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

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

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.

Study Overview

• Status: Unknown
• Conditions: Malignant Hematological Diseases
• Intervention / Treatment: Drug: Azithromycin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 480
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Ile De France
    • Paris, Ile De France, France, 75010
      • Saint Louis

Participation Criteria

Eligibility Criteria

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

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Bergeron A, Chevret S, Chagnon K, Godet C, Bergot E, Peffault de Latour R, Dominique S, de Revel T, Juvin K, Maillard N, Reman O, Contentin N, Robin M, Buzyn A, Socie G, Tazi A. Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2015 Jun 1;191(11):1242-9. doi: 10.1164/rccm.201410-1818OC.
• Bergeron A, Chevret S, Granata A, Chevallier P, Vincent L, Huynh A, Tabrizi R, Labussiere-Wallet H, Bernard M, Chantepie S, Bay JO, Thiebaut-Bertrand A, Thepot S, Contentin N, Fornecker LM, Maillard N, Risso K, Berceanu A, Blaise D, Peffault de La Tour R, Chien JW, Coiteux V, Socie G; ALLOZITHRO Study Investigators. Effect of Azithromycin on Airflow Decline-Free Survival After Allogeneic Hematopoietic Stem Cell Transplant: The ALLOZITHRO Randomized Clinical Trial. JAMA. 2017 Aug 8;318(6):557-566. doi: 10.1001/jama.2017.9938.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): April 1, 2017
• Study Completion (Anticipated): August 1, 2022

Study Registration Dates

• First Submitted: October 7, 2013
• First Submitted That Met QC Criteria: October 8, 2013
• First Posted (Estimate): October 9, 2013

Study Record Updates

• Last Update Posted (Actual): January 7, 2020
• Last Update Submitted That Met QC Criteria: January 6, 2020
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: hematopoietic stem cell transplantation; bronchiolitis obliterans syndrome; pulmonary non-infectious complications
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Hematologic Diseases; Bronchiolitis; Bronchiolitis Obliterans; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: P120110