Inhaled Corticosteroid Withdrawal in Patients With Chronic Obstructive Pulmonary Disease

Study Overview
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Brief Summary
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This is a randomised study to be conducted in patients with severe to very severe Chronic Obstructive Pulmonary Disease (COPD) to establish whether there is a need for these patients to be continuously treated with an inhaled corticosteroid on top of two potent long-acting bronchodilators. The study also aims to identify the type of patients who are likely to benefit from inhaled corticosteroid maintenance therapy.

Official Title
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A Randomised, Double-blind, Active-controlled Study to Evaluate the Impact of Stepwise Withdrawal of Inhaled Corticosteroid Treatment in Patients With Severe to Very Severe Chronic Obstructive Pulmonary Disease (COPD) on Optimized Bronchodilator Therapy

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: tiotropium inhalation
* Drug: salmeterol xinafoate
* Drug: fluticasone propionate
* Drug: placebo matched for fluticasone propionate


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female aged 40 years or more Severe to very severe chronic obstructive pulmonary disease (COPD) Current or ex-smoker with smoking history of at least 10 pack years At least one documented exacerbation of COPD in previous year Exclusion criteria: Significant diseases other than COPD; significant alcohol or drug abuse Current clinical diagnosis of asthma requiring steroid treatment History of thoracotomy with pulmonary resection Regular use of daytime oxygen Recent history (within 3 months) of myocardial infarction Recent (within 6 weeks) respiratory infection or COPD exacerbation Recent (within 6 weeks) treatment with systemic corticosteroids at doses in excess of 5milligram / day Recent (within 3 months) unstable or life-threatening cardiac arrhythmia requiring intervention Recent (within 1 year) hospitalisation for cardiac failure Malignancy requiring chemotherapy or radiotherapy Clinical diagnosis of bronchiectasis Pregnant or nursing women Known hypersensitivity to study drugs Current or recent (within 30 days) participation in another clinical study Current participation in or recent completion (within 4 weeks) of a pulmonary rehabilitation program

