Efficacy of Azithromycin to Prevent Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation

Study Overview
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Brief Summary
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The occurrence of bronchiolitis obliterans syndrome (SBO) after allogeneic hematopoietic stem cell transplantation (HSCT) is considered to be a chronic pulmonary graft versus host disease (GVHD) that is associated with significant mortality and morbidity. The reported incidence of SBO varies from 6 to 26% of allogeneic HSC recipients and is usually diagnosed within 2 years after transplantation. The diagnosis of SBO relies on the occurrence of a new airflow obstruction identified during pulmonary function testing, and the definition differs between studies. Currently, no curative immunosuppressive treatment is available, and recent data suggest that the use of these treatments, especially corticosteroids, should be limited because of their toxicity. The impairment of lung function parameters is likely caused by fibrous small airway lesions. Few data on the pathogenesis of SBO after allogeneic HSCT are available. Several hypotheses are based on the occurrence of SBO during chronic graft rejection after lung transplantation, which shares many clinical and histopathological similarities with SBO after allogeneic HSCT. One hypothesis is that the first step leading to SBO is lung epithelium injury. SBO is then identified as an alloimmune reaction with only one clearly identified risk factor: extrathoracic chronic GVHD. Due to their anti-inflammatory and immunomodulatory properties, recent data suggest that low-dose macrolides may be effective at preventing SBO after lung transplants. This well-tolerated treatment may be useful for preventing SBO after allogeneic HSCT. The objective of this Phase 3 multicentre randomized, double-blinded, clinical trial is to evaluate the efficacy of azithromycin in preventing BO syndrome after allogeneic HSCT in patients with malignant hematological diseases.

Official Title
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Evaluation of the Efficacy of Azithromycin to Prevent Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Malignant Hematological Diseases

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients> 16 years old Experimenting an allogeneic HSCT for a hematologic malignancy Pre-transplantation Pulmonary Function Testing With written informed consent Exclusion Criteria: Allergy or Intolerance to azithromycin, macrolides or ketolide or excipient Prolonged corrected QT (QTc) interval (>450 msec) Taking medications that prolong the QTc interval (Cisapride, ergotamine, dyhydroergotamine) Taking ergotamine and dyhydroergotamine due to the risk of ergotism Family history of a prolonged QTc interval. History of congestive heart failure Taking colchicine Severe liver insufficiency • History of infection due to atypical mycobacteria

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azithromycine<br>250 mg x 3/week during a meal for a period of 2 years | Drug: Azithromycin<br>* 250 mg x 3/week per os during a meal for a period of 2 years<br>|
| Placebo Comparator: Placebo<br>250 mg x 3/week during a meal for a period of 2 years. | Drug: Placebo<br>* 250 mg x 3/week during a meal for a period of 2 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Airflow decline (AFD)-free survival | Defined on the criteria from Chien JW et al (Am J Resp Crit Care Med 2003;168:208-14) by an annualized decline of percent predicted forced expiratory volume in 1 second (FEV1) of more than 5% | 2 year after allogeneic HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | within 2 years of inclusion | 
| Occurrence of late-onset pulmonary non-infectious complications (=bronchiolitis obliterans syndrome, SBO) | bronchiolitis obliterans syndrome (SBO) is defined as the absence of infection with an forced expiratory volume in 1 second (FEV1) of <75% of predicted or a decline of > 10% and FEV1/Slow vital capacity (SVC) < 0.7 or residual volume (RV) or RV/total lung capacity (TLC) > 120%, and interstitial lung disease, which is defined as the onset of new interstitial lung abnormalities observed with a lung CT scan and the absence of infection. | within 2 years after inclusion | 
| Variation of pulmonary function testing parameters | variation in mean forced expiratory volume in 1 second (FEV1) decline, forced vital capacity (FVC), residual volume (RV), Total Lung capacity (TLC), Forced expiratory flow at 25% point to the 75% point of Forced Vital Capacity (FEF25-75%) as compared to baseline values (at inclusion) | within 2 years after inclusion | 
| Occurrence of acute and chronic extra-thoracic graft versus host disease (GVHD) |  | within 2 years after inclusion | 
| Cumulative incidence of hematological relapse |  | within the 2 years after inclusion | 
| Quality of life |  | within 2 years after inclusion | 
| Tolerance | adverse events | within 2 years of inclusion | 
| Cumulative dose of steroids treatment |  | within the 2 years after inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hematopoietic stem cell transplantation, pulmonary non-infectious complications, bronchiolitis obliterans syndrome