AZI001: Azithromycin in Bronchiolitis Obliterans Syndrome

• Sponsor: KU Leuven (Other)
• Overall Status: Completed
• CT.gov ID: NCT01009619
• Collaborator: University Hospital, Gasthuisberg (Other), Fund for Scientific Research, Flanders, Belgium (Other)
• Enrollment: 83
• Location: 1
• Arms: 2
• Duration (Months): 51
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

Preventive treatment with azithromycin reduces the prevalence fo Bronchiolitis Obliterans Syndrome after lung transplantation.

Condition or Disease	Intervention/Treatment	Phase
Bronchiolitis Obliterans Syndrome; Graft Rejection; Lymphocytic Bronchiolitis; Respiratory Infection	Drug: Azithromycin; Drug: Placebo	Phase 4

Detailed Description

• Prospective, interventional, randomized, double-blind, placebo-controlled trial.

• Clinical setting (tertiary University Hospital).

• Investigator-driven, no pharmaceutical sponsor.

• Lung transplant recipients.

• Add-on of study-drug (placebo or azithromycin) to 'standard of care' (standardized, routine immunosuppressive and infectious prophylactic protocol).

• 1:1 inclusion ratio (placebo:azithromycin).

• Randomisation at discharge after informed consent.

Study Design

• Study Type: Interventional
• Actual Enrollment: 83 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Randomized Double-blind Placebo-controlled Prevention Trial of Azithromycin in Lung Transplantation.
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azithromycin 250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study	Drug: Azithromycin; Azithromycin 250 mg daily during 5 days followed by 250 mg three times a week on Mon., Wed. and Fri. during study-period.; Other Names: Zitromax (Azithromycin Dihydrate, Pfizer, ZTM250)
Placebo Comparator: Placebo PLacebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.	Drug: Placebo; Placebo once daily during 5 days, followed by one placebo three times a week on Mon., Wed. and Fri during rest of study-period.; Other Names: Lactose monohydricum Ph.Eur. (Fagron)

Outcome Measures

Primary Outcome Measures

1. Prevalence of Bronchiolitis Obliterans Syndrome (BOS) [2 years post-transplant]

   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.

2. Overall Survival [2 years post-transplant]

   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.

Secondary Outcome Measures

1. Acute Rejection Incidence Rate [2 years post-transplant]

   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.

2. Infection Incidence Rate [2 years post-transplant]

   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.

3. Pulmonary Function [during first two years post-transplant]

   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.

4. Broncho-alveolar (BAL) Neutrophilia [during first two years post-transplant]

   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.

5. Plasma C-reactive Protein (CRP) Levels [during the first two years post-transplant]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Stable LTx recipients at discharge after transplantation.

• Signed informed consent

• Adult (age at least 18 years old at moment of transplantation)

• Able to take oral medication

Exclusion Criteria:

• Prolonged and/or complicated ICU-course after transplantation.

• Early (<30 days post-transplant) post-operative death

• Major suture problems (airway stenosis or stent)

• Retransplantation (lung)

• Previous transplantation (solid organ)

• Multi-organ transplantation (lung+ other solid organ)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Katholieke Universiteit Leuven and University Hospital Gasthuisberg	Leuven		Belgium	B-3000

Sponsors and Collaborators

• KU Leuven
• University Hospital, Gasthuisberg
• Fund for Scientific Research, Flanders, Belgium

Investigators

• Principal Investigator: Geert M Verleden, Prof. Dr., KULeuven and University Hospitals Leuven

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT01009619
• Other Study ID Numbers: AZI001; EudraCT ref. 2005-003893-46
• First Posted: Nov 9, 2009
• Last Update Posted: Oct 3, 2011
• Last Verified: Aug 1, 2011

• Keywords provided by , ,: Bronchiolitis Obliterans Syndrome; Acute allograft Rejection; Lymphocytic bronchiolitis; Respiratory infection; Survival; Mortality; Pulmonary function; FEV1; Broncho-alveolar lavage; Neutrophils; Interleukin; Culture; Azithromycin
• Additional relevant MeSH terms: Bronchiolitis; Respiratory Tract Infections; Bronchiolitis Obliterans; Syndrome; Azithromycin

Study Results

Participant Flow

Arm/Group Title	Azithromycin	Placebo
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

Baseline Characteristics

Arm/Group Title	Azithromycin	Placebo	Total
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 Participants	40	43	83
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	38 95%	42 97.7%	80 96.4%
>=65 years	2 5%	1 2.3%	3 3.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.2 (0)	50.9 (0)	51.1 (0)
Sex: Female, Male (Count of Participants)
Female	23 57.5%	23 53.5%	46 55.4%
Male	17 42.5%	20 46.5%	37 44.6%
Region of Enrollment (participants) [Number]
Belgium	40 100%	43 100%	83 100%

Outcome Measures

1. Primary Outcome

Title	Prevalence of Bronchiolitis Obliterans Syndrome (BOS)
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

Outcome Measure Data

Analysis Population Description

intention to treat analysis

Arm/Group Title	Azithromycin	Placebo
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.
Measure Participants	40	43
Number [participants]	5 12.5%	19 44.2%

2. Primary Outcome

Title	Overall Survival
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

Outcome Measure Data

Analysis Population Description

intention to treat

Arm/Group Title	Azithromycin	Placebo
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.
Measure Participants	40	43
Number [participants]	6 15%	8 18.6%

3. Secondary Outcome

Title	Acute Rejection Incidence Rate
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azithromycin	Placebo
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.
Measure Participants	40	43
Mean (Standard Deviation) [incidence rate (events/person per year)]	0.86 (1.53)	0.78 (1.17)

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
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Chi-squared, Corrected
	Comments

4. Secondary Outcome

Title	Infection Incidence Rate
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

Outcome Measure Data

Analysis Population Description

intention to treat

Arm/Group Title	Azithromycin	Placebo
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.
Measure Participants	40	43
Mean (Standard Deviation) [incidence rate (events/person per year)]	0.95 (1.4)	0.73 (1.42)

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
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Chi-squared, Corrected
	Comments

5. Secondary Outcome

Title	Pulmonary Function
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azithromycin	Placebo
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.
Measure Participants	40	43
Mean (Standard Deviation) [percent predicted]	81.11 (20.31)	75.28 (25.31)

6. Secondary Outcome

Title	Broncho-alveolar (BAL) Neutrophilia
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azithromycin	Placebo
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.
Measure Participants	40	43
Mean (Standard Deviation) [percent cells]	9.68 (18.20)	15.73 (25.36)

7. Secondary Outcome

Title	Plasma C-reactive Protein (CRP) Levels
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azithromycin	Placebo
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.
Measure Participants	40	43
Mean (Standard Deviation) [mg/L]	7.06 (16.97)	10.02 (17.51)

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Azithromycin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/43 (0%)
Other (Not Including Serious) Adverse Events
	Azithromycin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/40 (7.5%)		0/43 (0%)
Gastrointestinal disorders
nausea and diarrhea after intake of study drug	3/40 (7.5%)	3	0/43 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.