Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
Optimal clinical management in early stages of COPD is not established. Tiotropium has been shown to improve exercise tolerance during (CWR) cycle ergometry with GOLD stage II to IV COPD, improvements in constant speed treadmill time in a study of patients who also received pulmonary rehabilitation in a population of patients with predominantly severe and very severe disease (GOLD stages III and IV) and improvements in exertional dyspnea, and Shuttle Walk Test distance in GOLD stage III and IV COPD. However, data are lacking on the benefits of tiotropium on exercise tolerance in a patients with early stages of COPD who are symptomatic. Patients with milder ventilatory limitations (GOLD stages I/II COPD patients) may benefit from maintenance therapy and there is limited data on exercise limitation in patients with early stage COPD who are symptomatic. This study is designed to evaluate the mechanisms of breathlessness and assess physical activity limitation in early stage COPD patients compared to age and gender matched controls and will secondly investigate the effectiveness of treatment with tiotropium in improving dyspnea during exercise and exercise duration as a result of the bronchodilation effects of tiotropium leading to a reduction of dynamic hyperinflation in Early Stage COPD patients.
Interventions
DRUGTiotropium
double blind randomized crossover
DRUGPlacebo
inhalation powder capsule identical to those containing tiotropium bromide inhalation powder
Sponsors
Pfizer
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
For COPD subjects: Male or female, age of 40 years or older, smoking history \>10 pack-years, symptomatic defined as baseline dyspnea index focal score of 9 or more and / or daily cough with production of sputum for three months per year during at least two consecutive years, diagnosis of early stage COPD according to: post-bronchodilator FEV1/FVC ratio \<70%., FEV1 \>/=50% post-bronchodilator predicted normal, and a decreased Inspiratory Capacity during exercise. For Age / Gender Matched Controls: Male or female, age of 40 years or older, nonsmoker, with no significant diseases.
Exclusion criteria
Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patient's ability to participate in the study. Patients with a history of asthma, Patients requiring the use of supplemental oxygen therapy, Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea, such as arthritis in the leg, angina pectoris, claudication or other conditions, or Patients with contraindications to exercise. Note: Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Inspiratory Capacity (IC) at Isotime | baseline, six weeks of treatment | Inspiratory capacity (IC) during CWR exercise testing measured at isotime (isotime was established during CWR exercise testing at baseline). Isotime is the minimum exercise time among all tests. Constant work rate exercise means the exercise is done under constant work rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Constant Work Rate (CWR) Endurance Time | six weeks of treatment | CWR exercise duration calculated as the length of time of the exercise period |
| Change From Baseline in Modified Borg Scale Ratings for Dyspnea Intensity at Isotime | baseline, six weeks of treatment | Modified Borg Scale is a participant rating of the intensity of dyspnea measured on a scale ranging from 0 (Nothing at all) to 10 (Maximal, most severe ever experienced). |
Countries
Canada, United States
Participant flow
Pre-assignment details
The study has two stages, in the first (exploratory) stage, the Control group (Healthy volunteer) is compared to the age-gender matched COPD patients in terms of baseline characteristics. In the second (confirmatory) stage, Placebo and Tiotropium are compared using a cross-over. Since the first stage is exploratory it is not reported.
