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Azithromycin for Acute Exacerbations Requiring Hospitalization (BACE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02135354
Recruitment Status : Terminated (slow recruitment)
First Posted : May 9, 2014
Last Update Posted : September 5, 2018
Sponsor:
Collaborator:
Agentschap voor Innovatie door Wetenschap en Technologie
Information provided by (Responsible Party):
Wim Janssens, KU Leuven

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.


Condition or disease Intervention/treatment Phase
Chronic Obstructive Pulmonary Disease Drug: Azithromycin Drug: Placebo Phase 3

Detailed 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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 301 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
  • 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.
Primary Purpose: Treatment
Official Title: Belgian Trial With Azithromycin During Acute COPD Exacerbations
Actual Study Start Date : August 1, 2014
Actual Primary Completion Date : October 2017
Actual Study Completion Date : April 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Azithromycin

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
  • 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
Other Names:
  • Azitromcyine CF
  • ATC code: J01FA10

Placebo Comparator: Placebo

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
  • 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
Other Name: Inactive substance




Primary Outcome Measures :
  1. Time to clinical failure [ Time Frame: Will be assessed between day 1 (from 1 hour after first drug intake) till day 90 (24 hours after last study drug intake) ]

    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


Secondary Outcome Measures :
  1. Number of clinical failures up to Day 90 (key secondary #1) [ Time Frame: Will be assessed on day 90 (last day of treatment phase) ]

    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

  2. COPD Assessment Test (CAT) score at Day 90 (key secondary #2) [ Time Frame: Will be assessed on day 90 (last day of treatment phase) ]

    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

  3. Total days of additional/prolonged systemic steroid use at Day 90 (key secondary #3) [ Time Frame: Will be assessed on day 90 (last day of treatment phase) ]

    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

  4. Number of clinical failures up to Day 270 [ Time Frame: Will be assessed on day 270 (last day of follow-up phase) ]

    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

  5. Time to clinical failure up to Day 90 and up to Day 270 [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  6. Time to new exacerbation within 90 and within 270 days [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  7. Number of new exacerbations up to 90 days and up to 270 days [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  8. Total days of hospital days within 90 and within 270 days [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  9. Total days in intensive care within 90 and within 270 days [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  10. Quality of Life - 5 Dimensions (EQ5D) score at Day 90 and at Day 270 [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  11. COPD Assessment Test (CAT) score at Day 270 [ Time Frame: Will be assessed on day 270 (last day of follow-up phase) ]

    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

  12. Modified Medical Research Council (mMRC) score at Day 90 and Day 270 [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  13. Speech, Spatial and Qualities of Hearing (SSQ5) score at Day 90 and Day 270 [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  14. Pre-bronchodilator forced expiratory volume in 1 second (FEV1) at Day 90 and Day 270 [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  15. Total dose of additional/prolonged systemic steroids at Day 270 [ Time Frame: Will be assessed on day 270 (last day of follow-up phase) ]

    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

  16. Total days of additional/prolonged systemic steroid use at Day 270 [ Time Frame: Will be assessed on day 270 (last day of follow-up phase) ]

    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

  17. Total days of non-study antibiotic use at Day 90 and Day 270 [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  18. Number of home physician contacts at Day 90 and Day 270 [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  19. Average cost of hospitalization at Day 90 and Day 270 including the index hospitalization [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  20. Time to death within 90 and within 270 days [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  21. Time to first treatment intensification within 90 and within 270 days [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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

  22. Time to first step up in hospital care for respiratory reasons within 90 and within 270 days [ Time Frame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase) ]

    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02135354


Locations
Show Show 20 study locations
Sponsors and Collaborators
Wim Janssens
Agentschap voor Innovatie door Wetenschap en Technologie
Investigators
Layout table for investigator information
Principal Investigator: Wim Janssens, MD. PhD KU Leuven - UZ Leuven
  Study Documents (Full-Text)

Documents provided by Wim Janssens, KU Leuven:
Study Protocol  [PDF] October 12, 2016
Statistical Analysis Plan  [PDF] December 5, 2017

Additional Information:
Study Data/Documents: Study Protocol  This link exits the ClinicalTrials.gov site

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Wim Janssens, MD. PhD, KU Leuven
ClinicalTrials.gov Identifier: NCT02135354    
Other Study ID Numbers: s55829 - BACE trial
2013-004420-11 ( EudraCT Number )
IWT-TBM 130233 ( Other Grant/Funding Number: Agentschap voor Innovatie door Wetenschap en Technologie )
First Posted: May 9, 2014    Key Record Dates
Last Update Posted: September 5, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Wim Janssens, KU Leuven:
AECOPD
Chronic Obstructive Pulmonary Disease
Acute exacerbation
Hospitalization
Azithromycin
Macrolides
Randomized Controlled Trial
Placebo
Additional relevant MeSH terms:
Layout table for MeSH terms
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Azithromycin
Anti-Bacterial Agents
Anti-Infective Agents