Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD
Brief summary
The overall objective of this study is to determine an optimal dose and dosing regimen of PT001 MDI for further evaluation in later stage studies.
Detailed description
The primary objective of this study is to assess efficacy relative to placebo of GP MDI in subjects with moderate to severe chronic obstructive pulmonary disease (COPD) within the range of doses evaluated in this protocol. To this end, each dose of GP MDI will be compared to placebo with respect to the primary efficacy endpoint, FEV1 AUC0-12 relative to baseline.
Interventions
DRUGPT001 MDI
Administered as two puffs BID for 14 days
DRUGTiotropium Bromide
Taken as 1 capsule containing 18 µg of tiotropium via the Handihaler DPI
DRUGPT001 Placebo MDI
Sponsors
Pearl Therapeutics, Inc.
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 80 Years
Healthy volunteers
No
Inclusion criteria
* Signed written informed consent * 40 - 80 years of age * Clinical history of COPD with airflow limitation that is not fully reversible * Females of non-child bearing potential or females of child bearing potential with negative pregnancy test; and acceptable contraceptive methods * Current/former smokers with at least a 10 pack-year history of cigarette smoking * A measured post- bronchodilator FEV1/FVC ratio of \< or = 0.70 * A measured post- bronchodilator FEV1 \> or = 750ml or 30% predicted and \< or = 80% of predicted normal values * Able to change COPD treatment as required by protocol
Exclusion criteria
* Women who are pregnant or lactating * Primary diagnosis of asthma * Alpha-1 antitrypsin deficiency as the cause of COPD * Active pulmonary diseases * Prior lung volume reduction surgery * Abnormal chest X-ray (or CT scan) not due to the presence of COPD * Hospitalized due to poorly controlled COPD within 3 months of Screening * Clinically significant medical conditions that preclude participation in the study (e.g. clinically significant abnormal ECG, uncontrolled hypertension, glaucoma, symptomatic prostatic hypertrophy) * Cancer that has not been in complete remission for at least 5 years * Treatment with investigational study drug or participation in another clinical trial or study within the last 30 days or 5 half lives Other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 AUC0-12 | Day 14 (-1 hr, -30 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 11.5 hr, 12 hr) | Forced expiratory volume in 1 second (FEV1) normalized area under the curve 0-12 hours (AUC0-12) following chronic dosing for 14 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | Day 1 (15 min, 30 min, 1 hr, 2 hrs, no onset within 2 hrs) | Time to Onset of Action (\>10% Improvement in FEV1) on Day 1. |
| Percentage of Subjects Achieving at Least 12% Improvement in FEV1 | Day 1 | Percentage of subjects achieving at least 12% improvement in FEV1. |
| Peak Change From Baseline in Inspiratory Capacity (IC) | Day 1 (1 hr and 2 hr post-dose ) | Peak change in Inspiratory Capacity (IC) mean of 1 and 2 hour post-dose assessments minus the baseline |
| Change From Baseline in Morning Pre-dose Trough FEV1 | Day 7 (average of the 60 and 30-minute pre-dose values on Treatment Day 7 minus the baseline) | Change from baseline in morning pre-dose trough FEV1 (average of the 60 and 30-minute pre-dose values on Treatment Day 7 minus the baseline) |
| Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC) | Day 7 | Change from baseline in morning pre-dose trough IC (average of the 60 and 30-minute pre-dose assessments minus the baseline) |
| Peak Change From Baseline in IC | Day 7 (mean of 1 hr and 2 hr post-dose assessments) | Peak change from baseline in IC (mean of 1 hr and 2 hr post-dose assessments) |
| Change From Baseline in Mean Morning Pre-dose Daily PEFR | Day 7 (60 minutes pre-dose, 30 minutes pre-dose) | Change from baseline in mean morning pre-dose daily PEFR (peak expiratory flow rate) taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (excluding reading taken pre-dose on Visit 2 \[Treatment Day 1\]) |
