Clinical trial NCT02135354: Azithromycin for Acute Exacerbations Requiring Hospitalization
Official title: Belgian Trial With Azithromycin During Acute COPD Exacerbations
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: AECOPD
Chronic Obstructive Pulmonary Disease
Acute exacerbation
Hospitalization
Azithromycin
Macrolides
Randomized Controlled Trial
Placebo
Lead sponsor: KU Leuven
Sponsor class: OTHER
Collaborators: name: Agentschap voor Innovatie door Wetenschap en Technologie
First posted: 2014-05-09
Enrollment: 301
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Time to clinical failure
timeFrame: 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:
measure: Number of clinical failures up to Day 90 (key secondary #1)
timeFrame: Will be assessed on day 90 (last day of treatment phase)
measure: COPD Assessment Test (CAT) score at Day 90 (key secondary #2)
timeFrame: Will be assessed on day 90 (last day of treatment phase)
measure: Total days of additional/prolonged systemic steroid use at Day 90 (key secondary #3)
timeFrame: Will be assessed on day 90 (last day of treatment phase)
measure: Number of clinical failures up to Day 270
timeFrame: Will be assessed on day 270 (last day of follow-up phase)
measure: Time to clinical failure up to Day 90 and up to Day 270
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Time to new exacerbation within 90 and within 270 days
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Number of new exacerbations up to 90 days and up to 270 days
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Total days of hospital days within 90 and within 270 days
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Total days in intensive care within 90 and within 270 days
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Quality of Life - 5 Dimensions (EQ5D) score at Day 90 and at Day 270
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: COPD Assessment Test (CAT) score at Day 270
timeFrame: Will be assessed on day 270 (last day of follow-up phase)
measure: Modified Medical Research Council (mMRC) score at Day 90 and Day 270
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Speech, Spatial and Qualities of Hearing (SSQ5) score at Day 90 and Day 270
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Pre-bronchodilator forced expiratory volume in 1 second (FEV1) at Day 90 and Day 270
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Total dose of additional/prolonged systemic steroids at Day 270
timeFrame: Will be assessed on day 270 (last day of follow-up phase)
measure: Total days of additional/prolonged systemic steroid use at Day 270
timeFrame: Will be assessed on day 270 (last day of follow-up phase)
measure: Total days of non-study antibiotic use at Day 90 and Day 270
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Number of home physician contacts at Day 90 and Day 270
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Average cost of hospitalization at Day 90 and Day 270 including the index hospitalization
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Time to death within 90 and within 270 days
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Time to first treatment intensification within 90 and within 270 days
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
measure: Time to first step up in hospital care for respiratory reasons within 90 and within 270 days
timeFrame: Will be assessed on day 90 (last day of treatment phase) and day 270 (last day of follow-up phase)
Other outcomes:
Locations:
city: Brussel
country: Belgium
facility: UZ Brussel
state: Brussel Hoofdstedelijk Gewest
city: Brussel
country: Belgium
facility: St. Pieterziekenhuis
state: Brussels Hoofdstedelijk Gewest
city: Antwerpen
country: Belgium
facility: ZNA Middelheim
state: Vlaanderen
city: Antwerpen
country: Belgium
facility: St. Augustinus Ziekenhuis
state: Vlaanderen
city: Bonheiden
country: Belgium
facility: Imelda Ziekenhuis
state: Vlaanderen
city: Brugge
country: Belgium
facility: St. Jan Brugge Ziekenhuis
state: Vlaanderen
city: Gent
country: Belgium
facility: Maria Middelaresziekenhuis
state: Vlaanderen
city: Gent
country: Belgium
facility: UZ Gent
state: Vlaanderen
city: Hasselt
country: Belgium
facility: Jessa Ziekenhuis
state: Vlaanderen
city: Kortrijk
country: Belgium
facility: AZ Groeninge Ziekenhuis
state: Vlaanderen
city: Leuven
country: Belgium
facility: UZ Gasthuisberg
state: Vlaanderen
city: Roeselare
country: Belgium
facility: Heilig Hart Ziekenhuis
state: Vlaanderen
city: Tielt
country: Belgium
facility: St. Andriesziekenhuis
state: Vlaanderen
city: Charleroi
country: Belgium
facility: CHU Charleroi
state: Wallonië
city: Gilly
country: Belgium
facility: Grand Hôpital de Charleroi
state: Wallonië
city: Liège
country: Belgium
facility: CHU Liège
state: Wallonië
city: Yvoir
country: Belgium
facility: CHU Mont-Godinne
state: Wallonië
city: Aalst
country: Belgium
facility: Onze-Lieve-Vrouwziekenhuis
city: Malmedy
country: Belgium
facility: Clinique Reine Astrid
city: Namur
country: Belgium
facility: Clinique Sainte-Elisabeth
Study officials:
affiliation: KU Leuven - UZ Leuven
name: Wim Janssens, MD. PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.