Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD, Theophylline, Oral corticosteroids, COPD exacerbations
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
Interventions
DRUGTheophylline
Theophylline is an oral methylxanthine which relaxes smooth muscle through its action as a phosphodiesterase inhibitor
DRUGPrednisone
Prednisone is an oral glucocorticosteroid which has anti-inflammatory properties
* 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
DRUGPlacebo (for Theophylline)
One tablet twice daily in arm 1 (theophylline placebo 1 BD + prednisone placebo 1 once daily)
Sponsors
National Health and Medical Research Council, Australia
The George Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total COPD Exacerbation Rate | 48 weeks observation; rate annualised | The total number of COPD exacerbations reported within 48 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Hospitalisations | 48 weeks | The total number of hospitalisation events within 48 weeks |
Countries
Australia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo theophylline, one tablet twice daily, and Placebo prednisone, one tablet once daily
Placebo (for prednisone): - 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
Placebo (for Theophylline): One tablet twice daily in arm 1 (theophylline placebo 1 BD + prednisone placebo 1 once daily) | 554 |
| Low-dose Theophylline Arm Theophylline 100 mg twice daily
Theophylline: Theophylline is an oral methylxanthine which relaxes smooth muscle through its action as a phosphodiesterase inhibitor
Placebo (for prednisone): - 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 | 568 |
| Theophylline and Prednisone Arm Theophylline 100 mg twice daily plus prednisone 5 mg once daily
Theophylline: Theophylline is an oral methylxanthine which relaxes smooth muscle through its action as a phosphodiesterase inhibitor
Prednisone: Prednisone is an oral glucocorticosteroid which has anti-inflammatory properties | 548 |
| Total | 1,670 |
Baseline characteristics
| Characteristic | Low-dose Theophylline Arm | Total | Theophylline and Prednisone Arm | Placebo |
|---|---|---|---|---|
| Age, Continuous | 64.4 years STANDARD_DEVIATION 7.8 | 64.4 years STANDARD_DEVIATION 8 | 64.9 years STANDARD_DEVIATION 7.7 | 63.9 years STANDARD_DEVIATION 8.5 |
| Current Smoker | 121 Participants | 332 Participants | 113 Participants | 98 Participants |
| Pack Years - Current Smoker | 40.5 years STANDARD_DEVIATION 22.3 | 42.7 years STANDARD_DEVIATION 23.9 | 44.4 years STANDARD_DEVIATION 22.7 | 43.5 years STANDARD_DEVIATION 27.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 568 Participants | 1670 Participants | 548 Participants | 554 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 568 participants | 1670 participants | 548 participants | 554 participants |
| Sex: Female, Male Female | 134 Participants | 406 Participants | 144 Participants | 128 Participants |
| Sex: Female, Male Male | 434 Participants | 1264 Participants | 404 Participants | 426 Participants |
| Spirometry - Pre bronchodilator Forced Expiratory Volume in one second (FEV1) | 1.0 L/sec STANDARD_DEVIATION 0.4 | 1.0 L/sec STANDARD_DEVIATION 0.4 | 0.9 L/sec STANDARD_DEVIATION 0.4 | 1.0 L/sec STANDARD_DEVIATION 0.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 554 | 2 / 568 | 2 / 548 |
| other Total, other adverse events | 196 / 554 | 222 / 568 | 202 / 548 |
| serious Total, serious adverse events | 96 / 554 | 91 / 568 | 83 / 548 |
Outcome results
Primary
Total COPD Exacerbation Rate
The total number of COPD exacerbations reported within 48 weeks
Time frame: 48 weeks observation; rate annualised
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Total COPD Exacerbation Rate | 1.00 Exacerbations per participant year |
| Low-dose Theophylline Arm | Total COPD Exacerbation Rate | 0.86 Exacerbations per participant year |
| Theophylline and Prednisone Arm | Total COPD Exacerbation Rate | 0.89 Exacerbations per participant year |
Secondary
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.
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in COPD Assessment Test (CAT) Score | -2.29 Score on a scale | Standard Deviation 0.33 |
| Low-dose Theophylline Arm | Change in COPD Assessment Test (CAT) Score | -2.77 Score on a scale | Standard Deviation 0.33 |
| Theophylline and Prednisone Arm | Change in COPD Assessment Test (CAT) Score | -2.57 Score on a scale | Standard Deviation 0.33 |
Secondary
Post Bronchodilator FEV1
The change in post bronchodilator FEV1 from baseline to 48 weeks
Time frame: Change at 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Post Bronchodilator FEV1 | -0.02 L/sec | Standard Deviation 0.01 |
| Low-dose Theophylline Arm | Post Bronchodilator FEV1 | -0.01 L/sec | Standard Deviation 0.01 |
| Theophylline and Prednisone Arm | Post Bronchodilator FEV1 | -0.02 L/sec | Standard Deviation 0.01 |
Secondary
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.
Time frame: Change over 48 week study duration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Quality of Life Measured by St. George's Respiratory Questionnaire (SGRQ) | -4.95 Scores on a scale | Standard Deviation 0.91 |
| Low-dose Theophylline Arm | Quality of Life Measured by St. George's Respiratory Questionnaire (SGRQ) | -6.85 Scores on a scale | Standard Deviation 0.91 |
| Theophylline and Prednisone Arm | Quality of Life Measured by St. George's Respiratory Questionnaire (SGRQ) | -6.48 Scores on a scale | Standard Deviation 0.89 |
Secondary
Time to First COPD Exacerbation
The median time (days) from randomisation to first exacerbation per participant
Time frame: Median time (days) from randomisation to first exacerbation over a 48 week period per participant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First COPD Exacerbation | 137 Days |
| Low-dose Theophylline Arm | Time to First COPD Exacerbation | 150 Days |
| Theophylline and Prednisone Arm | Time to First COPD Exacerbation | 151 Days |
Other Pre-specified
Hospitalisations
The total number of hospitalisation events within 48 weeks
Time frame: 48 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Hospitalisations | 120 Number of hospitalisation events |
| Low-dose Theophylline Arm | Hospitalisations | 101 Number of hospitalisation events |
| Theophylline and Prednisone Arm | Hospitalisations | 122 Number of hospitalisation events |