| Change From Baseline in Morning Post-dose Daily PEFR | Day 7 (30 minutes post-dose) | Change from baseline in morning post-dose daily PEFR (peak expiratory flow rate) taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (excluding reading taken pre-dose on Visit 2 \[Treatment Day 1\]) |
| Change From Baseline in Mean Evening Pre-dose PEFR | Day 7 | Change from baseline in mean evening pre-dose daily peak flow readings taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (subjects taking Spiriva performed a single evening assessment) |
| Peak Change From Baseline in FEV1 | Day 1 | Highest value of FEV1 post dose on day 1 |
| Mean Number of Puffs of Rescue Medication | Day 7 | Mean number of puffs of rescue medication recorded in subject diaries during each treatment period and by treatment and numbers of days treated |
| Change From Baseline for Mean Morning Pre-dose Trough IC | Day 14 (average of the 60 and 30-minute pre-dose assessments minus the baseline) | Change from baseline for mean morning pre-dose trough IC (average of the 60 and 30-minute pre-dose assessments minus the baseline) |
| Change From Baseline in 12-hour Post-dose Trough FEV1 | Day 14 (Baseline, 11.5 and 12 hours post dose) | 12-hour post-dose trough FEV1 was defined as the mean of the FEV1 assessments taken at 11.5 and 12 hours post-dose minus the baseline |
| Change From Baseline in Mean Morning Post-dose Daily PEFR | Baseline, Treatment Day 1 and every day, to the end of the 14-Day Treatment period 30 minutes post dosing, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7) | Change from baseline in mean morning post-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (mean reading excluded reading taken pre-dose on Visit 2 \[Treatment 1 Day 1\] |
| Change From Baseline in Mean Evening Pre-dose Daily PEFR | Treatment Day 1 to the end of the 14-Day Treatment, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7) | Change from baseline in mean evening pre-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (subjects taking Spiriva performed a single evening assessment) |
| Change From Baseline in Mean Evening Post-dose Daily PEFR | Through the end of the 14-Day Treatment | Change from baseline in mean evening post-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (subjects taking Spiriva performed a single evening assessment) |
| Mean Number of Puffs of Rescue Medication (End of Treatment) | Day 14 (End of treatment) | Mean number of puffs of rescue medication recorded in subject diaries during each treatment period and by treatment and numbers of days treated |
| Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 | Day 1 through Day 14 | Change from Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 |
| Change From Baseline in Mean Evening Post-dose PEFR | Day 7 | Change from baseline in mean evening post-dose daily peak flow readings taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (subjects taking Spiriva performed a single evening assessment) |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 10 sites in the US from April 2012 to August 2012. Study participation maximum of 26 weeks.
Pre-assignment details
A randomized, double-blind,chronic dosing, four-period, eight-treatment, placebo-controlled, incomplete block, crossover, multicenter study.
Participants by arm
| Arm | Count |
|---|---|
| All Subjects All Subjects | 140 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative reason | 1 |
| Overall Study | Adverse Event | 10 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Protocol specified criteria | 4 |
| Overall Study | Protocol Violation | 4 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Continuous | 61.3 Years STANDARD_DEVIATION 8.4 |
| Sex: Female, Male Female | 65 Participants |
| Sex: Female, Male Male | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 64 | 3 / 64 | 3 / 62 | 6 / 64 | 3 / 57 | 4 / 59 | 3 / 62 | 6 / 62 |
| serious Total, serious adverse events | 0 / 64 | 1 / 64 | 0 / 62 | 1 / 64 | 0 / 57 | 1 / 59 | 1 / 62 | 1 / 62 |
Outcome results
Primary
FEV1 AUC0-12
Forced expiratory volume in 1 second (FEV1) normalized area under the curve 0-12 hours (AUC0-12) following chronic dosing for 14 days.
