Bronchodilator Responsiveness in Obliterative Bronchiolitis (BD-OB)

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

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.

Study Overview

• Status: Completed
• Conditions: Obliterative Bronchiolitis
• Intervention / Treatment: Drug: albuterol plus tiotropium

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Genoa, Italy, 16132
    • Unit of Preventive and Occupational Medicine - Laboratory of Respiratory Pathophysiology, University Hospital San Martino

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: albuterol-tiotropium; 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; 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.; Other Names: Ventolin® and Spiriva®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
• Investigators: Principal Investigator: Giovanni Barisione, MD, Unit of Preventive and Occupational Medicine, University Hospital San Martino, Genoa, Italy

Publications and helpful links

General Publications

• Barisione G, Bacigalupo A, Crimi E, Van Lint MT, Lamparelli T, Brusasco V. Changes in lung volumes and airway responsiveness following haematopoietic stem cell transplantation. Eur Respir J. 2008 Dec;32(6):1576-82. doi: 10.1183/09031936.0139807. Epub 2008 Aug 6.
• Pellegrino R, Rodarte JR, Brusasco V. Assessing the reversibility of airway obstruction. Chest. 1998 Dec;114(6):1607-12. doi: 10.1378/chest.114.6.1607.
• Barisione G, Bacigalupo A, Crimi E, Brusasco V. Acute bronchodilator responsiveness in bronchiolitis obliterans syndrome following hematopoietic stem cell transplantation. Chest. 2011 Mar;139(3):633-639. doi: 10.1378/chest.10-1442. Epub 2010 Aug 19.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: April 27, 2010
• First Submitted That Met QC Criteria: April 27, 2010
• First Posted (Estimate): April 28, 2010

Study Record Updates

• Last Update Posted (Estimate): March 2, 2011
• Last Update Submitted That Met QC Criteria: February 28, 2011
• Last Verified: April 1, 2010

More Information

Terms related to this study

• Keywords: Obliterative bronchiolitis; Bronchodilator responsiveness; Partial forced expiratory flow; Lung volumes
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Bronchiolitis; Bronchiolitis Obliterans; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol; Tiotropium Bromide
• Other Study ID Numbers: BOS-01