Azithromycin in Bronchiolitis Obliterans Syndrome - Clinical Trial for Bronchiolitis Obliterans Syndrome | NCT01009619

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Primary Purpose

Status

Completed

Phase

Phase 4

Locations

Belgium

Study Type

Interventional

Intervention

Azithromycin

Placebo

About this trial

This is an interventional prevention trial for Bronchiolitis Obliterans Syndrome focused on measuring Bronchiolitis Obliterans Syndrome, Acute allograft Rejection, Lymphocytic bronchiolitis, Respiratory infection, Survival, Mortality, Pulmonary function, FEV1, Broncho-alveolar lavage, Neutrophils, Interleukin, Culture, Azithromycin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Katholieke Universiteit Leuven and University Hospital Gasthuisberg

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Azithromycin

Placebo

Arm 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.

Outcomes

Primary Outcome Measures

Prevalence of Bronchiolitis Obliterans Syndrome (BOS)

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.

Overall Survival

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

Acute Rejection Incidence Rate

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.

Infection Incidence Rate

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.

Pulmonary Function

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.

Broncho-alveolar (BAL) Neutrophilia

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.

Plasma C-reactive Protein (CRP) Levels

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.

Full Information

NCT ID

NCT01009619

First Posted

November 6, 2009

Last Updated

August 29, 2011

Sponsor

KU Leuven

Collaborators

University Hospital, Gasthuisberg, Fund for Scientific Research, Flanders, Belgium

1. Study Identification

Unique Protocol Identification Number

NCT01009619

Brief Title

Azithromycin in Bronchiolitis Obliterans Syndrome

Acronym

AZI001

Official Title

Randomized Double-blind Placebo-controlled Prevention Trial of Azithromycin in Lung Transplantation.

Study Type

Interventional

2. Study Status

Record Verification Date

August 2011

Overall Recruitment Status

Completed

Study Start Date

September 2005 (undefined)

Primary Completion Date

December 2009 (Actual)

Study Completion Date

December 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

KU Leuven

Collaborators

University Hospital, Gasthuisberg, Fund for Scientific Research, Flanders, Belgium

4. Oversight

Data Monitoring Committee

No

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Bronchiolitis Obliterans Syndrome, Graft Rejection, Lymphocytic Bronchiolitis, Respiratory Infection

Keywords

Bronchiolitis Obliterans Syndrome, Acute allograft Rejection, Lymphocytic bronchiolitis, Respiratory infection, Survival, Mortality, Pulmonary function, FEV1, Broncho-alveolar lavage, Neutrophils, Interleukin, Culture, Azithromycin

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

83 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Azithromycin

Arm Type

Experimental

Arm Description

250 mg daily for 5 days, followed by 250 mg three times a week (Mon.-Wed.-Fri.) until the end of study

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

PLacebo daily for 5 days, followed by placebo three times a week (Mon.-Wed.-Fri.) until end of study.

Intervention Type

Drug

Intervention Name(s)

Azithromycin

Other Intervention Name(s)

Zitromax (Azithromycin Dihydrate, Pfizer, ZTM250)

Intervention Description

Azithromycin 250 mg daily during 5 days followed by 250 mg three times a week on Mon., Wed. and Fri. during study-period.

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Lactose monohydricum Ph.Eur. (Fagron)

Intervention Description

Placebo once daily during 5 days, followed by one placebo three times a week on Mon., Wed. and Fri during rest of study-period.

Primary Outcome Measure Information:

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

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

Secondary Outcome Measure Information:

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

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

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

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

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Geert M Verleden, Prof. Dr.

Organizational Affiliation

KULeuven and University Hospitals Leuven

Official's Role

Principal Investigator

Facility Information:

Facility Name

Katholieke Universiteit Leuven and University Hospital Gasthuisberg

City

Leuven

ZIP/Postal Code

B-3000

Country

Belgium

12. IPD Sharing Statement

Citations:

PubMed Identifier

26372728

Citation

Ruttens D, Verleden SE, Vandermeulen E, Bellon H, Vanaudenaerde BM, Somers J, Schoonis A, Schaevers V, Van Raemdonck DE, Neyrinck A, Dupont LJ, Yserbyt J, Verleden GM, Vos R. Prophylactic Azithromycin Therapy After Lung Transplantation: Post hoc Analysis of a Randomized Controlled Trial. Am J Transplant. 2016 Jan;16(1):254-61. doi: 10.1111/ajt.13417. Epub 2015 Aug 4.

Results Reference

derived

PubMed Identifier

20562124

Citation

Vos R, Vanaudenaerde BM, Verleden SE, De Vleeschauwer SI, Willems-Widyastuti A, Van Raemdonck DE, Schoonis A, Nawrot TS, Dupont LJ, Verleden GM. A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur Respir J. 2011 Jan;37(1):164-72. doi: 10.1183/09031936.00068310. Epub 2010 Jun 18.

Results Reference

derived

Azithromycin in Bronchiolitis Obliterans Syndrome (AZI001)

Bronchiolitis Obliterans Syndrome, Graft Rejection, Lymphocytic Bronchiolitis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial