Chronic Bronchitis, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema
Conditions
Keywords
Pulmonary Disease, Chronic Obstructive, Tiotropium, Formoterol, Bronchodilator Agents, Exercise Tolerance, Randomized Controlled Trial [Publication Type], COPD
Brief summary
The primary objective is to comparatively evaluate the isolated effects of a long-acting beta2-adrenergic (formoterol fumarate 12µg b.i.d. via Aeroliser) and combined with a long-acting anti-cholinergic (tiotropium bromide 18µg o.d via Handihaler) on breathlessness, dynamic hyperinflation and exercise tolerance in patients with advanced, but stable, chronic obstructive pulmonary disease. The study hypothesis is that combining long acting bronchodilators with different action mechanisms would promote synergistic effects on clinical outcomes.
Detailed description
This will be a single center, randomized, double-blind study consisting of two 2-week treatment periods separated by a 5-7 days washout phase without long-acting bronchodilators. Eligible patients who complete the one week screening phase will be randomized to one of two treatment sequences: 1) Formoterol --\> Formoterol + Tiotropium or 2) Formoterol + Tiotropium --\> Formoterol. During the treatment periods, patients will be allowed to use a short-acting beta2-adrenergic+short-acting anticholinergic as rescue medication (salbutamol+ipratropium via MDI)
Interventions
DRUGFormoterol plus Placebo (Tiotropium)
Formoterol 12mcg-capsules (2x/d) + Placebo (Tiotropium) (1x/d). Double-blind medication will be dispensed in HandiHalers and Aerolisers during 2 weeks.
DRUGFormoterol plus Tiotropium
Formoterol 12mcg-capsule (2x/dia) + Tiotropium 18mcg-capsule (1x/d). Double-blind medication will be dispensed in HandiHalers and Aerolisers during 2 weeks.
Sponsors
Federal University of São Paulo
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* COPD patients aged ≥ 40 years with stable moderate-to-severe airflow obstruction (FEV1 \< 70% and FEV1/FVC ≤ 70% of predicted normal value) post-bronchodilator * presenting with a long history of smoking (\> 20 pack-years) and chronic breathlessness (Baseline Dyspnoea Index total score \< 9)
Exclusion criteria
* significant cardiovascular disease, hospitalization for COPD exacerbation or presence of a respiratory tract infection within 1 month of screening * current or childhood asthma * a history of allergic rhinitis or other atopic disease * inability to interrupt usual bronchodilator medication * use of oral steroids within a month before screening * need for long-term oxygen therapy, arterial oxygen saturation \< 85% at rest anemia, hypo- and hyperthyroidism, hyperadrenergic state * uncontrolled insulin dependent diabetes mellitus, malignancy, or any disease or condition which limits exercise performance other than COPD * change in inhaled corticosteroid or theophylline use within 1 month prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Exercise Tolerance From Baseline at 2 Weeks | Baseline and after 2 weeks with each treatment | Percentage change from baseline in time to the limit of tolerance on a high intensity constant-speed treadmill exercise test (with a speed corresponding to 80% of that obtained during incremental test) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Score on the Transitional Dyspnea Index (TDI) | After 2 week of each treatment | TDI is a multidimensional clinical instrument developed to provide a comprehensive assessment of change in dyspnea after an intervention, considering three components (functional impairment, magnitude of task, and magnitude of effort). It ranges from -9 (major deterioration) to +9 (major improvement). |
Countries
Brazil
Participant flow
Recruitment details
University clinic Period: January-August (2008)
Pre-assignment details
After screening and before first baseline visit, patients discontinued long-acting β2-agonists and inhaled anticholinergic bronchodilators (run in period). 50 patients recruited; 33 screened. 7 excluded: 4 due to chronic obstructive pulmonary disease (COPD) exacerbation and 3 due to protocol violation.
Participants by arm
| Arm | Count |
|---|---|
| Formoterol Plus Placebo (Tiotropium) First Formoterol + Placebo (Tiotropium) in first intervention period and Formoterol + Tiotropium in second intervention period (after washout period). | 16 |
| Formoterol Plus Tiotropium First Formoterol + Tiotropium in first intervention period and Formoterol + placebo in second intervention period (after washout period). | 17 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Mainly Exacerbation of COPD | 1 | 2 |
| Second Intervention | Protocol Violation | 3 | 1 |
Baseline characteristics
| Characteristic | Formoterol Plus Tiotropium First | Formoterol Plus Placebo (Tiotropium) First | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0.0 Participants |
| Age, Categorical >=65 years | 11 Participants | 6 Participants | 17.0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 10 Participants | 16.0 Participants |
| Age Continuous | 67.2 years STANDARD_DEVIATION 6.8 | 62.0 years STANDARD_DEVIATION 8.2 | 64.9 years STANDARD_DEVIATION 8.5 |
| Region of Enrollment Brazil | 17 participants | 16 participants | 33.0 participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 7.0 Participants |
| Sex: Female, Male Male | 15 Participants | 11 Participants | 26.0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Percentage Change in Exercise Tolerance From Baseline at 2 Weeks
Percentage change from baseline in time to the limit of tolerance on a high intensity constant-speed treadmill exercise test (with a speed corresponding to 80% of that obtained during incremental test)
Time frame: Baseline and after 2 weeks with each treatment
Population: The specific period where the patient received a given treatment were analysed together.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Formoterol Plus Placebo (Tiotropium) Treatment | Percentage Change in Exercise Tolerance From Baseline at 2 Weeks | 68 Percentage change | Standard Error 14 |
| Formoterol Plus Tiotropium Treatment | Percentage Change in Exercise Tolerance From Baseline at 2 Weeks | 124 Percentage change | Standard Error 27 |
Comparison: It was calculated a total sample size of a 2x2 cross-over design as 24 for a two-sided t-test achieves 85% power to infer that the mean difference is not zero, the actual mean difference is 20, the standard deviation of the differences is 15, and the significance level is 0.05p-value: 0.038t-test, 2 sided
Secondary
Mean Score on the Transitional Dyspnea Index (TDI)
TDI is a multidimensional clinical instrument developed to provide a comprehensive assessment of change in dyspnea after an intervention, considering three components (functional impairment, magnitude of task, and magnitude of effort). It ranges from -9 (major deterioration) to +9 (major improvement).
Time frame: After 2 week of each treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Formoterol Plus Placebo (Tiotropium) Treatment | Mean Score on the Transitional Dyspnea Index (TDI) | 2.9 score on scale | Standard Deviation 2.5 |
| Formoterol Plus Tiotropium Treatment | Mean Score on the Transitional Dyspnea Index (TDI) | 3.8 score on scale | Standard Deviation 1.8 |
p-value: 0.054t-test, 2 sided