Ignite Creation Date:
2024-05-05 @ 11:55 AM
Last Modification Date:
2024-10-26 @ 9:16 AM
Study NCT ID:
NCT00175747
Status:
COMPLETED
Last Update Posted:
2005-09-15
First Post:
2005-09-13
Brief Title:
A Phase IIb Trial of Pulmicort Turbuhaler Budesonide
Sponsor:
University of British Columbia
Organization:
University of British Columbia
Study Overview
Official Title:
A Randomized Phase IIb Trial of Pulmicort Turbuhaler Budesonide in People With Dysplasia of the Bronchial Epithelium
Status:
COMPLETED
Status Verified Date:
2005-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Studies in animals suggest that inhaled budesonide may prevent the occurrence of lung cancer We conducted a clinical trial to determine the effects of inhaled budesonide in smokers who had precancerous lesions in the breathing tubes ie bronchial dysplasia
Detailed Description:
Lung cancer is the most common cause of cancer death worldwide the mortality rate of lung cancer exceeds that of colon breast and prostate cancers combined Former heavy smokers retain an elevated risk for lung cancer even years after they stop smoking Given the large number of current and former smokers and the increasing incidence of lung cancers among women lung cancer will remain a major health issue for the next several decades
One potential strategy to inhibit the development of invasive cancer in those who are at risk of developing lung cancer is to use chemopreventive agents that can regress existing intraepithelial neoplastic lesions prevent the progression of these lesions to cancer or prevent the development of new lesions
We performed a randomized double-blind placebo-controlled phase IIb clinical trial to determine the efficacy and safety of inhaled budesonide Pulmicort Turbuhaler as a chemopreventive agent in smokers with premalignant lesions in their bronchial epithelia The primary end point was change in the histopathologic grade on repeat biopsy of the same sites at the end of 6 months The secondary end points of this study aimed to gather additional insight into the potential effects of budesonide on the central bronchial epithelial lung compartment on the peripheral lung that could not be directly assessed through bronchoscopic biopsy and on drug effect biomarkers that reflect the ability of inhaled budesonide to reach its target Thus the balance between proliferation and apoptosis was examined through immunohistochemical analysis of the expression of the proliferative marker MIB-1 and the antiapoptotic protein BclII Expression of the tumor suppressor p53 which functions to maintain the integrity of the human genome is a major determinant of cell survival is frequently mutated in lung cancer and was assessed in bronchial biopsies Examination of peripheral pulmonary nodules via spiral computed tomography CT was performed to assess for the first time the potential usefulness of spiral CT in response to chemopreventive interventions Finally prostaglandin E2 PGE2 a prostaglandin derived from arachidonic acid metabolism whose synthesis is inhibited by glucocorticoids was measured in the bronchoalveolar lavage fluid
Study subjects were recruited using television programs radio broadcasts and local newspapers between June 1 2000 and November 1 2001 Eligibility included age 40 years smoking history of 30 pack-years and normal organ function Sputum samples were obtained using simultaneous high-frequency chest wall oscillation with a ThAIRapy Vest Advanced Respiratory Inc St Paul MN and inhalation of 3 hypertonic saline from an ultrasonic nebulizer for 12 minutes The subjects were instructed to cough intermittently during the induction procedure and for at least 2 hours afterward to produce sputum samples The sputum samples were fixed in 50 etomidate cytospun onto glass slides and stained with Feulgen-thionin The DNA content the size shape and DNA distribution of at least 3000 epithelial cell nuclei per sample were measured using automated high-resolution image cytometry Cyto-Savant system Perceptronix Medical Inc Vancouver British Columbia Canada refs 13 14 Cells were classified as either epithelial inflammatory or pyknotic based on these features and an experienced cytotechnologist confirmed the automated classifications Diploid DNA had a DNA index of 10 Atypia was defined as the presence of more than or equal to five cells having a DNA index 12 This criterion was based on a retrospective analysis of 1885 apparently healthy volunteer smokers who underwent sputum quantitative cytometry as part of the Lung Health Study at the British Columbia Cancer Agency since 1990 Participants were followed by repeat chest X-ray and autofluorescence bronchoscopy if they were in a National Cancer Institute-sponsored chemoprevention trial or through the British Columbia Cancer Registry and the Medical Services Plan Hospital Registry Using the threshold of more than or equal to five cells with a DNA index 12 the sensitivity of detecting lung cancer in the initial screening or on follow-up was 94 with a specificity of 38 after a mean follow-up of 32 years This threshold was adopted in the current study to identify smokers with the highest risk for lung cancer for bronchoscopy
