Azithromycin in Bronchiolitis Obliterans Syndrome (AZI001)

• 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: KU Leuven
• Collaborators: University Hospital, Gasthuisberg; Fund for Scientific Research, Flanders, Belgium
• Information provided by: KU Leuven

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 (Clinical Trial)
• 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: September 2005
• Actual Primary Completion Date: December 2009
• Actual Study Completion Date: December 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 Name: 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 Name: Lactose monohydricum Ph.Eur. (Fagron)

Outcome Measures

Primary Outcome Measures :

1. Prevalence of Bronchiolitis Obliterans Syndrome (BOS) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

Belgium

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Prof. Dr. GM. Verleden, KULeuven and University Hospital Leuven
• ClinicalTrials.gov Identifier: NCT01009619
• Other Study ID Numbers: AZI001; EudraCT ref. 2005-003893-46 ( Registry Identifier: ISRCTN36220396 )
• First Posted: November 9, 2009
• Results First Posted: August 25, 2011
• Last Update Posted: October 3, 2011
• Last Verified: August 2011

Keywords provided by KU Leuven:

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; Disease; Pathologic Processes; Infections; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Azithromycin; Anti-Bacterial Agents; Anti-Infective Agents