Time frame: Day 14 (-1 hr, -30 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 11.5 hr, 12 hr)
Population: MITT (Modified Intent to Treat) Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | FEV1 AUC0-12 | 1.448 Liter |
| GP MDI 9 µg BID | FEV1 AUC0-12 | 1.416 Liter |
| GP MDI 4.6 µg BID | FEV1 AUC0-12 | 1.432 Liter |
| GP MDI 2.4 µg BID | FEV1 AUC0-12 | 1.416 Liter |
| GP MDI 1.2 µg BID | FEV1 AUC0-12 | 1.386 Liter |
| GP MDI 0.6 µg BID | FEV1 AUC0-12 | 1.353 Liter |
| Placebo MDI | FEV1 AUC0-12 | 1.290 Liter |
| Spiriva® Handihaler® | FEV1 AUC0-12 | 1.514 Liter |
Secondary
Change From Baseline for Mean Morning Pre-dose Trough IC
Change from baseline for mean morning pre-dose trough IC (average of the 60 and 30-minute pre-dose assessments minus the baseline)
Time frame: Day 14 (average of the 60 and 30-minute pre-dose assessments minus the baseline)
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline for Mean Morning Pre-dose Trough IC | 94 mL |
| GP MDI 9 µg BID | Change From Baseline for Mean Morning Pre-dose Trough IC | 45 mL |
| GP MDI 4.6 µg BID | Change From Baseline for Mean Morning Pre-dose Trough IC | 64 mL |
| GP MDI 2.4 µg BID | Change From Baseline for Mean Morning Pre-dose Trough IC | 104 mL |
| GP MDI 1.2 µg BID | Change From Baseline for Mean Morning Pre-dose Trough IC | 69 mL |
| GP MDI 0.6 µg BID | Change From Baseline for Mean Morning Pre-dose Trough IC | 34 mL |
| Placebo MDI | Change From Baseline for Mean Morning Pre-dose Trough IC | 9 mL |
| Spiriva® Handihaler® | Change From Baseline for Mean Morning Pre-dose Trough IC | 138 mL |
Secondary
Change From Baseline in 12-hour Post-dose Trough FEV1
12-hour post-dose trough FEV1 was defined as the mean of the FEV1 assessments taken at 11.5 and 12 hours post-dose minus the baseline
Time frame: Day 14 (Baseline, 11.5 and 12 hours post dose)
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in 12-hour Post-dose Trough FEV1 | 116 mL |
| GP MDI 9 µg BID | Change From Baseline in 12-hour Post-dose Trough FEV1 | 69 mL |
| GP MDI 4.6 µg BID | Change From Baseline in 12-hour Post-dose Trough FEV1 | 99 mL |
| GP MDI 2.4 µg BID | Change From Baseline in 12-hour Post-dose Trough FEV1 | 112 mL |
| GP MDI 1.2 µg BID | Change From Baseline in 12-hour Post-dose Trough FEV1 | 66 mL |
| GP MDI 0.6 µg BID | Change From Baseline in 12-hour Post-dose Trough FEV1 | 55 mL |
| Placebo MDI | Change From Baseline in 12-hour Post-dose Trough FEV1 | 1 mL |
| Spiriva® Handihaler® | Change From Baseline in 12-hour Post-dose Trough FEV1 | 164 mL |
Secondary
Change From Baseline in Mean Evening Post-dose Daily PEFR
Change from baseline in mean evening post-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (subjects taking Spiriva performed a single evening assessment)
Time frame: Through the end of the 14-Day Treatment
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Mean Evening Post-dose Daily PEFR | 41.4 L/min |
| GP MDI 9 µg BID | Change From Baseline in Mean Evening Post-dose Daily PEFR | 32.7 L/min |
| GP MDI 4.6 µg BID | Change From Baseline in Mean Evening Post-dose Daily PEFR | 24.7 L/min |
| GP MDI 2.4 µg BID | Change From Baseline in Mean Evening Post-dose Daily PEFR | 27.0 L/min |
| GP MDI 1.2 µg BID | Change From Baseline in Mean Evening Post-dose Daily PEFR | 19.4 L/min |
| GP MDI 0.6 µg BID | Change From Baseline in Mean Evening Post-dose Daily PEFR | 22.7 L/min |
| Placebo MDI | Change From Baseline in Mean Evening Post-dose Daily PEFR | 13.5 L/min |
| Spiriva® Handihaler® | Change From Baseline in Mean Evening Post-dose Daily PEFR | 35.9 L/min |
Secondary
Change From Baseline in Mean Evening Post-dose PEFR
Change from baseline in mean evening post-dose daily peak flow readings taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (subjects taking Spiriva performed a single evening assessment)
Time frame: Day 7
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Mean Evening Post-dose PEFR | 42.2 L/min |
| GP MDI 9 µg BID | Change From Baseline in Mean Evening Post-dose PEFR | 30.3 L/min |
| GP MDI 4.6 µg BID | Change From Baseline in Mean Evening Post-dose PEFR | 21.6 L/min |
| GP MDI 2.4 µg BID | Change From Baseline in Mean Evening Post-dose PEFR | 24.3 L/min |
