- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00524095
Bronchiectasis in Chronic Obstructive Pulmonary Disease (COPD) Patients: Role of Prophylaxis
Bronchiectasis in COPD Patients : Role of Prophylaxis With Inhaled Steroids and Antibiotic on the Natural History of the Disease
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
AIMS OF THE STUDY
As previously described the research program aims are the following:
- definition of bronchiectasis prevalence in patients affected by chronic obstructive pulmonary disease.
- After bronchiectasis patients identification, we will evaluate the pathophysiologic implications, and microbiologic and inflammatory features of this subgroup in comparison to non-bronchiectasis patients.
- Finally, the research will address the effects of long-term treatments with inhaled steroids and antibiotic on the natural history of the disease and their pathophysiologic implications. To these purposes, the study will be divided into two sections. In the Ist section 400 patients with COPD will be recruited. In these patients we intend to assess the prevalence of bronchiectasis using a CT spiral scanning. We will also detect bacterial colonisation by real time PCR and ELIspot technique, and airway inflammation by a non-invasive method (exhaled breath condensate) comparing patients with and without bronchiectasis.
COPD patients with bronchiectasis:
In this population we will study the effect of different "prophylaxis" i.e., macrolide and inhaled steroids.
Details of the Interventions Proposed STABLE COPD The patient will attend the clinic in the morning for enrolment, and provide written informed consent. During the visit medical history will be recorded and subjects will undergo a physical examination and lung function testing at baseline and post salbutamol 200 mcg. CT scan, exhaled breath condensate and the venopuncture will also be performed. Sputum samples will be obtained for bacterial colonization assessment.
Respiratory Assessment:
Lung function testing will be performed using a Fleish No. 3 heated pneumotachograph; the plethysmographic measurements, thoracic gas volume (TGV), residual volume (RV), total lung capacity (TLC), will be assessed using a body plethysmograph (Werner Gut, Basle, Switzerland) with electronic BTPS compensation at a constant volume (850L). DLCO determination will be performed.
CT scan All the multislice CT (MSCT) scan performed will be centrally analysed by UO 4 . The following protocol will be followed
- MSCT in inspiration at TLC with slice of 1 mm every 10 + 3 expiratory slices at RV using three predetermined levels (aortic arch, tracheal carina, right basal common vein)
- Technical parameters: 120 kV, 220 mA, filter bone, FOV including both lung, lung parenchyma window (-600/1600 HU)
- All CT will be saved on CD rom Two radiologists will analyse the same CT, every discrepancy will be solved by consensus
The diagnosis and evaluation of bronchiectasis will be performed according to Webb et al. (1):
The evaluation will be performed lobe by lobe including lingula (total lobes= 6)
- bronchiectasis extension on lobar base: 0, 1 (< 25% of the lobe), 2 (25-50%), 3 (>50%) - MAX TOT 18
- severity and kind of bronchiectasis and semi-quantitative, comparing the diameter to that of the adjacent artery: 0, 1 (bronchial diameter equal to 100-200% artery diameter), 2 (200-300%), 3 (> 300%) - MAX TOT 18
- Thickness of bronchial walls: 0, 1 (Thickness < 50% artery diameter), 2 (50-100%), 3 ( complete obliteration of lumen or Hydro-air levels) - MAX TOT 18
- Evaluation of emphysema (visual score on three levels (inspiration) (aortic arch, carina, vein)
- Evaluation of air trapping in expiration (idem)
- Bullae
- Ground glass areas (extension by visual score)
- bronchiolitis: prevalent site, lobar involvement, severity ( 0,1,2,3)
- Pulmonary artery diameter (pathological if > 2,9 cm)
- Other features
Exhaled breath condensate:
Exhaled breath condensate will be collected by using a condenser, which allows the non-invasive collection of nongaseous components of the expiratory air (EcoScreen, Jaeger, Germany). Subjects breathe tidally through a mouthpiece connected to the inlet for 8 min while wearing a nose-clip. The mouthpiece is also used as a saliva trap. Approximately 1 ml of breath condensate is collected and stored at -70° C. IL-6, IL-8, TNF-a and cysteinyl-leukotrienes (cys-LTs) will be measured by specific enzyme immunoassays (EIA) (Cayman Chemical, Ann Arbor, MI). Moreover proteomic analysis will be performed on the subset of patients enrolled by UO1 as previously reported (2); briefly, one-dimensional and two-dimensional electrophoresis will be performed and for qualitative evaluation and mass spectrometry analysis, the gels will be stained with silver nitrate, with or without glutaraldehyde in the sensitization step and formaldehyde in the impregnation solution. Spot volumes will be calculated using Image J 1.29x (W. Rasband, National Institutes of Health, Bethesda, Maryland) for one-dimensional gels, and with PDQUEST (Biorad, Hercules, California) for two-dimensional gels.
