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Azithromycin in Bronchiolitis Obliterans Syndrome (AZI001)

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ClinicalTrials.gov Identifier: NCT01009619
Recruitment Status : Completed
First Posted : November 9, 2009
Results First Posted : August 25, 2011
Last Update Posted : October 3, 2011
Sponsor:
Collaborators:
University Hospital, Gasthuisberg
Fund for Scientific Research, Flanders, Belgium
Information provided by:
KU Leuven

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Conditions Bronchiolitis Obliterans Syndrome
Graft Rejection
Lymphocytic Bronchiolitis
Respiratory Infection
Interventions Drug: Azithromycin
Drug: Placebo
Enrollment 83
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Azithromycin Placebo
Hide Arm/Group Description 250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study Placebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.
Period Title: Overall Study
Started 40 43
Completed 40 43
Not Completed 0 0
Arm/Group Title Azithromycin Placebo Total
Hide Arm/Group Description 250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study Placebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study. Total of all reporting groups
Overall Number of Baseline Participants 40 43 83
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 43 participants 83 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
38
  95.0%
42
  97.7%
80
  96.4%
>=65 years
2
   5.0%
1
   2.3%
3
   3.6%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 40 participants 43 participants 83 participants
51.2  (0) 50.9  (0) 51.1  (0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 43 participants 83 participants
Female
23
  57.5%
23
  53.5%
46
  55.4%
Male
17
  42.5%
20
  46.5%
37
  44.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Belgium Number Analyzed 40 participants 43 participants 83 participants
40 43 83
1.Primary Outcome
Title Prevalence of Bronchiolitis Obliterans Syndrome (BOS)
Hide Description BOS was defined as a sustained decrease in forced Expiratory Volume in one second (FEV1) of at least 20% from the patient's maximum post-operative values in the absence of other causes.
Time Frame 2 years post-transplant
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
intention to treat analysis
Arm/Group Title Azithromycin Placebo
Hide Arm/Group Description:
250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study
Placebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.
Overall Number of Participants Analyzed 40 43
Measure Type: Number
Unit of Measure: participants
5 19
2.Primary Outcome
Title Overall Survival
Hide Description Survival data were obtained using all-cause mortality information in the Leuven University Hospital transplant database, in which all our lung transplant recipients since 1991 are registered. For the end-point of all-cause mortality, survival times were not censored at retransplantation or at study-discontinuation if these preceded death, or else at 2 years after transplantation.
Time Frame 2 years post-transplant
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
intention to treat
Arm/Group Title Azithromycin Placebo
Hide Arm/Group Description:
250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study
Placebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.
Overall Number of Participants Analyzed 40 43
Measure Type: Number
Unit of Measure: participants
6 8
3.Secondary Outcome
Title Acute Rejection Incidence Rate
Hide Description Bronchoscopy and broncho-alveolar lavage (BAL) was routinely performed at discharge, 3, 6, 12, 18, 24 months post-transplantation and later at intervals of 1 year, or in case of clinically suspected acute allograft rejection, infection or chronic rejection. Transbronchial biopsies were routinely performed at discharge and 3 months post-transplant or in case of suspected acute rejection, infection or chronic rejection. Biopsies were graded according to the 1996 ISHLT-guidelines (grade A0-4 with concomitant B0-4), as well as assessed for other interstitial lesions of the pulmonary graft.
Time Frame 2 years post-transplant
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Azithromycin Placebo
Hide Arm/Group Description:
250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study
Placebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.
Overall Number of Participants Analyzed 40 43
Mean (Standard Deviation)
Unit of Measure: incidence rate (events/person per year)
0.86  (1.53) 0.78  (1.17)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Azithromycin, Placebo
Comments The frequency or rate of specific events (i.e. acute rejection, cytomegalovirus (CMV) and non-CMV infections) was calculated by determining the number of events per year of study time for each subject, correcting for CMV-mismatch status.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Chi-squared, Corrected
Comments [Not Specified]
4.Secondary Outcome
Title Infection Incidence Rate
Hide Description Cytomegalovirus (CMV)-status was assessed on on every broncho-alevolar lavage sample and by serum CMV DNA at weekly intervals during hospitalization and thereafter at each outpatient evaluation or hospital admission. Immunohistochemical staining for CMV was performed on transbronchial biopsies in case of clinical suspicion of infection (i.e. dyspnea, cough, sputum, fever, increased plasma C-reactive protein, new chest radiograph infiltrates, or a decrease of at least 10% in peak expiratory flow (PEF) as measured by patient’s peak flow measurements.
Time Frame 2 years post-transplant
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
intention to treat
Arm/Group Title Azithromycin Placebo
Hide Arm/Group Description:
250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study
Placebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.
Overall Number of Participants Analyzed 40 43
Mean (Standard Deviation)
Unit of Measure: incidence rate (events/person per year)
0.95  (1.4) 0.73  (1.42)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Azithromycin, Placebo
Comments The frequency or rate of specific events (i.e. acute rejection, cytomegalovirus (CMV) and non-CMV infections) was calculated by determining the number of events per year of study time for each subject, correcting for CMV-mismatch status.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Chi-squared, Corrected
Comments [Not Specified]
5.Secondary Outcome
Title Pulmonary Function
Hide Description Spirometry (Masterscreen, Jaeger, Hoechberg, Germany) was performed at twice weekly intervals for the first 2 postoperative months, thereafter at weekly to biweekly intervals until 6 months post-transplantation, then every 2 to 4 weeks until the first postoperative year and afterwards life-long at intervals of 2 to 3 months according to American Thoracic Society standards and forced expiratory volume in one second (FEV1) expressed in terms of the percentage of predicted values.
Time Frame during first two years post-transplant
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Azithromycin Placebo
Hide Arm/Group Description:
250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study
Placebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.
Overall Number of Participants Analyzed 40 43
Mean (Standard Deviation)
Unit of Measure: percent predicted
81.11  (20.31) 75.28  (25.31)
6.Secondary Outcome
Title Broncho-alveolar (BAL) Neutrophilia
Hide Description BAL was performed with two 50 mL aliquots of sterile saline at room temperature. Five mL of the recovered BAL fluid was sent for microbiological and virological assessment, whereas the remaining fluid was analysed for cell counts after a cytospin was made in a Shandon cytocentrifuge and stained with May-Grünwald-Giemsa. Differential cell counts were determined by counting at least 300 cells.
Time Frame during first two years post-transplant
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Azithromycin Placebo
Hide Arm/Group Description:
250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study
Placebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.
Overall Number of Participants Analyzed 40 43
Mean (Standard Deviation)
Unit of Measure: percent cells
9.68  (18.20) 15.73  (25.36)
7.Secondary Outcome
Title Plasma C-reactive Protein (CRP) Levels
Hide Description Plasma C-reactive protein (CRP) levels were assessed using Tina-quant CRP latex assay, Roche, Mannheim, Germany; sensitivity threshold of 1 mg/L, upper limit of normal 5 mg/L.
Time Frame during the first two years post-transplant
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Azithromycin Placebo
Hide Arm/Group Description:
250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study
Placebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.
Overall Number of Participants Analyzed 40 43
Mean (Standard Deviation)
Unit of Measure: mg/L
7.06  (16.97) 10.02  (17.51)
Time Frame A study-nurse verified compliance and possible adverse events at each contact with patients during routine follow-up visits at the outpatient clinic or hospital-admissions during the first two years post-transplant.
Adverse Event Reporting Description

