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 demonstrate efficacy relative to placebo of PT001 MDI in patients with moderate to severe chronic obstructive pulmonary disease (COPD) within the range of doses evaluated in this protocol. To this end, each dose of PT001 MDI will be compared to placebo with respect to the primary efficacy endpoint, FEV1 AUC0-12 relative to baseline.
Interventions
DRUGPT001 MDI
PT001 MDI administered as two puffs BID for 7 days
DRUGIpratropium Bromide HFA Inhalation Aerosol
Taken as 2 inhalations of the 17 µg per actuation strength MDI QID
OTHERPlacebo MDI
Matching placebo to PT001 MDI administered as two puffs BID for 7 days
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
Key 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 Key
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 7 ( -1 hour, -30 min, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 5.5 hours, 6.5 hours, 8 hours, 10 hours, 11.5 hours, and 12 hours) | FEV1 AUC0-12 following chronic dosing (1 week), normalized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | Day 1 (15 min, 30 min, 1 hour, 2 hours) | Time to onset of action ( ≥10% improvement in FEV1) |
| Proportion of Subjects Achieving at Least 12% Improvement in FEV1 on Day 1 | Day 1 | Proportion of subjects achieving at least 12% improvement in FEV1 (relative to baseline) |
| Peak Change From Baseline in IC on Day 1 | Day 1 | Peak change from baseline in Inspiratory Capacity (IC) on Day 1 (mean of 1 and 2 hours post-dose minus baseline on Day 1) |
| Peak Change From Baseline in FEV1 on Day 1 | Day 1 | Highest value of FEV1 post-dose minus baseline on Day 1 (baseline-adjusted) |
| Peak Change From Baseline in FEV1 on Day 7 | Day 7 | Peak change from baseline in FEV1 |
| Peak Change From Baseline in IC on Day 7 | Day 7 | Peak change from baseline in IC |
| Change From Baseline in 12-hour Post-dose Trough FEV1 on Day 7 | Day 7 | Change from baseline in 12-hour post-dose trough FEV1 |
| Change From Baseline in Morning Pre-dose FEV1 on Day 7 | Day 7 | Change from baseline in morning pre-dose FEV1 |
Countries
United States
Participant flow
Recruitment details
Conducted at 9 US sites from May-October 2011. Entire period of study participation per subject was a maximum of 15 weeks. Planned target enrollment of 84 subjects.
Pre-assignment details
This was a chronic dosing study (7 days), 3-period, 6-treatment, incomplete block, crossover study. Each subject received 3 of 6 possible treatments; each treatment period was separated by a washout period 7-28 days. By-treatment sequence tabulations of the data were not pre-specified.
Participants by arm
| Arm | Count |
|---|---|
| ITT Population ITT Population includes all subjects who were randomized, received at least 1 dose of study treatment, and had both baseline and post-baseline efficacy data for that treatment. | 103 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol discontinuation criteria | 8 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | ITT Population |
|---|---|
| Age, Continuous | 61.2 years STANDARD_DEVIATION 8.19 |
| Sex: Female, Male Female | 48 Participants |
| Sex: Female, Male Male | 55 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 49 | 2 / 49 | 4 / 49 | 4 / 45 | 3 / 48 | 1 / 48 |
| serious Total, serious adverse events | 0 / 49 | 0 / 49 | 0 / 49 | 1 / 45 | 1 / 48 | 0 / 48 |
Outcome results
Primary
FEV1 AUC0-12
FEV1 AUC0-12 following chronic dosing (1 week), normalized.