Serum Samples:
Serum aliquots will be arranged in duplicate and stored at - 20°C until the time of analysis. IL-6, IL-8, TNF-a and cysteinyl-leukotrienes (cys-LTs) will be measured by specific enzyme immunoassays (EIA) (Cayman Chemical, Ann Arbor, MI).
C-reactive protein and procalcitonin will be also measured.(3) UO 1 The ex-vivo Enzyme-Linked ImmunoSPOT (ELISPOT) assay is the most sensitive tool to detect and quantify the antigen-specific T-cell response, and can detect and enumerate T-cells producing one or more cytokines in response to specific antigens. This technique has been already used to detect low numbers of antigen-specific T-cells in infectious disorders, with particular emphasis to intracellular pathogens such as Mycobacterium tuberculosis . The ELISPOT technique is becoming a standard reference for the monitoring of many infectious diseases, including HIV infection, and is becoming more and more used in advanced clinical immunological applications, such as the detection of an antigen-specific T cell immune responses to oncogene peptides.
In the context of the proposed project, the ELISPOT technology will be used to detect the presence of a systemic (blood) and local (bronchoalveolar lavage) antigen-specific response using peptide pools of non tuberculous mycobacteria and other intracellular bacteria (such as Mycoplasma pneumoniae), bacteria (such as Pseudomonas spp) and fungi (such as Aspergillus species). The ELISPOT tests will be performed on samples of whole blood (after Ficoll separation of peripheral mononuclear cells) and bronchoalveolar cells measuring the number of T cells producing interferon-gamma after an overnight incubation with the specific antigenic peptide pools. (4-8)
Sputum collection:
A sample of spontaneous sputum will be obtained from all patients. Alternatively induced sputum according to Pizzichini, et al (9) will be collected. In summary, induced sputum is obtained after inhalation of hypertonic saline water at 3% for 20 minutes using an ultrasonic nebulizer (Ultraneb 2000; DeVilbiss Healthcare Inc, Somerset, PS, USA).Only samples of sputum degree IV or V of Murray-Washington classification (10) will be processed. A sputum sample will be frozen at -70°C for bacterial DNA detection using a PCR (qualitative analysis) and real time PCR (quantitative analysis) techniques.
The following Bacteria wil be detected using standard protocol in use in UO1: H. influenzae, M. catarrhalis, S. pneumoniae, P.
aeruginosa, Mycoplasma pneumoniae, Chlamydia pneumoniae. An aliquot will be cultivated using standard microbiologic techniques Patients 400 patients will be recruited at the UO 1,2,3 e 5. All the CT scan will be collected and examined at UO 4. UO2 will serve as second observer in a double-blind fashion; any discrepancy will be solved by consensus.
One subgroup of patients with stable COPD (n=15) and an subgroup of patients with COPD and bronchiectasis (n=15) will undergo bronchoscopy with biopsy collection. Subjects will be premedicated with atropine and anesthetized topically with lidocaine.
Bronchoscopy will be performed with a flexible fiberoptic bronchoscope. Bronchial biopsies will be taken through the bronchoscope with standard forceps from the carina of the basal segment bronchus of the right lower lobe. From this area two specimens will be obtained in each patients. Bronchial biopsies obtained will be prepared for electronic and light microscopy analysis (UO3 and UO 1).
Sample size: we can expect at least a 30% prevalence of bronchiectasis that means 120 patients to be included in the second step of the study (11)
COPD PATIENTS WITH BRONCHIECTASIS:
In this population we will study the effect of different "prophylaxis" i.e. macrolide and inhaled steroids. The population will be followed for 12 months.
The following procedure will be performed every 3 months and at each exacerbations:
Clinical assessment, Exhaled breath condensate, Serum Sampling, Sputum collection.