| GP MDI 1.2 µg BID | Change From Baseline in Mean Evening Post-dose PEFR | 20.2 L/min |
| GP MDI 0.6 µg BID | Change From Baseline in Mean Evening Post-dose PEFR | 22.1 L/min |
| Placebo MDI | Change From Baseline in Mean Evening Post-dose PEFR | 11.0 L/min |
| Spiriva® Handihaler® | Change From Baseline in Mean Evening Post-dose PEFR | 35.6 L/min |
Secondary
Change From Baseline in Mean Evening Pre-dose Daily PEFR
Change from baseline in mean evening pre-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (subjects taking Spiriva performed a single evening assessment)
Time frame: Treatment Day 1 to the end of the 14-Day Treatment, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Mean Evening Pre-dose Daily PEFR | 15.7 L/min |
| GP MDI 9 µg BID | Change From Baseline in Mean Evening Pre-dose Daily PEFR | 14.9 L/min |
| GP MDI 4.6 µg BID | Change From Baseline in Mean Evening Pre-dose Daily PEFR | 7.2 L/min |
| GP MDI 2.4 µg BID | Change From Baseline in Mean Evening Pre-dose Daily PEFR | 11.7 L/min |
| GP MDI 1.2 µg BID | Change From Baseline in Mean Evening Pre-dose Daily PEFR | 5.0 L/min |
| GP MDI 0.6 µg BID | Change From Baseline in Mean Evening Pre-dose Daily PEFR | 6.9 L/min |
| Placebo MDI | Change From Baseline in Mean Evening Pre-dose Daily PEFR | 5.7 L/min |
Secondary
Change From Baseline in Mean Evening Pre-dose PEFR
Change from baseline in mean evening pre-dose daily peak flow readings taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (subjects taking Spiriva performed a single evening assessment)
Time frame: Day 7
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Mean Evening Pre-dose PEFR | 15.8 L/min |
| GP MDI 9 µg BID | Change From Baseline in Mean Evening Pre-dose PEFR | 12.6 L/min |
| GP MDI 4.6 µg BID | Change From Baseline in Mean Evening Pre-dose PEFR | 4.7 L/min |
| GP MDI 2.4 µg BID | Change From Baseline in Mean Evening Pre-dose PEFR | 11.2 L/min |
| GP MDI 1.2 µg BID | Change From Baseline in Mean Evening Pre-dose PEFR | 7.5 L/min |
| GP MDI 0.6 µg BID | Change From Baseline in Mean Evening Pre-dose PEFR | 5.9 L/min |
| Placebo MDI | Change From Baseline in Mean Evening Pre-dose PEFR | 3.3 L/min |
Secondary
Change From Baseline in Mean Morning Post-dose Daily PEFR
Change from baseline in mean morning post-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (mean reading excluded reading taken pre-dose on Visit 2 \[Treatment 1 Day 1\]
Time frame: Baseline, Treatment Day 1 and every day, to the end of the 14-Day Treatment period 30 minutes post dosing, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Mean Morning Post-dose Daily PEFR | 33.5 L/min |
| GP MDI 9 µg BID | Change From Baseline in Mean Morning Post-dose Daily PEFR | 26.7 L/min |
| GP MDI 4.6 µg BID | Change From Baseline in Mean Morning Post-dose Daily PEFR | 20.2 L/min |
| GP MDI 2.4 µg BID | Change From Baseline in Mean Morning Post-dose Daily PEFR | 20.3 L/min |
| GP MDI 1.2 µg BID | Change From Baseline in Mean Morning Post-dose Daily PEFR | 14.8 L/min |
| GP MDI 0.6 µg BID | Change From Baseline in Mean Morning Post-dose Daily PEFR | 14.3 L/min |
| Placebo MDI | Change From Baseline in Mean Morning Post-dose Daily PEFR | 5.3 L/min |
| Spiriva® Handihaler® | Change From Baseline in Mean Morning Post-dose Daily PEFR | 39.8 L/min |
Secondary
Change From Baseline in Mean Morning Pre-dose Daily PEFR
Change from baseline in mean morning pre-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (mean reading excluded reading taken pre-dose on Visit 2 \[Treatment 1 Day 1\]
Time frame: Baseline, Treatment Day 1 and every day, to the end of the 14-Day Treatment period before dosing, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 8.6 L/min |
| GP MDI 9 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 6.2 L/min |
| GP MDI 4.6 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 2.0 L/min |
| GP MDI 2.4 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 4.4 L/min |
| GP MDI 1.2 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 0.3 L/min |
| GP MDI 0.6 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | -0.5 L/min |