Time frame: Day 7 ( -1 hour, -30 min, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 5.5 hours, 6.5 hours, 8 hours, 10 hours, 11.5 hours, and 12 hours)
Population: Modified Intent to Treat (MITT) Population includes subjects who completed at least 2 treatment periods, with minimally 1 pre-dose assessment on Day 7 for each of those 2 treatment periods with no protocol deviations believed to have a potential impact on efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| PT001 MDI 36 µg BID | FEV1 AUC0-12 | 1.477 Liter |
| PT001 MDI 18 µg BID | FEV1 AUC0-12 | 1.497 Liter |
| PT001 MDI 9 µg BID | FEV1 AUC0-12 | 1.443 Liter |
| PT001 MDI 4.6 µg BID | FEV1 AUC0-12 | 1.514 Liter |
| Ipratropium Bromide HFA Inhalation Aerosol | FEV1 AUC0-12 | 1.465 Liter |
| Placebo MDI BID | FEV1 AUC0-12 | 1.323 Liter |
Secondary
Change From Baseline in 12-hour Post-dose Trough FEV1 on Day 7
Change from baseline in 12-hour post-dose trough FEV1
Time frame: Day 7
Population: MITT Population includes subjects who completed at least 2 treatment periods, with minimally 1 pre-dose assessment on Day 7 for each of those 2 treatment periods with no protocol deviations believed to have a potential impact on efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PT001 MDI 36 µg BID | Change From Baseline in 12-hour Post-dose Trough FEV1 on Day 7 | 0.018 Liters | 95% Confidence Interval 0.0313 |
| PT001 MDI 18 µg BID | Change From Baseline in 12-hour Post-dose Trough FEV1 on Day 7 | 0.079 Liters | 95% Confidence Interval 0.0304 |
| PT001 MDI 9 µg BID | Change From Baseline in 12-hour Post-dose Trough FEV1 on Day 7 | 0.004 Liters | 95% Confidence Interval 0.0306 |
| PT001 MDI 4.6 µg BID | Change From Baseline in 12-hour Post-dose Trough FEV1 on Day 7 | 0.077 Liters | 95% Confidence Interval 0.0307 |
| Ipratropium Bromide HFA Inhalation Aerosol | Change From Baseline in 12-hour Post-dose Trough FEV1 on Day 7 | -0.041 Liters | 95% Confidence Interval 0.0311 |
| Placebo MDI BID | Change From Baseline in 12-hour Post-dose Trough FEV1 on Day 7 | -0.054 Liters | 95% Confidence Interval 0.0316 |
Secondary
Change From Baseline in Morning Pre-dose FEV1 on Day 7
Change from baseline in morning pre-dose FEV1
Time frame: Day 7
Population: MITT Population includes subjects who completed at least 2 treatment periods, with minimally 1 pre-dose assessment on Day 7 for each of those 2 treatment periods with no protocol deviations believed to have a potential impact on efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PT001 MDI 36 µg BID | Change From Baseline in Morning Pre-dose FEV1 on Day 7 | 0.088 Liter | 95% Confidence Interval 0.0246 |
| PT001 MDI 18 µg BID | Change From Baseline in Morning Pre-dose FEV1 on Day 7 | 0.075 Liter | 95% Confidence Interval 0.0245 |
| PT001 MDI 9 µg BID | Change From Baseline in Morning Pre-dose FEV1 on Day 7 | 0.010 Liter | 95% Confidence Interval 0.0248 |
| PT001 MDI 4.6 µg BID | Change From Baseline in Morning Pre-dose FEV1 on Day 7 | 0.084 Liter | 95% Confidence Interval 0.0247 |
| Ipratropium Bromide HFA Inhalation Aerosol | Change From Baseline in Morning Pre-dose FEV1 on Day 7 | -0.088 Liter | 95% Confidence Interval 0.0256 |
| Placebo MDI BID | Change From Baseline in Morning Pre-dose FEV1 on Day 7 | -0.043 Liter | 95% Confidence Interval 0.0246 |
Secondary
Peak Change From Baseline in FEV1 on Day 1
Highest value of FEV1 post-dose minus baseline on Day 1 (baseline-adjusted)
Time frame: Day 1
Population: MITT Population includes subjects who completed at least 2 treatment periods, with minimally 1 pre-dose assessment on Day 7 for each of those 2 treatment periods with no protocol deviations believed to have a potential impact on efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PT001 MDI 36 µg BID | Peak Change From Baseline in FEV1 on Day 1 | 0.245 Liter | 95% Confidence Interval 0.0252 |
| PT001 MDI 18 µg BID | Peak Change From Baseline in FEV1 on Day 1 | 0.221 Liter | 95% Confidence Interval 0.0247 |
| PT001 MDI 9 µg BID | Peak Change From Baseline in FEV1 on Day 1 | 0.181 Liter | 95% Confidence Interval 0.0256 |
| PT001 MDI 4.6 µg BID | Peak Change From Baseline in FEV1 on Day 1 | 0.204 Liter | 95% Confidence Interval 0.0206 |
