Bronchodilator Responsiveness in Obliterative Bronchiolitis

Study Overview
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Brief Summary
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This study has been designed to provide a substantial evidence of acute bronchodilator responsiveness to two sequentially inhaled drugs, a beta2-agonist (i.e., albuterol) and an anticholinergic (i.e., tiotropium bromide), in a group of patients who developed obliterative bronchiolitis after hematopoietic stem cell transplantation.

Detailed Description
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Obliterative bronchiolitis is a life-threatening non-infectious pulmonary complication of allogeneic hematopoietic stem cell transplantation (HSCT). It is characterized by the development of an obstructive abnormality which has been considered to be insensitive to bronchodilator treatments. However, this knowledge stems from measurements of forced expiratory volume in 1 s (FEV1) which is relatively insensitive to changes in small airway caliber. Moreover, it is known from studies in chronic obstructive pulmonary disease that symptoms improve after bronchodilator treatment even when FEV1 is minimally increased and correlate with the reduction of lung hyperinflation, which is the major consequence of severe expiratory airflow limitation. Therefore, measurements of airway caliber by parameters not affected by volume history and absolute lung volumes are preferable for assessing the effect of bronchodilator interventions. In the current study, the bronchodilators responsiveness will be assessed by using not only spirometry but also measurements of absolute lung volumes and the forced expiratory flow of a partial maneuver (V'part) started from submaximal lung inflation, thus free of volume history effects.

Official Title
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Acute Bronchodilator Responsiveness in Obliterative Bronchiolitis (OB) Following Hematopoietic Stem Cell Transplantation

Conditions
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Obliterative Bronchiolitis

