Chronic Obstructive Pulmonary Disorder
Conditions
Keywords
COPD
Brief summary
This is a Phase III randomized, double-blind, parallel group, multi-center, 24-week lung function study with BFF MDI (320/9.6 μg and 160/9.6 μg) compared to FF MDI 9.6 μg, BD MDI 320 μg, and open-label Symbicort® TBH (200/6 μg) administered BID.
Detailed description
This is a Phase III randomized, double-blind, parallel group, multi-center, 24-week lung function study with BFF MDI (320/9.6 μg and 160/9.6 μg) compared to FF MDI 9.6 μg, BD MDI 320 μg, and open-label Symbicort® TBH (200/6 μg) administered BID. Subjects will undergo a 1- to 4-week Screening Period. Subjects who successfully complete the Screening Period will be to one of the following five treatment groups:BFF MDI 320/9.6 μg BID (N=660), BFF MDI 160/9.6 μg BID, FF MDI 9.6 μg BID, BD MDI 320 μg BID, Symbicort®, TBH 400/12 μg BID. Following randomization, subjects will enter the Treatment Period and undergo additional treatment visits over 24 weeks.
Interventions
Blinded Treatment
Blinded Treatment
DRUGFF MDI 9.6 μg
Blinded Treatment
DRUGBD MDI 320 μg
Blinded Treatment
DRUGSymbicort® TBH 400/12 μg BID
Open Label
Sponsors
Pearl Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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
1. Give their signed written informed consent to participate 2. Are at least 40 years of age and no older than 80 years 3. COPD patients who are symptomatic 4. Must be receiving one or more inhaled bronchodilators as maintenance therapy
Exclusion criteria
1. Current diagnosis of asthma, 2. COPD due to α1-Antitrypsin Deficiency 3. Known active tuberculosis, lung cancer, cystic fibrosis, significant bronchiectasis, Pulmonary resection or Lung Volume Reduction Surgery during the past 6 months 4. Long-term-oxygen therapy (≥ 12 hours a day).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI) | at Week 24 | Changes from baseline in FEV1 AUC0-4 were normalized by taking the area under the curve value and dividing by the length of time under consideration (usually 4 hours). This normalization represents a weighted average of the change from baseline in FEV1 over the 4-hour period. |
| Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI Versus FF MDI) | at Week 24 | Change from baseline in morning pre-dose trough FEV1 (Forced expiratory volume in 1 second) at Week 24 (BFF MDI versus FF MDI) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving an MCID (Minimal Clinically Important Difference) of 4 Units or More in SGRQ at Week 24 | at Week 24 | The SGRQ (St. George's Respiratory Questionnaire) is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of BFF MDI, FF MDI, BD MDI, & Symbicort TBH on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life. |
| Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI vs BD MDI) | at Week 24 | Change from baseline in morning pre-dose trough FEV1(Forced Expiratory Volume in 1 second) at Week 24 (BFF MDI vs BD MDI) |
| Peak Change From Baseline in FEV1 at Week 24 (BFF MDI vs BD MDI) | at Week 24 | Peak change from baseline in FEV1 (Forced Expiratory Volume in 1 second) at Week 24 (BFF MDI vs BD MDI) |
| Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks (BFF MDI vs BD MDI) | over 24 Weeks | Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI vs BD MDI) |
| FEV1 on Day 1, 5 Minutes, Time to Onset of Action Determination | Day 1 - 5 Minutes | Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment. |
| FEV1 on Day 1, 30 Minutes, Time to Onset of Action Determination | Day 1 - 30 Minutes | Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment. |
| FEV1 on Day 1, 1 Hour, Time to Onset of Action Determination | Day 1 - 1 Hour | Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment. |
| FEV1 on Day 1, 2 Hours, Time to Onset of Action Determination | Day 1 - 2 Hours | Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment. |
| FEV1 on Day 1, 4 Hours, Time to Onset of Action Determination | Day 1 - 4 Hours | Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment. |
| FEV1 on Day 1, 15 Minutes, Time to Onset of Action Determination | Day 1 - 15 Minutes | Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment. |
| Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | over 24 Weeks (timepoints of 4, 12 & 20 weeks) | Time to first moderate or severe COPD (Chronic Obstructive Pulmonary Disease) exacerbation (BFF MDI vs FF MDI). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Substudy: 12-hour PFT Endpoint FEV1 AUC0-12 | at Week 12 | Substudy: 12-hour PFT (Pulmonary Function Test) endpoint FEV1 (Forced Expiratory Volume) AUC0-12 (Area under the Curve 0-12). Changes from baseline in FEV1 AUC0-12 were normalized by taking the area under the curve value and dividing by the length of time under consideration. This normalization represents a weighted average of the change from baseline in FEV1 over the 12-hour period. |
Countries
Canada, Czechia, Germany, Hungary, Poland, Russia, South Korea, United States
Participant flow
Recruitment details
This study randomized subjects at 244 study centers in 7 countries, from June 2016 and November 2017. The study period was scheduled to take up to approximately 30 weeks for each individual subject from the time of screening through the follow-up period.