| Ipratropium Bromide HFA Inhalation Aerosol | Peak Change From Baseline in FEV1 on Day 1 | 0.250 Liter | 95% Confidence Interval 0.0258 |
| Placebo MDI BID | Peak Change From Baseline in FEV1 on Day 1 | 0.071 Liter | 95% Confidence Interval 0.0251 |
Secondary
Peak Change From Baseline in FEV1 on Day 7
Peak change from baseline in FEV1
Time frame: Day 7
Population: MITT Population includes subjects who completed at least 2 treatment periods, with minimally 1 pre-dose assessment on Day 7 for each of those 2 treatment periods with no protocol deviations believed to have a potential impact on efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PT001 MDI 36 µg BID | Peak Change From Baseline in FEV1 on Day 7 | 0.242 Liter | 95% Confidence Interval 0.0303 |
| PT001 MDI 18 µg BID | Peak Change From Baseline in FEV1 on Day 7 | 0.224 Liter | 95% Confidence Interval 0.03 |
| PT001 MDI 9 µg BID | Peak Change From Baseline in FEV1 on Day 7 | 0.223 Liter | 95% Confidence Interval 0.0307 |
| PT001 MDI 4.6 µg BID | Peak Change From Baseline in FEV1 on Day 7 | 0.238 Liter | 95% Confidence Interval 0.0308 |
| Ipratropium Bromide HFA Inhalation Aerosol | Peak Change From Baseline in FEV1 on Day 7 | 0.225 Liter | 95% Confidence Interval 0.0307 |
| Placebo MDI BID | Peak Change From Baseline in FEV1 on Day 7 | 0.070 Liter | 95% Confidence Interval 0.0305 |
Secondary
Peak Change From Baseline in IC on Day 1
Peak change from baseline in Inspiratory Capacity (IC) on Day 1 (mean of 1 and 2 hours post-dose minus baseline on Day 1)
Time frame: Day 1
Population: MITT Population includes subjects who completed at least 2 treatment periods, with minimally 1 pre-dose assessment on Day 7 for each of those 2 treatment periods with no protocol deviations believed to have a potential impact on efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PT001 MDI 36 µg BID | Peak Change From Baseline in IC on Day 1 | 0.240 Liter | 95% Confidence Interval 0.0379 |
| PT001 MDI 18 µg BID | Peak Change From Baseline in IC on Day 1 | 0.276 Liter | 95% Confidence Interval 0.0377 |
| PT001 MDI 9 µg BID | Peak Change From Baseline in IC on Day 1 | 0.185 Liter | 95% Confidence Interval 0.0374 |
| PT001 MDI 4.6 µg BID | Peak Change From Baseline in IC on Day 1 | 0.187 Liter | 95% Confidence Interval 0.038 |
| Ipratropium Bromide HFA Inhalation Aerosol | Peak Change From Baseline in IC on Day 1 | 0.252 Liter | 95% Confidence Interval 0.0396 |
| Placebo MDI BID | Peak Change From Baseline in IC on Day 1 | 0.040 Liter | 95% Confidence Interval 0.0385 |
Secondary
Peak Change From Baseline in IC on Day 7
Peak change from baseline in IC
Time frame: Day 7
Population: MITT Population includes subjects who completed at least 2 treatment periods, with minimally 1 pre-dose assessment on Day 7 for each of those 2 treatment periods with no protocol deviations believed to have a potential impact on efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PT001 MDI 36 µg BID | Peak Change From Baseline in IC on Day 7 | 0.213 Liters | 95% Confidence Interval 0.0416 |
| PT001 MDI 18 µg BID | Peak Change From Baseline in IC on Day 7 | 0.189 Liters | 95% Confidence Interval 0.0411 |
| PT001 MDI 9 µg BID | Peak Change From Baseline in IC on Day 7 | 0.161 Liters | 95% Confidence Interval 0.0424 |
| PT001 MDI 4.6 µg BID | Peak Change From Baseline in IC on Day 7 | 0.192 Liters | 95% Confidence Interval 0.0426 |
| Ipratropium Bromide HFA Inhalation Aerosol | Peak Change From Baseline in IC on Day 7 | 0.191 Liters | 95% Confidence Interval 0.0424 |
| Placebo MDI BID | Peak Change From Baseline in IC on Day 7 | -0.029 Liters | 95% Confidence Interval 0.0419 |
Secondary
Proportion of Subjects Achieving at Least 12% Improvement in FEV1 on Day 1
Proportion of subjects achieving at least 12% improvement in FEV1 (relative to baseline)
Time frame: Day 1
Population: MITT Population: This includes subjects who completed at least 2 treatment periods, with minimally 1 pre-dose assessment on Day 7 for each of those 2 treatment periods with no protocol deviations believed to have a potential impact on efficacy results.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PT001 MDI 36 µg BID | Proportion of Subjects Achieving at Least 12% Improvement in FEV1 on Day 1 | 66.67 Percent |