| Placebo MDI | Change From Baseline in Mean Morning Pre-dose Daily PEFR | -6.3 L/min |
| Spiriva® Handihaler® | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 14.8 L/min |
Secondary
Change From Baseline in Mean Morning Pre-dose Daily PEFR
Change from baseline in mean morning pre-dose daily PEFR (peak expiratory flow rate) taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (excluding reading taken pre-dose on Visit 2 \[Treatment Day 1\])
Time frame: Day 7 (60 minutes pre-dose, 30 minutes pre-dose)
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 8.0 L/min |
| GP MDI 9 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 3.2 L/min |
| GP MDI 4.6 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 0.2 L/min |
| GP MDI 2.4 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 2.4 L/min |
| GP MDI 1.2 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | -2.4 L/min |
| GP MDI 0.6 µg BID | Change From Baseline in Mean Morning Pre-dose Daily PEFR | -2.5 L/min |
| Placebo MDI | Change From Baseline in Mean Morning Pre-dose Daily PEFR | -7.2 L/min |
| Spiriva® Handihaler® | Change From Baseline in Mean Morning Pre-dose Daily PEFR | 12.7 L/min |
Secondary
Change From Baseline in Morning Post-dose Daily PEFR
Change from baseline in morning post-dose daily PEFR (peak expiratory flow rate) taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (excluding reading taken pre-dose on Visit 2 \[Treatment Day 1\])
Time frame: Day 7 (30 minutes post-dose)
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Morning Post-dose Daily PEFR | 32.3 L/min |
| GP MDI 9 µg BID | Change From Baseline in Morning Post-dose Daily PEFR | 23.9 L/min |
| GP MDI 4.6 µg BID | Change From Baseline in Morning Post-dose Daily PEFR | 17.2 L/min |
| GP MDI 2.4 µg BID | Change From Baseline in Morning Post-dose Daily PEFR | 18.3 L/min |
| GP MDI 1.2 µg BID | Change From Baseline in Morning Post-dose Daily PEFR | 14.3 L/min |
| GP MDI 0.6 µg BID | Change From Baseline in Morning Post-dose Daily PEFR | 13.7 L/min |
| Placebo MDI | Change From Baseline in Morning Post-dose Daily PEFR | 4.5 L/min |
| Spiriva® Handihaler® | Change From Baseline in Morning Post-dose Daily PEFR | 38.0 L/min |
Secondary
Change From Baseline in Morning Pre-dose Trough FEV1
Change from baseline in morning pre-dose trough FEV1 (average of the 60 and 30-minute pre-dose values on Treatment Day 7 minus the baseline)
Time frame: Day 7 (average of the 60 and 30-minute pre-dose values on Treatment Day 7 minus the baseline)
Population: MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 88 mL |
| GP MDI 9 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 90 mL |
| GP MDI 4.6 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 109 mL |
| GP MDI 2.4 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 96 mL |
| GP MDI 1.2 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 43 mL |
| GP MDI 0.6 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 23 mL |
| Placebo MDI | Change From Baseline in Morning Pre-dose Trough FEV1 | 10 mL |
| Spiriva® Handihaler® | Change From Baseline in Morning Pre-dose Trough FEV1 | 156 mL |
Secondary
Change From Baseline in Morning Pre-dose Trough FEV1
Change from baseline in morning pre-dose trough FEV1 (average of the 60 and 30-minute pre-dose values on Treatment Day 14 minus the baseline)
Time frame: Day 14 (average of the 60 and 30-minute pre-dose values on Treatment Day 14 minus the baseline)
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 89 mL |
| GP MDI 9 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 80 mL |
| GP MDI 4.6 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 67 mL |
| GP MDI 2.4 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 77 mL |
| GP MDI 1.2 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 68 mL |
| GP MDI 0.6 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 | 29 mL |
| Placebo MDI | Change From Baseline in Morning Pre-dose Trough FEV1 | -8 mL |
| Spiriva® Handihaler® | Change From Baseline in Morning Pre-dose Trough FEV1 | 126 mL |
Secondary
Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14
Change from Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14
Time frame: Day 1 through Day 14