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: fluticasone high dose<br>fluticasone priopionate high dose and tiotropium inhalation and salmeterol xinafoate | Drug: tiotropium inhalation<br> <br> Drug: salmeterol xinafoate<br> <br> Drug: fluticasone propionate<br> <br> |
| Experimental: fluticasone medium & low doses<br>fluticasone priopionate medium and high doses; and tiotropium inhalation; and salmeterol xinafoate; and placebo matched to fluticasone priopionate | Drug: tiotropium inhalation<br> <br> Drug: salmeterol xinafoate<br> <br> Drug: fluticasone propionate<br> <br> Drug: placebo matched for fluticasone propionate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Moderate or Severe On-treatment COPD Exacerbation | A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as an increase or new onset of ≥2 lower respiratory symptoms related to COPD, with ≥1 symptom lasting ≥3 days, requiring a change in treatment. Lower respiratory symptoms included shortness of breath, sputum production (volume), sputum purulence, cough, wheezing and chest tightness. A change in treatment included: hospitalisation/treatment in an urgent care unit, prescription of antibiotics and/or systemic steroids or a significant change of prescribed respiratory medication such as theophyllines, long-acting beta-agonists or inhaled corticosteroids. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital.The measure type displays the 25th percentile and its 95% confidence interval. | During randomised treatment, up to 488 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Moderate or Severe On-treatment COPD Exacerbations | Number of moderate or severe on-treatment COPD exacerbations, based on a 7-day gap rule: exacerbations where the onset date of the second exacerbation event was ≤7 days after the end date of the first exacerbation event were combined and counted as moderate or severe if ≥1 of the contributing exacerbation events was moderate or severe. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital. Exacerbations were considered moderate if they required prescription of antibiotics and/or systemic steroids. Measured values show adjusted mean event rate. | During randomised treatment, up to 488 days | 
| Proportion of Patients With ≥1 Moderate or Severe On-treatment COPD Exacerbation | Presence (yes vs no) of at least one moderate or severe on-treatment COPD exacerbation, displayed as a percentage. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital. Exacerbations were considered moderate if they required prescription of antibiotics and/or systemic steroids. | During randomised treatment, up to 488 days | 
| Time to First Severe On-treatment COPD Exacerbation | Time to first severe on-treatment COPD exacerbation. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital. The measure type displays the 25th percentile and its 95% confidence interval. | During randomised treatment, up to 488 days | 
| Number of Severe On-treatment COPD Exacerbations | Number of severe on-treatment COPD exacerbations based on a 7-day gap rule: exacerbations where the onset date of the second exacerbation event was ≤7 days after the end date of the first exacerbation event were combined and counted as severe if ≥1 of the contributing exacerbation events was severe. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital. Measured values show adjusted event rate. | During randomised treatment, up to 488 days | 
| Proportion of Patients With at Least One Severe On-treatment COPD Exacerbation. | Presence (yes vs no) of at least one severe on-treatment COPD exacerbation, displayed as a percentage. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital. | During randomised treatment, up to 488 days | 
| Time to First On-treatment COPD Exacerbation | Time to first on-treatment COPD exacerbation of any severity. The measure type displays the 25th percentile and its 95% confidence interval. | During randomised treatment, up to 488 days | 
| Number of On-treatment COPD Exacerbations | Number of on-treatment COPD exacerbations of any severity, based on a 7-day gap rule: exacerbations where the onset date of the second exacerbation event was ≤7 days after the end date of the first exacerbation event were combined. Measured values show adjusted event rate. | During randomised treatment, up to 488 days | 
| Proportion of Patients With at Least One On-treatment COPD Exacerbation | Presence (yes vs no) of at least one on-treatment COPD exacerbation of any severity, displayed as a percentage. | During randomised treatment, up to 488 days | 
| Severity of On-treatment COPD Exacerbations | Severity of on-treatment COPD exacerbations: for each patient, the worst applicable category was taken (i.e. none, mild, moderate or severe) | During randomised treatment, up to 488 days | 
| Change in On-treatment Lung Function as Measured by Trough FEV1 | Change from baseline in on-treatment lung function as measured by trough forced expiratory volume in one second (FEV1); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 6, 12, 18 and 52 visits | 
| Changes in On-treatment Dyspnoea as Measured by the Modified Medical Research Council (MMRC) Dyspnoea Scale | Change from baseline in on-treatment dyspnoea as measured by the Modified Medical Research Council (MMRC) dyspnoea scale; change was calculated as week score minus baseline score. Negative changes from baseline indicate an improvement in health. Scale from 0 to 4: 0 = not troubled by breathlessness, except during strenuous exercise 1 = short of breath when hurrying or walking up a slight hill 2 = walks slower than contemporaries on the same level because of breathlessness, or has to stop for breath when walking at own pace 3 = stops for breath after approximately 100 yards, or after a few minutes on the level 4 = too breathless to leave the house, or breathless when dressing or undressing No breathlessness was given a score of -1 Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 18 and 52 visits | 
| Change in On-treatment Physical Health Status as Determined by Body Mass Index (BMI) | Change from baseline in on-treatment physical health status as determined by body mass index (BMI); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 18 and 52 visits | 
| Change in On-treatment Exercise Capacity Measured by Six-minute Walk Test (6-MWT) | Change from baseline in on-treatment exercise capacity measured by six-minute walk test (6-MWT); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 18 and 52 visits | 
| Change in On-treatment BODE Index | Change from baseline in on-treatment BODE index (Body mass index, airflow Obstruction, Dyspnea and Exercise capacity index), a composite score ranging from 0 (best) to 10 (worst); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 18 and 52 visits | 
| Change in On-treatment Cough and Expectoration as Measured by the CASA-Q: Cough Impact Domain | Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Cough impact domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from not at all/never to extremely/always on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less impact due to cough. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 12, 18 and 52 visits | 
| Change in On-treatment Cough and Expectoration as Measured by the CASA-Q: Cough Symptoms Domain | Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Cough symptoms domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from not at all/never to a lot/always on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less symptoms due to cough. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 12, 18 and 52 visits | 
| Change in On-treatment Cough and Expectoration as Measured by the CASA-Q: Sputum Impact Domain | Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Sputum impact domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from not at all/never to a lot/always on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less impact due to sputum. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 12, 18 and 52 visits | 
| Change in On-treatment Cough and Expectoration as Measured by the CASA-Q: Sputum Symptoms Domain | Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Sputum symptoms domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from not at all/never to extremely/always on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less symptoms due to sputum. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 12, 18 and 52 visits | 
| Change in On-treatment FEV1 as Measured by Home Based Spirometry | Change from baseline in on-treatment Forced Expiratory Volume in One Second (FEV1) as measured by home based spirometry. Change was calculated as week score minus baseline score. The weekly mean was defined as the mean of the measurements taken during the last 7 days prior to the visit date, and was calculated if ≥4 of the 7 days had non-missing measurements. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 6, 12, 18, 27, 36, 45 and 52 visits | 
| Change in On-treatment FVC as Measured by Home Based Spirometry | Change from baseline in on-treatment forced vital capacity (FVC) as measured by home based spirometry. Change was calculated as week score minus baseline score. The weekly mean was defined as the mean of the measurements taken during the last 7 days prior to the visit date, and was calculated if ≥4 of the 7 days had non-missing measurements. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 6, 12, 18, 27, 36, 45 and 52 visits | 
| Change in On-treatment PEFR as Measured by Home Based Spirometry | Change from baseline in on-treatment peak expiratory flow rate (PEFR) as measured by home based spirometry; change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 6, 12, 18, 27, 36, 45 and 52 visits | 
| Change in On-treatment St Georges Respiratory Questionnaire (SGRQ) Scores: Activity Domain | Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Activity domain. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 27 and 52 visits | 
| Change in On-treatment St Georges Respiratory Questionnaire (SGRQ) Scores: Impact Domain | Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Impact Domain. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 27 and 52 visits | 
| Change in On-treatment St Georges Respiratory Questionnaire (SGRQ) Scores: Symptoms Domain | Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Symptoms domain. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 27 and 52 visits | 
| Change in On-treatment St Georges Respiratory Questionnaire (SGRQ) Scores: Total Score | Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Total score. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 27 and 52 visits | 
| Change in On-treatment Physician Global Evaluation | Change from baseline in on-treatment physician global evaluation. The evaluation reflected the physician's opinion of the patient's overall condition and was based on the need for concomitant medication, the number and severity of exacerbations, the severity of cough, the ability to exercise, the amount of wheezing and any other relevant clinical observations. Patients were graded on a scale of 1 (poor) to 8 (excellent). Change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. | Baseline and week 27 and 52 visits |