Autofluorescence bronchoscopy was performed in subjects with sputum atypia who agreed to undergo bronchoscopy to localize areas of dysplasia using the LIFE-Lung device Xillix Technologies Corp Richmond British Columbia Canada Biopsy samples were taken from areas with abnormal fluorescence that were at least 12 mm in size as well as from at least two control areas of normal fluorescence The median number of biopsy samples obtained per subject was 6 range 4-14 samples Bronchoalveolar lavage was performed using standard techniques The collected fluid 30 mL per participant was immediately placed at 4C and a differential cell count was obtained within 1 hour of collection The fluid was separated from the cells by centrifugation and frozen at -160C for subsequent PGE2 assays
The biopsy samples were fixed in buffered formalin embedded in paraffin and serially sectioned HE-stained sections were systematically reviewed by two pathologists who were blinded to intervention assignments J leRiche A Gazdar All biopsy samples were classified into one of the following seven groups normal basal cell hyperplasia metaplasia mildmoderatesevere dysplasia or carcinoma in situ according to WHO criteria Because individual biopsies frequently contained more than one histologic cell type the diagnosis was based on the most advanced histology present
The two pathologists resolved minor ie one grade differences in sample classification by telephone consultation If the histopathology diagnosis differed by two or more grades both pathologists reviewed the slides again and if necessary reached a consensus diagnosis after verbal communication by phone or e-mail
One hundred fifty-one subjects 27 of subjects who underwent bronchoscopy had one or more sites of bronchial dysplasia with a surface diameter 12 mm ie greater than the size of a bronchial biopsy using standard biopsy forceps Only subjects with dysplastic lesions 12 mm were enrolled onto the chemoprevention trial to minimize the effect of mechanical removal of these lesions by the biopsy procedure
Participants were randomly assigned to receive either budesonide Pulmicort Turbuhaler AstraZeneca Lund Sweden at a dose of 800 µg twice daily by inhalation or placebo for 6 months The placebo turbuhalers were identical to the ones containing the active drug Randomization was stratified according to smoking status current versus former and gender All study personnel were blinded to the study codes as was confirmed by independent review
The participants were interviewed monthly for compliance and drug-related adverse events Compliance was determined from a drug diary and from estimation of the number of doses remaining in the turbuhaler Toxicity was monitored according to the National Cancer Institute Common Toxicity Criteria version 2010 Dose modification was performed for any grade 2 toxicity or for evidence of cortisol suppression ante meridiem AM plasma cortisol 140 nmolLL For grade 3 or 4 toxicity therapy was discontinued until toxicity resolved to grade 1 or less At that time the use of the study drug was resumed with a 75 dose reduction
All participants underwent a second fluorescence bronchoscopy with bronchoalveolar lavage after 6 months on study medication and biopsies were obtained from the same sites biopsied at baseline Biopsy samples were also taken from new areas that displayed abnormal fluorescence The bronchoscopist was blinded to the intervention assignment
Current smokers were encouraged to stop smoking and were invited to take part in the Fresh Start Program at the British Columbia Cancer Agency The Clinical Investigations Committees of the British Columbia Cancer Agency and the University of British Columbia approved this study Written informed consent was obtained from all participants
One potential strategy to inhibit the development of invasive cancer in those who are at risk of developing lung cancer is to use chemopreventive agents that can regress existing intraepithelial neoplastic lesions prevent the progression of these lesions to cancer or prevent the development of new lesions
We performed a randomized double-blind placebo-controlled phase IIb clinical trial to determine the efficacy and safety of inhaled budesonide Pulmicort Turbuhaler as a chemopreventive agent in smokers with premalignant lesions in their bronchial epithelia The primary end point was change in the histopathologic grade on repeat biopsy of the same sites at the end of 6 months The secondary end points of this study aimed to gather additional insight into the potential effects of budesonide on the central bronchial epithelial lung compartment on the peripheral lung that could not be directly assessed through bronchoscopic biopsy and on drug effect biomarkers that reflect the ability of inhaled budesonide to reach its target Thus the balance between proliferation and apoptosis was examined through immunohistochemical analysis of the expression of the proliferative marker MIB-1 and the antiapoptotic protein BclII Expression of the tumor suppressor p53 which functions to maintain the integrity of the human genome is a major determinant of cell survival is frequently mutated in lung cancer and was assessed in bronchial biopsies Examination of peripheral pulmonary nodules via spiral computed tomography CT was performed to assess for the first time the potential usefulness of spiral CT in response to chemopreventive interventions Finally prostaglandin E2 PGE2 a prostaglandin derived from arachidonic acid metabolism whose synthesis is inhibited by glucocorticoids was measured in the bronchoalveolar lavage fluid