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 | 0.088 Liter |
| GP MDI 9 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 | 0.087 Liter |
| GP MDI 4.6 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 | 0.090 Liter |
| GP MDI 2.4 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 | 0.086 Liter |
| GP MDI 1.2 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 | 0.056 Liter |
| GP MDI 0.6 µg BID | Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 | 0.023 Liter |
| Placebo MDI | Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 | 0.001 Liter |
| Spiriva® Handihaler® | Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 | 0.141 Liter |
Secondary
Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC)
Change from baseline in morning pre-dose trough IC (average of the 60 and 30-minute pre-dose assessments minus the baseline)
Time frame: Day 7
Population: MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC) | 137 mL |
| GP MDI 9 µg BID | Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC) | 57 mL |
| GP MDI 4.6 µg BID | Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC) | 101 mL |
| GP MDI 2.4 µg BID | Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC) | 142 mL |
| GP MDI 1.2 µg BID | Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC) | 73 mL |
| GP MDI 0.6 µg BID | Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC) | 54 mL |
| Placebo MDI | Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC) | 62 mL |
| Spiriva® Handihaler® | Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC) | 184 mL |
Secondary
Mean Number of Puffs of Rescue Medication
Mean number of puffs of rescue medication recorded in subject diaries during each treatment period and by treatment and numbers of days treated
Time frame: Day 7
Population: MITT Population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Mean Number of Puffs of Rescue Medication | 0.9 Puffs |
| GP MDI 9 µg BID | Mean Number of Puffs of Rescue Medication | 1.3 Puffs |
| GP MDI 4.6 µg BID | Mean Number of Puffs of Rescue Medication | 1.2 Puffs |
| GP MDI 2.4 µg BID | Mean Number of Puffs of Rescue Medication | 1.2 Puffs |
| GP MDI 1.2 µg BID | Mean Number of Puffs of Rescue Medication | 1.5 Puffs |
| GP MDI 0.6 µg BID | Mean Number of Puffs of Rescue Medication | 1.6 Puffs |
| Placebo MDI | Mean Number of Puffs of Rescue Medication | 2.0 Puffs |
| Spiriva® Handihaler® | Mean Number of Puffs of Rescue Medication | 0.9 Puffs |
Secondary
Mean Number of Puffs of Rescue Medication (End of Treatment)
Mean number of puffs of rescue medication recorded in subject diaries during each treatment period and by treatment and numbers of days treated
Time frame: Day 14 (End of treatment)
Population: MITT Population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Mean Number of Puffs of Rescue Medication (End of Treatment) | 0.85 Puffs |
| GP MDI 9 µg BID | Mean Number of Puffs of Rescue Medication (End of Treatment) | 1.25 Puffs |
| GP MDI 4.6 µg BID | Mean Number of Puffs of Rescue Medication (End of Treatment) | 1.19 Puffs |
| GP MDI 2.4 µg BID | Mean Number of Puffs of Rescue Medication (End of Treatment) | 1.11 Puffs |
| GP MDI 1.2 µg BID | Mean Number of Puffs of Rescue Medication (End of Treatment) | 1.43 Puffs |
| GP MDI 0.6 µg BID | Mean Number of Puffs of Rescue Medication (End of Treatment) | 1.57 Puffs |
| Placebo MDI | Mean Number of Puffs of Rescue Medication (End of Treatment) | 1.92 Puffs |
| Spiriva® Handihaler® | Mean Number of Puffs of Rescue Medication (End of Treatment) | 0.87 Puffs |
Secondary
Peak Change From Baseline in FEV1
Highest value of FEV1 post dose on day 1
Time frame: Day 1
Population: MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Peak Change From Baseline in FEV1 | 231 mL |
| GP MDI 9 µg BID | Peak Change From Baseline in FEV1 | 226 mL |
| GP MDI 4.6 µg BID | Peak Change From Baseline in FEV1 | 165 mL |
| GP MDI 2.4 µg BID | Peak Change From Baseline in FEV1 | 170 mL |
| GP MDI 1.2 µg BID | Peak Change From Baseline in FEV1 | 136 mL |
| GP MDI 0.6 µg BID | Peak Change From Baseline in FEV1 | 107 mL |
| Placebo MDI | Peak Change From Baseline in FEV1 | 57 mL |