Intervention / Treatment
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* Drug: albuterol plus tiotropium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Obliterative bronchiolitis (OB) following allogeneic HSCT FEV1 to slow inspiratory vital capacity (VC) ratio (FEV1/VC)<5th percentile FEV1 <75% predicted or absolute FEV1 fall >10% of pre-HSCT value evidence of OB by computed tomography scanning negative microbiological yields in bronchoalveolar lavage fluid chronic graft-versus-host disease score >0 negative history for bronchial asthma, chronic obstructive pulmonary disease or other significant respiratory disease. Exclusion Criteria: inability to perform lung function maneuvers pre-existent chronic lung disease other than OB
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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: albuterol-tiotropium<br>At visit 1, lung function measurements will be performed in triplicate before and 90 min after inhaling four separate doses of 100 μg of albuterol (Ventolin®) and soon after 18 μg of tiotropium bromide [Spiriva®] to ensure maximal or near-maximal bronchodilation. Albuterol will be given by a metered-dose inhaler connected to a valved-holding chamber (Volumatic®) and tiotropium by a dry-powder device (Handihaler®). | Drug: albuterol plus tiotropium<br>* Four separate doses of 100 μg of albuterol and 18 μg of tiotropium bromide. Albuterol will be given by a metered-dose inhaler connected to a valved-holding chamber and tiotropium by a dry-powder device.<br>* Other names: Ventolin® and Spiriva®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Per Cent Change of Forced Expiratory Volume in 1 Second (FEV1) After Bronchodilators | Following albuterol plus tiotropium inhalation, FEV1 increments ≥12 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to the American Thoracic Society-European Respiratory Society standard criteria [Pellegrino et al. Eur Respir J 2005; 26: 948-968]. They were calculated as follows: [FEV1, expressed in liters (L), after bronchodilators - FEV1 (L) before bronchodilators/FEV1 (L) before bronchodilators x 100]. | Baseline and 90 min after bronchodilators | 
| Absolute Change of Forced Expiratory Volume in 1 Second (FEV1) After Bronchodilators | Following albuterol plus tiotropium inhalation, FEV1 increments ≥0.20 liters (L) as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to the American Thoracic Society-European Respiratory Society standard criteria [Pellegrino et al. Eur Respir J 2005; 26: 948-968]. They were calculated as follows: [FEV1 (L) after bronchodilators - FEV1 (L) before bronchodilators]. | Baseline and 90 min after bronchodilators | 
| Per Cent Change of Forced Vital Capacity (FVC) After Bronchodilators | Following albuterol plus tiotropium inhalation, FVC increments ≥12 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to the American Thoracic Society-European Respiratory Society standard criteria [Pellegrino et al. Eur Respir J 2005; 26: 948-968]. They were calculated as follows: [FVC, expressed in liters (L), after bronchodilators - FVC (L) before bronchodilators/FVC (L) before bronchodilators x 100]. | Baseline and 90 min after bronchodilators | 
| Absolute Change of Forced Vital Capacity (FVC) After Bronchodilators | Following albuterol plus tiotropium inhalation, FVC increments ≥0.20 liters (L) compared with baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to the American Thoracic Society-European Respiratory Society standard criteria [Pellegrino et al. Eur Respir J 2005; 26: 948-968]. They were calculated as follows: [FVC (L) after bronchodilators - FVC (L) before bronchodilators]. | Baseline and 90 min after bronchodilators | 
| Per Cent Change of Instantaneous Maximal Forced Expiratory Flow (V'Max) After Bronchodilators | Following albuterol plus tiotropium inhalation, V'max increments ≥40 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to Pellegrino et al. [Chest 1998; 114:1607-1612]. They were calculated as follows: [V'max, expressed in liters.second-1 (L.s-1), after bronchodilators - V'max (L.s-1) before bronchodilators/V'max (L.s-1) before bronchodilators x 100]. | Baseline and 90 min after bronchodilators | 
| Per Cent Change of Partial Forced Expiratory Flow (V'Part) After Bronchodilators | Following albuterol plus tiotropium inhalation, V'part increments ≥40 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to Pellegrino et al. [Chest 1998; 114:1607-1612]. They were calculated as follows: [V'part, expressed in liters.second-1 (L.s-1), after bronchodilators - V'part (L.s-1) before bronchodilators/V'part (L.s-1) before bronchodilators x 100]. | Baseline and 90 min after bronchodilators | 
| Per Cent Change of Residual Volume (RV) After Bronchodilators | Following albuterol plus tiotropium inhalation, RV decrements ≥10 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to O'Donnell et al. [Eur Respir J 2001; 18: 914-920]. They were calculated as follows: [RV, expressed in liters (L), before bronchodilators - RV (L) after bronchodilators/RV (L) after bronchodilators x 100]. | Baseline and 90 min after bronchodilators | 
| Absolute Change of Residual Volume (RV) After Bronchodilators | Following albuterol plus tiotropium inhalation, RV decrements ≥0.30 liters (L) as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to O'Donnell et al. [Eur Respir J 2001; 18: 914-920]. They were calculated as follows: [RV (L), before bronchodilators - RV (L) after bronchodilators]. | Baseline and 90 min after bronchodilators | 
| Per Cent Change of Functional Residual Capacity (FRC) After Bronchodilators | Following albuterol plus tiotropium inhalation, FRC decrements ≥10 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to O'Donnell et al. [Eur Respir J 2001; 18: 914-920]. They were calculated as follows: [FRC, expressed in liters (L), before bronchodilators - FRC (L) after bronchodilators/FRC (L) after bronchodilators x 100]. | Baseline and 90 min after bronchodilators | 
| Absolute Change of Functional Residual Capacity (FRC) After Bronchodilators | Following albuterol plus tiotropium inhalation, FRC decrements ≥0.30 liters (L) as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to O'Donnell et al. [Eur Respir J 2001; 18: 914-920]. They were calculated as follows: [FRC (L), before bronchodilators - FRC (L) after bronchodilators]. | Baseline and 90 min after bronchodilators | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obliterative bronchiolitis, Bronchodilator responsiveness, Partial forced expiratory flow, Lung volumes