Pre-assignment details
Subjects were randomized in a 3:3:3:1:1 ratio to BFF 320/9.6, BFF 160/9.6, FF 9.6, BD 320, and Symbicort.
Participants by arm
| Arm | Count |
|---|---|
| BFF MDI 320/9.6 μg Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg | 664 |
| BFF MDI 160/9.6 μg Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg | 649 |
| FF MDI 9.6 μg Formoterol Fumarate Metered Dose Inhalation 9.6 μg | 648 |
| BD MDI 320 μg Budesonide Metered Dose Inhalation 320 μg | 209 |
| Symbicort TBH 400/12 μg Symbicort Turbuhaler 400/12 μg | 219 |
| Total | 2,389 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Administrative Reasons | 3 | 1 | 1 | 0 | 0 |
| Overall Study | Adverse Event | 27 | 22 | 17 | 13 | 12 |
| Overall Study | Lack of Efficacy | 16 | 15 | 32 | 8 | 2 |
| Overall Study | Lost to Follow-up | 6 | 3 | 5 | 2 | 2 |
| Overall Study | Physician Decision | 3 | 2 | 3 | 1 | 2 |
| Overall Study | Protocol disc criteria | 3 | 3 | 4 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 4 | 4 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 21 | 20 | 24 | 13 | 10 |
Baseline characteristics
| Characteristic | BFF MDI 320/9.6 μg | BFF MDI 160/9.6 μg | FF MDI 9.6 μg | BD MDI 320 μg | Symbicort TBH 400/12 μg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 64.2 Years STANDARD_DEVIATION 7.7 | 64.3 Years STANDARD_DEVIATION 7.6 | 64.1 Years STANDARD_DEVIATION 8 | 64.2 Years STANDARD_DEVIATION 7.4 | 65.3 Years STANDARD_DEVIATION 7 | 64.3 Years STANDARD_DEVIATION 7.7 |
| Ethnicity (NIH/OMB) Values listed are mITT population Hispanic or Latino | 16 Participants | 18 Participants | 21 Participants | 8 Participants | 6 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Values listed are mITT population Not Hispanic or Latino | 637 Participants | 616 Participants | 623 Participants | 198 Participants | 212 Participants | 2286 Participants |
| Ethnicity (NIH/OMB) Values listed are mITT population Unknown or Not Reported | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Values listed are mITT population American Indian or Alaska Native | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Values listed are mITT population Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Values listed are mITT population Black or African American | 19 Participants | 15 Participants | 20 Participants | 9 Participants | 8 Participants | 71 Participants |
| Race (NIH/OMB) Values listed are mITT population More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Values listed are mITT population Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Values listed are mITT population Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Values listed are mITT population White | 633 Participants | 619 Participants | 622 Participants | 197 Participants | 210 Participants | 2281 Participants |
| Sex: Female, Male Values listed are mITT population Female | 253 Participants | 260 Participants | 261 Participants | 81 Participants | 78 Participants | 933 Participants |
| Sex: Female, Male Values listed are mITT population Male | 402 Participants | 377 Participants | 383 Participants | 125 Participants | 141 Participants | 1428 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 655 | 2 / 637 | 2 / 644 | 0 / 206 | 2 / 219 |
| other Total, other adverse events | 240 / 655 | 201 / 637 | 219 / 644 | 75 / 206 | 57 / 219 |
| serious Total, serious adverse events | 42 / 655 | 45 / 637 | 72 / 644 | 15 / 206 | 20 / 219 |
Outcome results
Primary
Change From Baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI)
Changes from baseline in FEV1 AUC0-4 were normalized by taking the area under the curve value and dividing by the length of time under consideration (usually 4 hours). This normalization represents a weighted average of the change from baseline in FEV1 over the 4-hour period.