| Spiriva® Handihaler® | Peak Change From Baseline in FEV1 | 270 mL |
Secondary
Peak Change From Baseline in FEV1
Peak change from baseline in FEV1 (defined as the change at the highest value of FEV1 post-dose minus the baseline)
Time frame: Day 14
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Peak Change From Baseline in FEV1 | 288 mL |
| GP MDI 9 µg BID | Peak Change From Baseline in FEV1 | 288 mL |
| GP MDI 4.6 µg BID | Peak Change From Baseline in FEV1 | 287 mL |
| GP MDI 2.4 µg BID | Peak Change From Baseline in FEV1 | 261 mL |
| GP MDI 1.2 µg BID | Peak Change From Baseline in FEV1 | 246 mL |
| GP MDI 0.6 µg BID | Peak Change From Baseline in FEV1 | 188 mL |
| Placebo MDI | Peak Change From Baseline in FEV1 | 130 mL |
| Spiriva® Handihaler® | Peak Change From Baseline in FEV1 | 361 mL |
Secondary
Peak Change From Baseline in FEV1
Peak change from baseline in FEV1 (defined as the change at the highest value of FEV1 post-dose minus the baseline)
Time frame: Day 7
Population: MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Peak Change From Baseline in FEV1 | 286 mL |
| GP MDI 9 µg BID | Peak Change From Baseline in FEV1 | 269 mL |
| GP MDI 4.6 µg BID | Peak Change From Baseline in FEV1 | 266 mL |
| GP MDI 2.4 µg BID | Peak Change From Baseline in FEV1 | 235 mL |
| GP MDI 1.2 µg BID | Peak Change From Baseline in FEV1 | 225 mL |
| GP MDI 0.6 µg BID | Peak Change From Baseline in FEV1 | 166 mL |
| Placebo MDI | Peak Change From Baseline in FEV1 | 114 mL |
| Spiriva® Handihaler® | Peak Change From Baseline in FEV1 | 366 mL |
Secondary
Peak Change From Baseline in IC
Peak change from baseline in IC (mean of 1 hr and 2 hr post-dose assessments)
Time frame: Day 7 (mean of 1 hr and 2 hr post-dose assessments)
Population: MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Peak Change From Baseline in IC | 302 mL |
| GP MDI 9 µg BID | Peak Change From Baseline in IC | 234 mL |
| GP MDI 4.6 µg BID | Peak Change From Baseline in IC | 254 mL |
| GP MDI 2.4 µg BID | Peak Change From Baseline in IC | 312 mL |
| GP MDI 1.2 µg BID | Peak Change From Baseline in IC | 195 mL |
| GP MDI 0.6 µg BID | Peak Change From Baseline in IC | 159 mL |
| Placebo MDI | Peak Change From Baseline in IC | 99 mL |
| Spiriva® Handihaler® | Peak Change From Baseline in IC | 390 mL |
Secondary
Peak Change From Baseline in IC
Peak change from baseline in IC (mean of 1 and 2 hour post-dose assessments minus the baseline)
Time frame: Day 14 (mean of 1 and 2 hour post-dose assessments minus the baseline)
Population: MITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Peak Change From Baseline in IC | 280 mL |
| GP MDI 9 µg BID | Peak Change From Baseline in IC | 259 mL |
| GP MDI 4.6 µg BID | Peak Change From Baseline in IC | 288 mL |
| GP MDI 2.4 µg BID | Peak Change From Baseline in IC | 226 mL |
| GP MDI 1.2 µg BID | Peak Change From Baseline in IC | 261 mL |
| GP MDI 0.6 µg BID | Peak Change From Baseline in IC | 172 mL |
| Placebo MDI | Peak Change From Baseline in IC | 77 mL |
| Spiriva® Handihaler® | Peak Change From Baseline in IC | 284 mL |
Secondary
Peak Change From Baseline in Inspiratory Capacity (IC)
Peak change in Inspiratory Capacity (IC) mean of 1 and 2 hour post-dose assessments minus the baseline
Time frame: Day 1 (1 hr and 2 hr post-dose )
Population: MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GP MDI 18 µg BID | Peak Change From Baseline in Inspiratory Capacity (IC) | 234 mL |
| GP MDI 9 µg BID | Peak Change From Baseline in Inspiratory Capacity (IC) | 263 mL |
| GP MDI 4.6 µg BID | Peak Change From Baseline in Inspiratory Capacity (IC) | 151 mL |
| GP MDI 2.4 µg BID | Peak Change From Baseline in Inspiratory Capacity (IC) | 183 mL |
| GP MDI 1.2 µg BID | Peak Change From Baseline in Inspiratory Capacity (IC) | 126 mL |
| GP MDI 0.6 µg BID | Peak Change From Baseline in Inspiratory Capacity (IC) | 82 mL |
| Placebo MDI | Peak Change From Baseline in Inspiratory Capacity (IC) | 80 mL |
| Spiriva® Handihaler® | Peak Change From Baseline in Inspiratory Capacity (IC) | 343 mL |
Secondary
Percentage of Subjects Achieving at Least 12% Improvement in FEV1
Percentage of subjects achieving at least 12% improvement in FEV1.