| PT001 MDI 18 µg BID | Proportion of Subjects Achieving at Least 12% Improvement in FEV1 on Day 1 | 58.70 Percent |
| PT001 MDI 9 µg BID | Proportion of Subjects Achieving at Least 12% Improvement in FEV1 on Day 1 | 52.27 Percent |
| PT001 MDI 4.6 µg BID | Proportion of Subjects Achieving at Least 12% Improvement in FEV1 on Day 1 | 60.98 Percent |
| Ipratropium Bromide HFA Inhalation Aerosol | Proportion of Subjects Achieving at Least 12% Improvement in FEV1 on Day 1 | 77.78 Percent |
| Placebo MDI BID | Proportion of Subjects Achieving at Least 12% Improvement in FEV1 on Day 1 | 17.39 Percent |
Secondary
Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1
Time to onset of action ( ≥10% improvement in FEV1)
Time frame: Day 1 (15 min, 30 min, 1 hour, 2 hours)
Population: MITT Population includes subjects who completed at least 2 treatment periods, with minimally 1 pre-dose assessment on Day 7 for each of those 2 treatment periods with no protocol deviations believed to have a potential impact on efficacy results.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PT001 MDI 36 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 2 hours | 2 % of subjects |
| PT001 MDI 36 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 30 minutes | 32 % of subjects |
| PT001 MDI 36 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 15 minutes | 32 % of subjects |
| PT001 MDI 36 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 30 % of subjects |
| PT001 MDI 36 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 1 hour | 5 % of subjects |
| PT001 MDI 18 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 30 minutes | 18 % of subjects |
| PT001 MDI 18 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 2 hours | 13 % of subjects |
| PT001 MDI 18 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 15 minutes | 31 % of subjects |
| PT001 MDI 18 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 27 % of subjects |
| PT001 MDI 18 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 1 hour | 11 % of subjects |
| PT001 MDI 9 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 30 minutes | 7 % of subjects |
| PT001 MDI 9 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 2 hours | 14 % of subjects |
| PT001 MDI 9 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 37 % of subjects |
| PT001 MDI 9 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 1 hour | 23 % of subjects |
| PT001 MDI 9 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 15 minutes | 19 % of subjects |
| PT001 MDI 4.6 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 1 hour | 8 % of subjects |
| PT001 MDI 4.6 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 15 minutes | 25 % of subjects |
| PT001 MDI 4.6 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 30 minutes | 20 % of subjects |
| PT001 MDI 4.6 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 2 hours | 15 % of subjects |
| PT001 MDI 4.6 µg BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 33 % of subjects |
| Ipratropium Bromide HFA Inhalation Aerosol | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 2 hours | 2 % of subjects |
| Ipratropium Bromide HFA Inhalation Aerosol | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 15 minutes | 48 % of subjects |
| Ipratropium Bromide HFA Inhalation Aerosol | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 16 % of subjects |
| Ipratropium Bromide HFA Inhalation Aerosol | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 30 minutes | 25 % of subjects |
| Ipratropium Bromide HFA Inhalation Aerosol | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 1 hour | 9 % of subjects |
| Placebo MDI BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 15 minutes | 7 % of subjects |
| Placebo MDI BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 2 hours | 13 % of subjects |
| Placebo MDI BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 30 minutes | 9 % of subjects |
| Placebo MDI BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | No onset within 2 hours | 67 % of subjects |
| Placebo MDI BID | Time to Onset of Action ( ≥10% Improvement in FEV1) on Day 1 | 1 hour | 4 % of subjects |