COPD
Conditions
Keywords
COPD
Brief summary
The investigator wish therefore to continue these studies on theophylline principally by conducting a small clinical pilot study on 20-30 COPD patients in a randomised, double-blind, placebo-controlled, parallel-group study.
Detailed description
The global burden of COPD - a common and debilitating chronic inflammatory disease that is characterised by the progressive development of airflow limitation (shortness of breath - SOB) and is poorly reversible with currently available drugs -is increasing. Cigarette smoking is strongly linked with the ongoing inflammation; inflammation that can continue even when the patient has stopped smoking. The severity of airflow limitation (SOB) is correlated with the degree of pulmonary (lung) inflammation. Histone deacetylases (HDACs)are important molecules in suppressing this pulmonary inflammation. We have recently shown that patients with COPD have a reduction in total HDAC which correlates with the severity of their lung disease. Corticosteroids (anti-inflammatory treatment) act, at least in part, by recruitment of these HDACs to the site of active inflammatory gene transcription (which reduces the production of inflammatory molecules) and are widely used in COPD in patients with severe disease. Unfortunately, in COPD, inhaled corticosteroids seem to have little effect on the underlying inflammation (though in a selective group of patients with COPD they do reduce the number of infections a patient may have by a small amount). Theophylline has been used in the treatment of asthma and COPD for over 70 years, but its use has recently declined. Data so far obtained in primary cells (cells from patients used in the laboratory) from COPD patients suggests that low dose theophylline (\ 5mg/l) should be effective in restoring steroid sensitivity in patients with COPD (and hence reduce inflammation thus improving SOB).
Interventions
DRUGFluticasone Propionate
500 u
DRUGplacebo
DRUGTheophylline
Theophylline placebo capcule
Sponsors
Tanabe Pharma Corporation
Medical Research Council
Imperial College London
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
Participants with COPD with an FEV1 of 80-30% predicted. This will incorporate the majority of participants with COPD seen within the chest clinic. Patients with an FEV1 \> 80% predicted are not generally severe enough to warrant hospital follow up. These patients are also unlikely to have severe enough disease (and therefore airway inflammation) which may be modified by the therapeutic agents we are studying. Patients with an FEV1 \< 30% tend to have more severe symptom limitation and generally (though not always) find participation in a clinical trial involving 4 visits to the clinic difficult. Their airway disease is also generally less responsive to therapeutic intervention and as a consequence finding measurements which show changes to these therapeutic interventions is more difficult. COPD patients * All participants will be classified to Stage 2-3 of the GOLD (Global initiative for Obstructive Lung Disease) guidelines * Male or female, aged 45-80 years (according to GOLD guidelines) * 30% \< FEV1 \< 80% predicted * FEV1/FVC \< 70% * Cigarette exposure of \>10 pack-years# * With or without chronic symptoms (cough, sputum production, dyspnea). * Steroid therapy will be stopped before run-in, but long acting bronchodilators are acceptable. * The participants are able to give informed consent # The smoking history should include both the number smoked, for how long, and an estimate of total pack-years of smoking. One pack of 20 cigarettes smoked per day for 1 year = one pack year. Total pack years = No. cigarettes smoked per day/20 x no. years of smoking
Exclusion criteria
Any history or evidence of asthma * Pregnancy, breast-feeding or planned pregnancy during the study. Fertile women not using acceptable contraceptive measures, as judged by the investigator * Hospital admission with respiratory infection within the last 6 months * Upper respiratory infection within the last 4 weeks * Participants who have received research medication within the previous one month * Participants unable to give informed consent * Any mental condition rendering the participant unable to understand the nature, scope and possible consequences of the study * Known or suspected hypersensitivity to study therapy or excipients * Participants with significant or unstable ischemic heart disease, arrhythmia, cardiomyopathy, heart failure, uncontrolled hypertension as defined by the investigator, or any other relevant cardiovascular disorder as judged by the investigator * Any current respiratory tract disorders other than COPD, which is considered by the investigator to be clinically significant * Any significant disease or disorder (e.g. gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) or abnormality laboratory tests which, in the opinion of the investigator, may either put the participant at risk because of inclusion in the study, or may influence the results of the study, or the participants ability to take part in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sputum Inflammatory Cell Counts | 10 weeks | Supernatant collect, cell pellets count on slides |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Interleukin 8 (IL8) | 10 weeks | Interleukin 8 (IL8) assessed from sputum |
| Total Sputum Eosinophils | 10 weeks | Total eosinophils cells assessed from sputum |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Inhaled Theophylline placebo capsule, then inhaled placebo, then active Theophylline | 14 |
| Steroid Inhaled Theophylline placebo capsule, then Fluticasone Propionate 500 ug bid, then active Theophylline | 16 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase 1 (4 Weeks) | Lack of Efficacy | 0 | 1 |
| Phase 1 (4 Weeks) | Lost to Follow-up | 3 | 0 |
| Phase 1 (4 Weeks) | sore throat | 1 | 0 |
| Phase 1 (4 Weeks) | Withdrawal by Subject | 4 | 4 |
| Run in (2 Weeks) | Physician Decision | 3 | 3 |
Baseline characteristics
| Characteristic | Steroid | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 1.9 | 65 years STANDARD_DEVIATION 2 | 61 years STANDARD_DEVIATION 2.2 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United Kingdom | 16 participants | 30 participants | 14 participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Male | 14 Participants | 25 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 16 |
| other Total, other adverse events | 0 / 14 | 4 / 16 |
| serious Total, serious adverse events | 0 / 14 | 0 / 16 |
Outcome results
Primary
Sputum Inflammatory Cell Counts
Supernatant collect, cell pellets count on slides
Time frame: 10 weeks
Population: Using marginal means as results
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Sputum Inflammatory Cell Counts | 5.42 millions cells/ ml |
| Steroid | Sputum Inflammatory Cell Counts | 3.89 millions cells/ ml |
p-value: 0.012Mixed Models Analysis
Secondary
Interleukin 8 (IL8)
Interleukin 8 (IL8) assessed from sputum
Time frame: 10 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Interleukin 8 (IL8) | 33.3 ng/mL |
| Steroid | Interleukin 8 (IL8) | 28.3 ng/mL |
p-value: <0.05Mixed Models Analysis
Secondary
Total Sputum Eosinophils
Total eosinophils cells assessed from sputum
Time frame: 10 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Total Sputum Eosinophils | 0.132 millions cells/ml |
| Steroid | Total Sputum Eosinophils | 0.053 millions cells/ml |
p-value: <0.05Mixed Models Analysis