Evaluation of Efficacy and Safety of Symbicort® as an add-on Treatment to Spiriva® in Patients With Severe COPD.

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect of combined treatment with Symbicort and Spiriva, in terms of improvement of lung function, symptoms and inflammatory markers, in patients with severe COPD.

Official Title
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A 12-week, Double-blind, Randomised, Parallel Group, Multi-centre, Study to Evaluate Efficacy and Safety of Budesonide/Formoterol (Symbicort Turbuhaler®) 320/9 µg One Inhalation Twice Daily on Top of Tiotropium (Spiriva®) 18 µg One Inhalation Once Daily

Conditions
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Chronic Obstructive Pulmonary Disease, COPD

Intervention / Treatment
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* Drug: Symbicort (budesonide/formoterol turbuhaler 320/9ug)
* Drug: Spiriva (tiotropium bromide 18ug)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: >=40 years of age, diagnosed COPD with symptoms >=2 years, pre-bronchodilatory FEV1 <=50% of PN Exclusion Criteria: Current respiratory tract disorder other than COPD, history of asthma or rhinitis, significant or unstable cardiovascular disorder

Ages Eligible for Study
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Minimum Age: 40 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Symbicort+TIO<br>Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily | Drug: Symbicort (budesonide/formoterol turbuhaler 320/9ug)<br>* Symbicort (budesonide/formoterol turbuhaler 320/9ug)<br>|
| Active Comparator: Spiriva® + Placebo Turbuhaler<br>Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily | Drug: Spiriva (tiotropium bromide 18ug)<br>* Spiriva (tiotropium bromide 18ug)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in 1 Second (FEV1) Pre-dose | Change in the pre-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) | Baseline to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in 1 Second (FEV1) 5 Min Post-dose | Change in the 5 min post-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) | Baseline to 12 weeks | 
| Forced Expiratory Volume in 1 Second (FEV1) 60 Min Post-dose | Change in the 60 min post-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) | Baseline to 12 weeks | 
| Forced Vital Capacity (FVC) Pre-dose | Change in the pre-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) | Baseline to 12 weeks | 
| Forced Vital Capacity (FVC) 5 Minutes Post-dose | Change in the 5 min post-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) | Baseline to 12 weeks | 
| Forced Vital Capacity (FVC) 60 Minutes Post-dose | Change in the 60 min post-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12 | Baseline to 12 weeks | 
| Inspiratory Capacity (IC) Pre-dose | Change in the pre-dose IC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) | Baseline to 12 weeks | 
| Inspiratory Capacity (IC) 60 Minutes Post-dose | Change in the 60 min post-dose IC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) | Baseline to 12 weeks | 
| St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Score | Change in total score from baseline (Visit 3) to end of treatment (Visit 6, or last available visit). SGRQ-C is a health related quality of life questionnaire consisting of 40 items divided into two components: 1) symptoms, 2) activity& impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. | Baseline and 12 weeks | 
| Morning Peak Expiratory Flow (PEF) Pre-dose | Daily diary record. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Evening Peak Expiratory Flow (PEF) Pre-dose | Daily diary record. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Morning Peak Expiratory Flow (PEF) 5 Min Post-dose | Daily diary record. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Morning Peak Expiratory Flow (PEF) 15 Min Post-dose | Daily diary record. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Morning Diary FEV1 Pre-dose | Daily diary record. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Evening Diary FEV1, Pre-dose | Daily diary record. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Morning Diary FEV1, 5 Minutes Post-dose | Daily diary record. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Morning Diary FEV1, 15 Minutes Post-dose | Daily diary record. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Global Chest Symptoms Questionnaire (GCSQ) Score, Pre-dose | Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions. | Baseline to 12 weeks | 
| GCSQ Score, 5 Minutes Post-dose | Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions. | Baseline to 12 weeks | 
| GCSQ Score, 15 Minutes Post-dose | Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions. | Baseline to 12 weeks | 
| Capacity of Day Living in the Morning (CDLM) Score | Daily diary record. Change in average values from run-in to the full treatment period. The CDLM questionnaire is as a questionnaire to report on patient's ability to carry out each of six different morning activities (score ranging from 0 not performed to 1performed) and rank the difficulty of performing each of those activities (score ranging from 0 so difficult that the activity could not be carried out by the patient on their own to 5 activity was not at all difficult to carry out. Total score for each morning activity range from 0-6. Total score for whole CDLM questionnaire range from 0-36. | Baseline to 12 weeks | 
| Use of Rescue Medication, Night | Daily diary record - Night, after evening measurement till morning. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Use of Rescue Medication, Morning | Daily diary record - Morning, after morning measurement till midday. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Use of Rescue Medication, Day | Daily diary record - Day, after morning measurement till evening. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| Use of Rescue Medication, Total | Daily diary record - Total, 24 hours, during the night, and during the day. Change in average values from run-in to the full treatment period | Baseline to 12 weeks | 
| COPD Symptoms, Breathing Score | Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe | Baseline to 12 weeks | 
| COPD Symptoms, Sleeping Score | Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe | Baseline to 12 weeks | 
| COPD Symptoms, Chest Score | Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe | Baseline to 12 weeks | 
| COPD Symptoms, Cough Score | Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe | Baseline to 12 weeks | 
| Severe COPD Exacerbations | Patients with worsening of COPD leading to treatment with systemic steroids (oral or parenteral), emergency room treatment or hospitalisation | 12 weeks | 
| Serum High-sensitivity C-reactive Protein (hsCRP) | Ratio of treatment period mean to run-in value | Baseline to 12 weeks | 
| Serum Interleukin 6 (IL-6) | Ratio of treatment period mean to run-in value | Baseline to 12 weeks | 
| Serum Interleukin 8 (IL-8) | Ratio of treatment period mean to run-in value | Baseline to 12 weeks | 
| Serum Monocyte Chemoattractant Protein-1 (MCP-1) | Ratio of treatment period mean to run-in value | Baseline to 12 weeks | 
| Serum Soluble Tumor Necrosis Factor-alpha (sTNF-alpha) | Ratio of treatment period mean to run-in value | Baseline to 12 weeks | 
| Serum Tumor Necrosis Factor-alpha (TNF-alpha) | Ratio of treatment period mean to run-in value | Baseline to 12 weeks | 
| Serum Vascular Cell Adhesion Molecule-1 (VCAM-1) | Ratio of treatment period mean to run-in value | Baseline to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Obstructive Pulmonary Disease, COPD