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

Phase 4

Completed

Interventions: Drug: Placebo (for prednisone)
Drug: Theophylline
Drug: Placebo (for Theophylline)
Drug: Prednisone

Brief Summary: 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: 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

Recruitment & Eligibility

Inclusion Criteria

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

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo (for prednisone)	Placebo theophylline, one tablet twice daily, and Placebo prednisone, one tablet once daily
Placebo	Placebo (for Theophylline)	Placebo theophylline, one tablet twice daily, and Placebo prednisone, one tablet once daily
Low-dose theophylline arm	Theophylline	Theophylline 100 mg twice daily
Low-dose theophylline arm	Placebo (for prednisone)	Theophylline 100 mg twice daily
Theophylline and Prednisone arm	Theophylline	Theophylline 100 mg twice daily plus prednisone 5 mg once daily
Theophylline and Prednisone arm	Prednisone	Theophylline 100 mg twice daily plus prednisone 5 mg once daily

Primary Outcome Measures

Name	Time	Method
Total COPD Exacerbation Rate	48 weeks observation; rate annualised	The total number of COPD exacerbations reported within 48 weeks

Secondary Outcome Measures

Name	Time	Method
Quality of Life Measured by St. George's Respiratory Questionnaire (SGRQ)	Change over 48 week study duration	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.
Time to First COPD Exacerbation	Median time (days) from randomisation to first exacerbation over a 48 week period per participant	The median time (days) from randomisation to first exacerbation per participant
Post Bronchodilator FEV1	Change at 48 weeks	The change in post bronchodilator FEV1 from baseline to 48 weeks
Change in COPD Assessment Test (CAT) Score	48 weeks	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.