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

Phase 3

• Conditions: Malignant Hematological Diseases
• Interventions: Drug: Placebo; Drug: Azithromycin

• Registration Number: NCT01959100
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2013-10-07
• Study First Submitted QC: 2013-10-08
• Study First Posted: 2013-10-09
• Study Start: 2014-02
• Primary Completion: 2017-04
• Status Verified: 2019-12
• Last Update Submitted: 2020-01-06
• Last Update Posted: 2020-01-07
• Study Completion: 2022-08

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 480

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	250 mg x 3/week during a meal for a period of 2 years.
Azithromycine	Azithromycin	250 mg x 3/week during a meal for a period of 2 years

Primary Outcome Measures

Name	Time	Method
Airflow decline (AFD)-free survival	2 year after allogeneic HSCT	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%

Secondary Outcome Measures

Name	Time	Method
Occurrence of acute and chronic extra-thoracic graft versus host disease (GVHD)	within 2 years after inclusion
Overall survival	within 2 years of inclusion
Cumulative incidence of hematological relapse	within the 2 years after inclusion
Quality of life	within 2 years after inclusion
Cumulative dose of steroids treatment	within the 2 years after inclusion
Occurrence of late-onset pulmonary non-infectious complications (=bronchiolitis obliterans syndrome, SBO)	within 2 years after inclusion	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.
Variation of pulmonary function testing parameters	within 2 years after inclusion	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)
Tolerance	within 2 years of inclusion	adverse events

Trial Locations

Locations (1)

Saint Louis; 🇫🇷 Paris, Ile De France, France