic use at Day 90 and Day 270	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Number of home physician contacts at Day 90 and Day 270	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Average cost of hospitalization at Day 90 and Day 270 including the index hospitalization	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Time to death within 90 and within 270 days	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Time to first treatment intensification within 90 and within 270 days	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Secondary	Time to first step up in hospital care for respiratory reasons within 90 and within 270 days	Secondary outcome measure will also be analysed in following subgroups as 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 on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)

External Links

•   Protocol paper