Theophylline and Steroids in Chronic Obstructive Pulmonary Disease (COPD) Study

Study Overview
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Brief Summary
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The aim of this multi-centre, double blind, randomised, controlled trial (DBRCT) is to assess the effect of low dose theophylline, singly and in combination with low dose oral prednisone, on COPD (Chronic Obstructive Pulmonary Disease) exacerbations, quality of life and secondary clinical outcomes compared with usual therapy and placebo over 48 weeks of treatment. 1670 symptomatic patients with COPD will be recruited in China for comparison of low dose theophylline versus placebo and low dose theophylline + low dose prednisone The primary end-point for this study is the annualised COPD exacerbation rate between the treatment groups. Secondary outcomes included time to first severe exacerbation requiring hospitalisation or death, health status, and pre- and post-bronchodilator spirometry.

Detailed Description
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The investigators hypothesise that patients with COPD will have beneficial responses to low dose theophylline and prednisone, superior to placebo and low dose theophylline alone, reflected by a range of clinical outcomes. The study aims to demonstrate that treatment with low dose oral prednisone and low dose, slow release theophylline compared to low dose, slow release theophylline only or placebo will reduce COPD exacerbations and improve a range of secondary outcomes including quality of life, COPD Assessment Test (CAT) score, hospital admissions and lung function. Eligible participants will be randomised to one of three treatment arms in a DBRCT and will receive placebo OR low-dose theophylline (100 mg twice a day) OR low-dose theophylline 100 mg twice a day (BD) plus low-dose prednisone (5 mg once a day) Patients will be eligible for inclusion if all the following criteria are met: Current or former smokers (>10 pack years) or biomass exposure 40 - 80 years of age Clinical diagnosis of COPD Post-bronchodilator forced expiratory volume at one second (FEV1) <70% predicted Post bronchodilator FEV1/forced vital capacity (FVC) ratio<0.7

Official Title
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The Effect of Low-dose Corticosteroids and Theophylline on the Risk of Acute Exacerbations of COPD: the TASCS Randomised Clinical Trial

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Theophylline
* Drug: Prednisone
* Drug: Placebo (for prednisone)
* Drug: Placebo (for Theophylline)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current or former smokers (> 10 pack years) or biomass exposure 40 - 80 years of age Clinical diagnosis of COPD Post-bronchodilator FEV1 < 70% predicted Post bronchodilator FEV1/FVC ratio < 0.7 Exclusion Criteria: Life expectancy of less than 12 months Exacerbation or respiratory infection within 4 weeks prior to randomisation Patient is taking and requires maintenance oral corticosteroids Patient is on domiciliary oxygen There has been previous pulmonary resection Previous sensitivity to, or intolerance of theophylline Coexistent illness precluding participation in the study (epilepsy, chronic liver disease, unstable cardiovascular disease, diabetes, active malignancy) Inability to complete quality of life questionnaire Concomitant major illness that would interfere with visits, assessments and follow-up Have evidence of chronic liver disease, or transaminase or gamma-glutamyltransferase (GGT) elevation > 1.5 x upper limit of normal (ULN) Random blood glucose level > 8mmol/L High chance in the view of the treating physician that the patient will not adhere to study treatment and follow up

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo theophylline, one tablet twice daily, and Placebo prednisone, one tablet once daily | Drug: Placebo (for prednisone)<br>* Arm 1 : Theophylline Placebo 1 tab twice daily and Prednisone placebo 1 tab once daily Arm 2 : Theophylline 100mg 1 tab twice daily and Prednisone placebo 1 tab once daily<br>* Other names: Prednisone placebo 1 tab once daily in arms 1 and 2;Drug: Placebo (for Theophylline)<br>* One tablet twice daily in arm 1 (theophylline placebo 1 BD + prednisone placebo 1 once daily)<br>* Other names: Theophylline placebo 1 tab twice daily;|
| Active Comparator: Low-dose theophylline arm<br>Theophylline 100 mg twice daily | Drug: Theophylline<br>* Theophylline is an oral methylxanthine which relaxes smooth muscle through its action as a phosphodiesterase inhibitor<br>* Other names: Theophylline (100 mg twice a day);Drug: Placebo (for prednisone)<br>* Arm 1 : Theophylline Placebo 1 tab twice daily and Prednisone placebo 1 tab once daily Arm 2 : Theophylline 100mg 1 tab twice daily and Prednisone placebo 1 tab once daily<br>* Other names: Prednisone placebo 1 tab once daily in arms 1 and 2;|
| Active Comparator: Theophylline and Prednisone arm<br>Theophylline 100 mg twice daily plus prednisone 5 mg once daily | Drug: Theophylline<br>* Theophylline is an oral methylxanthine which relaxes smooth muscle through its action as a phosphodiesterase inhibitor<br>* Other names: Theophylline (100 mg twice a day);Drug: Prednisone<br>* Prednisone is an oral glucocorticosteroid which has anti-inflammatory properties<br>* Other names: cortisone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total COPD Exacerbation Rate | The total number of COPD exacerbations reported within 48 weeks | 48 weeks observation; rate annualised | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First COPD Exacerbation | The median time (days) from randomisation to first exacerbation per participant | Median time (days) from randomisation to first exacerbation over a 48 week period per participant | 
| Quality of Life Measured by St. George's Respiratory Questionnaire (SGRQ) | THe St. George's Respiratory Questionnaire (SGRQ) is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating more limitations. | Change over 48 week study duration | 
| Post Bronchodilator FEV1 | The change in post bronchodilator FEV1 from baseline to 48 weeks | Change at 48 weeks | 
| Change in COPD Assessment Test (CAT) Score | The COPD Assessment Test (CAT) is a patient-completed questionnaire assessing globally the impact of COPD (cough, sputum, dysnea, chest tighteness) on health status. The range of CAT scores from 0-40. Higher scores denote a more severe impact of COPD on a patient's life. The outcome measure is assessing the change in score from baseline to 48 weeks. A negative change denotes an improvement in health status. | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Theophylline, Oral corticosteroids, COPD exacerbations