Azithromycin in Bronchiolitis Obliterans Syndrome (AZI001)

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

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

Study Overview

• Status: Completed
• Conditions: Graft Rejection; Respiratory Infection; Bronchiolitis Obliterans Syndrome; Lymphocytic Bronchiolitis
• Intervention / Treatment: Drug: Azithromycin; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, B-3000
    • Katholieke Universiteit Leuven and University Hospital Gasthuisberg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	2 years post-transplant
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.	2 years post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	2 years post-transplant
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.	2 years post-transplant
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.	during first two years post-transplant
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.	during first two years post-transplant
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.	during the first two years post-transplant

Collaborators and Investigators

• Sponsor: KU Leuven
• Collaborators: University Hospital, Gasthuisberg; Fund for Scientific Research, Flanders, Belgium
• Investigators: Principal Investigator: Geert M Verleden, Prof. Dr., KULeuven and University Hospitals Leuven

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (ACTUAL): December 1, 2009
• Study Completion (ACTUAL): December 1, 2009

Study Registration Dates

• First Submitted: November 6, 2009
• First Submitted That Met QC Criteria: November 6, 2009
• First Posted (ESTIMATE): November 9, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): October 3, 2011
• Last Update Submitted That Met QC Criteria: August 29, 2011
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Keywords: Survival; Azithromycin; Mortality; Respiratory infection; Neutrophils; FEV1; Pulmonary function; Interleukin; Bronchiolitis Obliterans Syndrome; Culture; Broncho-alveolar lavage; Acute allograft Rejection; Lymphocytic bronchiolitis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Diseases; Lung Diseases; Disease; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Syndrome; Respiratory Tract Infections; Bronchiolitis; Bronchiolitis Obliterans; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: AZI001; EudraCT ref. 2005-003893-46 (REGISTRY: ISRCTN36220396)