Definition for adverse events:

Serious adverse events: allergic (rash, urticaria, Stevens-Johnson syndrome, angioneurotic edema or anaphylaxis), cardiac (ventricular tachycardia or Torsades de Pointes), neurologic (convulsions).

Other adverse events: gastro-intestinal (nausea, dyspepsia, pain or cramps, diarrhea or pseudomembranous colitis).

 
Arm/Group Title Azithromycin Placebo
Hide Arm/Group Description 250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study Placebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.
All-Cause Mortality
Azithromycin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Azithromycin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/40 (0.00%)      0/43 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Azithromycin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/40 (7.50%)      0/43 (0.00%)    
Gastrointestinal disorders     
nausea and diarrhea after intake of study drug   3/40 (7.50%)  3 0/43 (0.00%)  0
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Prof. Dr. GM Verleden
Organization: Katholieke Universiteit Leuven and University Hospital Leuven
Phone: +32 16 34 68 08
Responsible Party: Prof. Dr. GM. Verleden, KULeuven and University Hospital Leuven
ClinicalTrials.gov Identifier: NCT01009619     History of Changes
Other Study ID Numbers: AZI001
EudraCT ref. 2005-003893-46 ( Registry Identifier: ISRCTN36220396 )
First Submitted: November 6, 2009
First Posted: November 9, 2009
Results First Submitted: April 21, 2011
Results First Posted: August 25, 2011
Last Update Posted: October 3, 2011