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

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Unknown status

CT.gov ID

NCT01959100

Collaborator

(none)

480

Enrollment

Location

Arms

101.9

Duration (Months)

4.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Malignant Hematological Diseases	Drug: Azithromycin Drug: Placebo	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

480 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

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

Study Start Date :

Feb 1, 2014

Actual Primary Completion Date :

Apr 1, 2017

Anticipated Study Completion Date :

Aug 1, 2022

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Overall survival [within 2 years of 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)
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 [within 2 years of inclusion]
adverse events
Cumulative dose of steroids treatment [within the 2 years after inclusion]

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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