Efficacy Study of Azithromycin-based Therapy for Bronchiolitis Obliterans

Study Overview
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Brief Summary
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[Study Objectives] To evaluate the efficacy of azithromycin, N-acetylcystein, and inhaled corticosteroid combination therapy in patients with bronchiolitis obliterans as a complication of allogeneic hematopoietic cell transplantation in terms of response rate at 6 months after treatment initiation based on the improvement of FEV1.

Detailed Description
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Bronchiolitis obliterans (BO) is a graft-versus-host disease of respiratory organs. Prognosis of BO is very poor, and the overall outcome of patients who are involved in BO is very dismal. The mechanism of BO has been known to be associated with immune / non-immune response. Corticosteroid and immunosuppressants are recommended as a best current treatment options for BO, which have been not satisfactory. Many treatment options have been tried to improve the outcome of BO. Azithromycin, as an immune modulating agent, has been tried for the treatment of BO, and has been reported to show hopeful results. N-acetylcystein, as an antioxidative agent, has been tried for BO. Inhaled corticosteroid may help to improve airway inflammation and decrease the amount of systemic corticosteroid. These 3 drugs are widely used for other respiratory disease, have been proven to be safe, and have shown some efficacy for BO in various depth of evidence. In these rationale, we'd like to try the 3-drug combination for BO, to assess the efficacy and safety of these drug combination.

Official Title
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A Pilot Study Evaluating the Efficacy of Azithromycin, N-acetylcystein and Inhaled Corticosteroid Combination Therapy for Bronchiolitis Obliterans After Allogeneic Hematopoietic Cell Transpantation

Conditions
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Graft vs Host Disease, Bronchiolitis Obliterans

Intervention / Treatment
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* Drug: azithromycin + N-acetylcystein + inhaled corticosteroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who previously received allogeneic hematopoietic cell transplantation due to hematologic malignancy, bone marrow failure syndrome, and other compatible disease. Patients who are diagnosed as bronchiolitis obliterans (BO) according to the NIH diagnostic guideline which is suggested as below. Patients should be 15 years of age or older, but younger than 75 years. Patients should have estimated life expectancy of more than 3 months. Patients must have adequate hepatic function (bilirubin less than 3.0 ㎎/㎗, AST and ALT less than three times the upper normal limit). Patients must have adequate renal function (creatinine less than 2.0 ㎎/㎗). Exclusion Criteria: Presence of significant active infection Presence of uncontrolled bleeding Any coexisting major illness or organ failure Patients with a psychiatric disorder or mental deficiency severe as to make compliance with the treatment unlike, and making informed consent impossible. Nursing women, pregnant women, women of childbearing potential who do not want adequate contraception Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years following therapy with curative intent (except curatively treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia)

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 75 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azithromycin<br>Patient who are diagnosed as bronchiolitis obliterans according to the WHO criteria | Drug: azithromycin + N-acetylcystein + inhaled corticosteroid<br>* Azithromycin 500mg qd x 1 week --> 250mg qod x 6 months N-acetylcystein 200mg tid x 6 months Fluticasone 250mcg puff x2/day x 6 months<br>* Other names: Zithromax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate based on the improvement of FEV1 | Response rate at 6 months after treatment initiation based on the improvement of FEV1 | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit rate based on the degree of change in FEV1 | Clinical benefit rate at 6 months after treatment initiation based on the degree of change in FEV1 | 6 months | 
| change in FEV1 compared with pretreatment level | Change in FEV1 at 6 months after treatment initiation compared with pretreatment level | 6 months after treatment initiation | 
| Reduction rate in immunosuppressive agent / systemic corticosteroid | Reduction rate in immunosuppressive agent / systemic corticosteroid at 6 months after treatment initiation | 6 months after treatment initiation | 
| Discontinuation rate in immunosuppressive agent / systemic corticosteroid | Discontinuation rate in immunosuppressive agent / systemic corticosteroid at 6 months after treatment initiation | 6 months after treatment initiation | 
| Change in dose-intensity of immunosuppressive agent / systemic corticosteroid compared with pretreatment dose-intensity | Change in dose-intensity of immunosuppressive agent / systemic corticosteroid at 6 month after treatment initiation compared with pretreatment dose-intensity | 6 months after treatment initiation | 
| event-free survival |  | 1 year | 
| overall survival |  | 1year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic hematopoietic cell transplantation, Graft versus host disease, Bronchiolitis obliterans, Azithromycin, N-acetylcystein, Fluticasone, Inhaled steroid