Study of Azithromycin for Lymphocytic Bronchiolitis/Bronchitis After Lung Transplantation (AZI002)

A Prospective, Open-label Study of Azithromycin for Lymphocytic Bronchiolitis/Bronchitis After Lung Transplantation

This study investigates the role of azithromycin treatment for lymphocytic bronchitis/bronchiolitis after lung transplantation.

Study Overview

• Status: Completed
• Conditions: Lymphocytic Bronchi(Oli)Tis Post-lung Transplantation
• Intervention / Treatment: Drug: Azithromycin Dihydrate

Detailed Description

Lymphocytic bronchitis/bronchiolitis is one of the major risk factors for development of chronic rejection/BOS after lung transplantation. There is currently no established treatment available for this condition. There is now mounting evidence that IL-17 producing lymphocytes (TH17) not only participate in chronic allograft rejection/BOS, but are also present within the airway wall during lymphocytic bronchiolitis and that IL-17 mRNA-levels in bronchoalveolar lavage fluid of these patients are upregulated. As such, TH17 may account for the increased BAL neutrophilia seen in these patients, as IL-17 may be responsible for driving IL-8 secretion (a neutrophil-attracting chemokine) from various cell types in the airways. Since azithromycin has previously been shown to reduce both IL-17 induced IL-8 production by human airway smooth muscle cells 'in vitro' and bronchoalveolar IL-8/neutrophil levels in LTx recipients with established BOS, we believe that azithromycin has great potential for treating lymphocytic bronchi(oli)tis by attenuating this TH17/IL-17/IL-8-mediated airway inflammation, possibly even halting the subsequent development of chronic rejection/BOS after lung transplantation. In this study, histologic, spirometric, bronchoalveolar an radiologic features will be investigated in patients treated with confirmed lymphocytic bronchitis/bronchiolitis treated with azithromycin.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, B-3000
      • University Hospital Gasthuisberg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent
• Adult (age at least 18 years old at moment of transplantation)
• Able to take oral medication
• Histologic diagnosis of lymphocytic bronchiolitis or bronchitis ('grade B') without concurrent acute cellular allograft rejection 'grade A' ≥2

Exclusion Criteria:

• Severe suture problems (e.g. airway stenosis) requiring lasering or stenting

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azithromycin; Add-on of study-drug (azithromycin) to 'standard of care': 250 mg daily for 5 days, followed by 250 mg every other day until the end of the study-period (6 months treatment).	Drug: Azithromycin Dihydrate; Add-on of study-drug (azithromycin) to 'standard of care' at diagnosis of lymphocytic bronchi(oli)tis. Study-drug regime: 250 mg daily for 5 days, followed by 250 mg every other day until the end of the study-period (6 months treatment).; Other Names: Azithromycin 250 mg, ZTM250, Zitromax TM (ATC J01FA10)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Histology on bronchial and/or transbronchial biopsies	Evolution of lymphocytic airway inflammation after 3 months of treatment	after 3 months of treatment
Pulmonary function (FEV1)	Evolution of FEV1 after 3 months of treatment	after 3 months of treatment
Bronchoalveolar cellularity and protein levels (IL-8, IL-17)	Evolution of bronchoalveolar cellularity and protein levels (IL-8, IL-17) after 3 months of treatment	after 3 months of treatment
Radiologic features	Evolution of radiologic features (e.g. tree-in-bud, consolidation, bronchiectasis, air trapping, etc.) on chest X-ray or HRCT after 3 months of treatment	after 3 months of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary function (FEV1)	Evolution of FEV1 after 6 months of treatment	after 6 months of treatment

Collaborators and Investigators

• Sponsor: KU Leuven
• Collaborators: Fund for Scientific Research, Flanders, Belgium
• Investigators: Principal Investigator: Geert M Verleden, MD, PhD, KULeuven and UZ Leuven

Publications and helpful links

General Publications

• Vanaudenaerde BM, De Vleeschauwer SI, Vos R, Meyts I, Bullens DM, Reynders V, Wuyts WA, Van Raemdonck DE, Dupont LJ, Verleden GM. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant. 2008 Sep;8(9):1911-20. doi: 10.1111/j.1600-6143.2008.02321.x.
• Vanaudenaerde BM, Wuyts WA, Geudens N, Dupont LJ, Schoofs K, Smeets S, Van Raemdonck DE, Verleden GM. Macrolides inhibit IL17-induced IL8 and 8-isoprostane release from human airway smooth muscle cells. Am J Transplant. 2007 Jan;7(1):76-82. doi: 10.1111/j.1600-6143.2006.01586.x. Epub 2006 Oct 25.
• Vanaudenaerde BM, Dupont LJ, Wuyts WA, Verbeken EK, Meyts I, Bullens DM, Dilissen E, Luyts L, Van Raemdonck DE, Verleden GM. The role of interleukin-17 during acute rejection after lung transplantation. Eur Respir J. 2006 Apr;27(4):779-87. doi: 10.1183/09031936.06.00019405.
• Verleden GM, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2006 Sep 1;174(5):566-70. doi: 10.1164/rccm.200601-071OC. Epub 2006 Jun 1.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: April 21, 2010
• First Submitted That Met QC Criteria: April 22, 2010
• First Posted (Estimate): April 23, 2010

Study Record Updates

• Last Update Posted (Estimate): July 4, 2013
• Last Update Submitted That Met QC Criteria: July 3, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: lung transplantation; azithromycin; bronchiolitis obliterans syndrome; lymphocytic bronchitis or bronchiolitis; acute allograft rejection; chronic allograft rejection
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchiolitis; Bronchitis; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: AZI002; 2010-018724-16 (EudraCT Number)