Study subjects were recruited using television programs radio broadcasts and local newspapers between June 1 2000 and November 1 2001 Eligibility included age 40 years smoking history of 30 pack-years and normal organ function Sputum samples were obtained using simultaneous high-frequency chest wall oscillation with a ThAIRapy Vest Advanced Respiratory Inc St Paul MN and inhalation of 3 hypertonic saline from an ultrasonic nebulizer for 12 minutes The subjects were instructed to cough intermittently during the induction procedure and for at least 2 hours afterward to produce sputum samples The sputum samples were fixed in 50 etomidate cytospun onto glass slides and stained with Feulgen-thionin The DNA content the size shape and DNA distribution of at least 3000 epithelial cell nuclei per sample were measured using automated high-resolution image cytometry Cyto-Savant system Perceptronix Medical Inc Vancouver British Columbia Canada refs 13 14 Cells were classified as either epithelial inflammatory or pyknotic based on these features and an experienced cytotechnologist confirmed the automated classifications Diploid DNA had a DNA index of 10 Atypia was defined as the presence of more than or equal to five cells having a DNA index 12 This criterion was based on a retrospective analysis of 1885 apparently healthy volunteer smokers who underwent sputum quantitative cytometry as part of the Lung Health Study at the British Columbia Cancer Agency since 1990 Participants were followed by repeat chest X-ray and autofluorescence bronchoscopy if they were in a National Cancer Institute-sponsored chemoprevention trial or through the British Columbia Cancer Registry and the Medical Services Plan Hospital Registry Using the threshold of more than or equal to five cells with a DNA index 12 the sensitivity of detecting lung cancer in the initial screening or on follow-up was 94 with a specificity of 38 after a mean follow-up of 32 years This threshold was adopted in the current study to identify smokers with the highest risk for lung cancer for bronchoscopy
Autofluorescence bronchoscopy was performed in subjects with sputum atypia who agreed to undergo bronchoscopy to localize areas of dysplasia using the LIFE-Lung device Xillix Technologies Corp Richmond British Columbia Canada Biopsy samples were taken from areas with abnormal fluorescence that were at least 12 mm in size as well as from at least two control areas of normal fluorescence The median number of biopsy samples obtained per subject was 6 range 4-14 samples Bronchoalveolar lavage was performed using standard techniques The collected fluid 30 mL per participant was immediately placed at 4C and a differential cell count was obtained within 1 hour of collection The fluid was separated from the cells by centrifugation and frozen at -160C for subsequent PGE2 assays
The biopsy samples were fixed in buffered formalin embedded in paraffin and serially sectioned HE-stained sections were systematically reviewed by two pathologists who were blinded to intervention assignments J leRiche A Gazdar All biopsy samples were classified into one of the following seven groups normal basal cell hyperplasia metaplasia mildmoderatesevere dysplasia or carcinoma in situ according to WHO criteria Because individual biopsies frequently contained more than one histologic cell type the diagnosis was based on the most advanced histology present
The two pathologists resolved minor ie one grade differences in sample classification by telephone consultation If the histopathology diagnosis differed by two or more grades both pathologists reviewed the slides again and if necessary reached a consensus diagnosis after verbal communication by phone or e-mail
One hundred fifty-one subjects 27 of subjects who underwent bronchoscopy had one or more sites of bronchial dysplasia with a surface diameter 12 mm ie greater than the size of a bronchial biopsy using standard biopsy forceps Only subjects with dysplastic lesions 12 mm were enrolled onto the chemoprevention trial to minimize the effect of mechanical removal of these lesions by the biopsy procedure
Participants were randomly assigned to receive either budesonide Pulmicort Turbuhaler AstraZeneca Lund Sweden at a dose of 800 µg twice daily by inhalation or placebo for 6 months The placebo turbuhalers were identical to the ones containing the active drug Randomization was stratified according to smoking status current versus former and gender All study personnel were blinded to the study codes as was confirmed by independent review
The participants were interviewed monthly for compliance and drug-related adverse events Compliance was determined from a drug diary and from estimation of the number of doses remaining in the turbuhaler Toxicity was monitored according to the National Cancer Institute Common Toxicity Criteria version 2010 Dose modification was performed for any grade 2 toxicity or for evidence of cortisol suppression ante meridiem AM plasma cortisol 140 nmolLL For grade 3 or 4 toxicity therapy was discontinued until toxicity resolved to grade 1 or less At that time the use of the study drug was resumed with a 75 dose reduction
All participants underwent a second fluorescence bronchoscopy with bronchoalveolar lavage after 6 months on study medication and biopsies were obtained from the same sites biopsied at baseline Biopsy samples were also taken from new areas that displayed abnormal fluorescence The bronchoscopist was blinded to the intervention assignment
Current smokers were encouraged to stop smoking and were invited to take part in the Fresh Start Program at the British Columbia Cancer Agency The Clinical Investigations Committees of the British Columbia Cancer Agency and the University of British Columbia approved this study Written informed consent was obtained from all participants
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None