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Tiotropium Patients were randomized to receive treatment with Placebo for six weeks followed by treatment with Tiotropium 18 micrograms for six weeks | 63 |
| Tiotropium/Placebo Patients were randomized to receive treatment with Tiotropium 18 micrograms for six weeks followed by treatment with placebo for six weeks | 63 |
| Total | 126 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period One | Adverse Event | 1 | 1 |
| Period One | Protocol Violation | 2 | 1 |
| Period One | Withdrawal by Subject | 2 | 0 |
| Period Two | Adverse Event | 0 | 3 |
| Period Two | Lost to Follow-up | 1 | 0 |
| Washout Period | Missing termination information | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo/Tiotropium | Tiotropium/Placebo | Total |
|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 9.1 | 60.5 years STANDARD_DEVIATION 8.6 | 61.2 years STANDARD_DEVIATION 8.8 |
| Age, Customized >55 to <=65 years | 28 Participants | 23 Participants | 51 Participants |
| Age, Customized <=55 years | 14 Participants | 21 Participants | 35 Participants |
| Age, Customized >65 years | 21 Participants | 19 Participants | 40 Participants |
| Duration of COPD (Chronic Obstructive Pulmonary Disease) | 4.4 years STANDARD_DEVIATION 4.6 | 5.3 years STANDARD_DEVIATION 5.7 | 4.9 years STANDARD_DEVIATION 5.2 |
| Race/Ethnicity, Customized Black | 6 Participants | 6 Participants | 12 Participants |
| Race/Ethnicity, Customized White | 57 Participants | 57 Participants | 114 Participants |
| Sex: Female, Male Female | 28 Participants | 33 Participants | 61 Participants |
| Sex: Female, Male Male | 35 Participants | 30 Participants | 65 Participants |
| Smoking history | 46.0 pack years STANDARD_DEVIATION 24.4 | 48.1 pack years STANDARD_DEVIATION 20 | 47.0 pack years STANDARD_DEVIATION 22.3 |
| Smoking Status Currently smokes | 30 Participants | 29 Participants | 59 Participants |
| Smoking Status Ex-smoker | 33 Participants | 34 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 123 | 0 / 121 |
| serious Total, serious adverse events | 2 / 123 | 1 / 121 |
Outcome results
Primary
Change From Baseline in Inspiratory Capacity (IC) at Isotime
Inspiratory capacity (IC) during CWR exercise testing measured at isotime (isotime was established during CWR exercise testing at baseline). Isotime is the minimum exercise time among all tests. Constant work rate exercise means the exercise is done under constant work rate.
Time frame: baseline, six weeks of treatment
Population: Full Analysis Set (FAS) includes all patients with at least one baseline (at Visit 3 or 5) and two non-missing post-dosing data (at Visits 4 and 6) for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Inspiratory Capacity (IC) at Isotime | 0.0035 liter | Standard Error 0.02 |
| Tiotropium | Change From Baseline in Inspiratory Capacity (IC) at Isotime | 0.07 liter | Standard Error 0.02 |
Comparison: Placebo versus Tiotropium - crossover designp-value: 0.008795% CI: [0.02, 0.11]Mixed Models Analysis
Secondary
Change From Baseline in Modified Borg Scale Ratings for Dyspnea Intensity at Isotime
Modified Borg Scale is a participant rating of the intensity of dyspnea measured on a scale ranging from 0 (Nothing at all) to 10 (Maximal, most severe ever experienced).
Time frame: baseline, six weeks of treatment
Population: Full Analysis Set (FAS) includes all patients with at least one baseline (at Visit 3 or 5) and two non-missing post-dosing data (at Visits 4 and 6) for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Modified Borg Scale Ratings for Dyspnea Intensity at Isotime | -0.0485 Scores on a scale | Standard Error 0.133 |
| Tiotropium | Change From Baseline in Modified Borg Scale Ratings for Dyspnea Intensity at Isotime | -0.2544 Scores on a scale | Standard Error 0.133 |
Comparison: Placebo versus Tiotropium - corssover designp-value: 0.241795% CI: [-0.5527, 0.1408]Mixed Models Analysis
Secondary
Constant Work Rate (CWR) Endurance Time
CWR exercise duration calculated as the length of time of the exercise period
Time frame: six weeks of treatment
Population: Full Analysis Set (FAS) includes all patients with at least one baseline (at Visit 3 or 5) and two non-missing post-dosing data (at Visits 4 and 6) for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Constant Work Rate (CWR) Endurance Time | 6.0796 seconds | Standard Error 0.0313 |
| Tiotropium | Constant Work Rate (CWR) Endurance Time | 6.1458 seconds | Standard Error 0.0313 |
Comparison: Placebo versus Tiotropium - corssover designp-value: 0.06795% CI: [0.9953, 1.147]Mixed Models Analysis