On biological samples all the previously described techniques plus renal and hepatic function tests (safety) will be performed.
Sputum culture will be performed to assess bacterial flora and resistance patterns.
Design of the study:
120 patients will be randomized in 3 groups (40 pts) to receive :
- Standard of care
- azithromycin 500 mg OD 3 days a week (Monday, Wednesday, Friday) for 6 months and then inhaled steroids (fluticasone 500 ug bid) for 6 months
- inhaled steroids (fluticasone 500 ug bid) for 6 months and then azithromycin 500 mg OD 3 days a week (Monday, Wednesday, Friday) for 6 months
End-points:
PRIMARY
- effects of treatments on bronchial inflammation parameters SECONDARY
- effects of treatments on exacerbations frequency
- effects of treatments on pulmonary function
Sample size:
We can expect a 40% difference between treated and non-treated patients for at least one among TNFa, IL6, IL8, and cysteinyl-leukotrienes. In this case we need 35 treated patients (for each arm) and 35 non-treated patients for an alpha error of 0.05 and a beta of 0.1.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
-
Milan, Italy, 20122
- Istituto Malattie Respiratorie University of Milan
-
Modena, Italy, 41100
- Clinica di Malattie dell'Apparato Respiratorio Università di Modena e Reggio Emilia
-
Padova, Italy
- Dip. SCIENZE CARDIOLOGICHE, TORACICHE E VASCOLARI UNIVERSITY OF PADOVA
-
Parma, Italy, 43100
- Dip. SCIENZE CLINICHE Università degli Studi di PARMA
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Smokers or former smokers of at least 10 pack-years
- COPD demonstrated by forced spirometry with FEV1 > 0,7 L, FEV1 post-BD <60% and FEV1/FVC < 70%
- Bronchodilator test performed at inclusion or no more than 6 months before inclusion should have been negative (increase in FEV1 < 200 ml and 12%, 10 minutes after administration of 2 puffs of salbutamol
- Stable phase defined by clinical criteria of the attending investigator, but at least 6 weeks from the last exacerbation
- Informed consent
Exclusion Criteria:
- Patients receiving oral corticosteroids at any dose or another immunosuppressor
- Formal contraindication for sputum collection or impossibility to obtain a sample of sputum valid for analysis.
- Allergy to steroids or macrolides
Study Plan
How is the study designed?
Design Details
- Primary Purpose: PREVENTION
- Allocation: RANDOMIZED
- Interventional Model: CROSSOVER
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
NO_INTERVENTION: 1
standard of care
|
|
EXPERIMENTAL: 2
azithromycin 500 mg once a day three times a week for 6 months and then inhaled steroids (fluticasone 500 ug bid) for 6 months
|
azithromycin 500 mg once a day three times a week for 6 months and then inhaled steroids (fluticasone 500 ug bid) for 6 months
Other Names:
|
EXPERIMENTAL: 3
inhaled steroids (fluticasone 500 ug bid) for 6 months and then azithromycin 500 mg once a day three times a week for 6 months
|
inhaled steroids (fluticasone 500 ug bid) for 6 months and then azithromycin 500 mg once a day three times a week for 6 months
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
effects of treatments on bronchial inflammation parameters
Time Frame: six months
|
six months
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
effects of treatments on exacerbations frequency
Time Frame: six months
|
six months
|
effects of treatments on pulmonary function
Time Frame: six months
|
six months
|
Collaborators and Investigators
Sponsor
Investigators
- Study Director: Francesco Blasi, MD, University of Milan Italy
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Bronchial Diseases
- Lung Diseases, Obstructive
- Pulmonary Disease, Chronic Obstructive
- Bronchiectasis
- Lung Diseases
- Bronchitis
- Bronchitis, Chronic
- Physiological Effects of Drugs
- Anti-Infective Agents
- Autonomic Agents
- Peripheral Nervous System Agents
- Anti-Inflammatory Agents
- Dermatologic Agents
- Anti-Bacterial Agents
- Bronchodilator Agents
- Anti-Asthmatic Agents
- Respiratory System Agents
- Anti-Allergic Agents
- Fluticasone
- Xhance
- Azithromycin
Other Study ID Numbers
- PRIN2005
- MIUR 2005067041 PRIN 2005
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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