Time frame: Day 1
Population: MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GP MDI 18 µg BID | Percentage of Subjects Achieving at Least 12% Improvement in FEV1 | 70 Percentage of participants |
| GP MDI 9 µg BID | Percentage of Subjects Achieving at Least 12% Improvement in FEV1 | 59 Percentage of participants |
| GP MDI 4.6 µg BID | Percentage of Subjects Achieving at Least 12% Improvement in FEV1 | 40 Percentage of participants |
| GP MDI 2.4 µg BID | Percentage of Subjects Achieving at Least 12% Improvement in FEV1 | 47 Percentage of participants |
| GP MDI 1.2 µg BID | Percentage of Subjects Achieving at Least 12% Improvement in FEV1 | 40 Percentage of participants |
| GP MDI 0.6 µg BID | Percentage of Subjects Achieving at Least 12% Improvement in FEV1 | 31 Percentage of participants |
| Placebo MDI | Percentage of Subjects Achieving at Least 12% Improvement in FEV1 | 71 Percentage of participants |
Secondary
Time to Onset of Action (>10% Improvement in FEV1) on Day 1
Time to Onset of Action (\>10% Improvement in FEV1) on Day 1.
Time frame: Day 1 (15 min, 30 min, 1 hr, 2 hrs, no onset within 2 hrs)
Population: MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GP MDI 18 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 30 minutes | 22 % of participants |
| GP MDI 18 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 2 hours | 0 % of participants |
| GP MDI 18 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 24 % of participants |
| GP MDI 18 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 15 minutes | 29 % of participants |
| GP MDI 18 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 1 hour | 26 % of participants |
| GP MDI 9 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 32 % of participants |
| GP MDI 9 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 1 hour | 11 % of participants |
| GP MDI 9 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 15 minutes | 30 % of participants |
| GP MDI 9 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 2 hours | 16 % of participants |
| GP MDI 9 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 30 minutes | 11 % of participants |
| GP MDI 4.6 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 56 % of participants |
| GP MDI 4.6 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 15 minutes | 14 % of participants |
| GP MDI 4.6 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 1 hour | 11 % of participants |
| GP MDI 4.6 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 2 hours | 11 % of participants |
| GP MDI 4.6 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 30 minutes | 9 % of participants |
| GP MDI 2.4 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 2 hours | 7 % of participants |
| GP MDI 2.4 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 15 minutes | 21 % of participants |
| GP MDI 2.4 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 30 minutes | 16 % of participants |
| GP MDI 2.4 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 1 hour | 10 % of participants |
| GP MDI 2.4 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 47 % of participants |
| GP MDI 1.2 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 30 minutes | 12 % of participants |
| GP MDI 1.2 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 15 minutes | 18 % of participants |
| GP MDI 1.2 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 50 % of participants |
| GP MDI 1.2 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 1 hour | 10 % of participants |
| GP MDI 1.2 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 2 hours | 10 % of participants |
| GP MDI 0.6 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 15 minutes | 7 % of participants |
| GP MDI 0.6 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 2 hours | 7 % of participants |
| GP MDI 0.6 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 30 minutes | 9 % of participants |
| GP MDI 0.6 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 59 % of participants |
| GP MDI 0.6 µg BID | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 1 hour | 17 % of participants |
| Placebo MDI | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 30 minutes | 7 % of participants |
| Placebo MDI | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 78 % of participants |
| Placebo MDI | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 1 hour | 9 % of participants |
| Placebo MDI | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 15 minutes | 4 % of participants |
| Placebo MDI | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 2 hours | 2 % of participants |
| Spiriva® Handihaler® | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 20 % of participants |
| Spiriva® Handihaler® | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 2 hours | 11 % of participants |
| Spiriva® Handihaler® | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 15 minutes | 39 % of participants |
| Spiriva® Handihaler® | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 30 minutes | 15 % of participants |
| Spiriva® Handihaler® | Time to Onset of Action (>10% Improvement in FEV1) on Day 1 | 1 hour | 15 % of participants |