Time frame: at Week 24
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | Change From Baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI) | 0.194 Liter |
| BFF MDI 160/9.6 μg | Change From Baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI) | 0.179 Liter |
| FF MDI 9.6 μg | Change From Baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI) | 0.161 Liter |
| BD MDI 320 ug | Change From Baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI) | 0.022 Liter |
| Symbicort TBH 400/12 ug | Change From Baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI) | 0.187 Liter |
Primary
Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI Versus FF MDI)
Change from baseline in morning pre-dose trough FEV1 (Forced expiratory volume in 1 second) at Week 24 (BFF MDI versus FF MDI)
Time frame: at Week 24
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI Versus FF MDI) | 0.036 Liter |
| BFF MDI 160/9.6 μg | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI Versus FF MDI) | 0.017 Liter |
| FF MDI 9.6 μg | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI Versus FF MDI) | -0.003 Liter |
Secondary
Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks (BFF MDI vs BD MDI)
Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI vs BD MDI)
Time frame: over 24 Weeks
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks (BFF MDI vs BD MDI) | -1.3 Puffs per day |
| BFF MDI 160/9.6 μg | Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks (BFF MDI vs BD MDI) | -1.3 Puffs per day |
| FF MDI 9.6 μg | Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks (BFF MDI vs BD MDI) | -1.1 Puffs per day |
| BD MDI 320 ug | Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks (BFF MDI vs BD MDI) | -0.6 Puffs per day |
| Symbicort TBH 400/12 ug | Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks (BFF MDI vs BD MDI) | -1.2 Puffs per day |
Secondary
Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI vs BD MDI)
Change from baseline in morning pre-dose trough FEV1(Forced Expiratory Volume in 1 second) at Week 24 (BFF MDI vs BD MDI)
Time frame: at Week 24
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI vs BD MDI) | 0.036 Liter |
| BFF MDI 160/9.6 μg | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI vs BD MDI) | 0.017 Liter |
| FF MDI 9.6 μg | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI vs BD MDI) | -0.003 Liter |
| BD MDI 320 ug | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI vs BD MDI) | -0.028 Liter |
| Symbicort TBH 400/12 ug | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 (BFF MDI vs BD MDI) | 0.039 Liter |
Secondary
FEV1 on Day 1, 15 Minutes, Time to Onset of Action Determination
Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment.
Time frame: Day 1 - 15 Minutes
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | FEV1 on Day 1, 15 Minutes, Time to Onset of Action Determination | 0.190 Liter |
| BFF MDI 160/9.6 μg | FEV1 on Day 1, 15 Minutes, Time to Onset of Action Determination | 0.186 Liter |
| FF MDI 9.6 μg | FEV1 on Day 1, 15 Minutes, Time to Onset of Action Determination | 0.201 Liter |
| BD MDI 320 ug | FEV1 on Day 1, 15 Minutes, Time to Onset of Action Determination | 0.040 Liter |
| Symbicort TBH 400/12 ug | FEV1 on Day 1, 15 Minutes, Time to Onset of Action Determination | 0.167 Liter |
Secondary
FEV1 on Day 1, 1 Hour, Time to Onset of Action Determination
Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment.
Time frame: Day 1 - 1 Hour
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | FEV1 on Day 1, 1 Hour, Time to Onset of Action Determination | 0.225 Liter |
| BFF MDI 160/9.6 μg | FEV1 on Day 1, 1 Hour, Time to Onset of Action Determination | 0.221 Liter |
| FF MDI 9.6 μg | FEV1 on Day 1, 1 Hour, Time to Onset of Action Determination | 0.236 Liter |
| BD MDI 320 ug | FEV1 on Day 1, 1 Hour, Time to Onset of Action Determination | 0.053 Liter |
| Symbicort TBH 400/12 ug | FEV1 on Day 1, 1 Hour, Time to Onset of Action Determination | 0.211 Liter |
Secondary
FEV1 on Day 1, 2 Hours, Time to Onset of Action Determination
Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment.
Time frame: Day 1 - 2 Hours
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | FEV1 on Day 1, 2 Hours, Time to Onset of Action Determination | 0.253 Liter |
| BFF MDI 160/9.6 μg | FEV1 on Day 1, 2 Hours, Time to Onset of Action Determination | 0.234 Liter |
| FF MDI 9.6 μg | FEV1 on Day 1, 2 Hours, Time to Onset of Action Determination | 0.244 Liter |
| BD MDI 320 ug | FEV1 on Day 1, 2 Hours, Time to Onset of Action Determination | 0.063 Liter |
| Symbicort TBH 400/12 ug | FEV1 on Day 1, 2 Hours, Time to Onset of Action Determination | 0.221 Liter |
Secondary
FEV1 on Day 1, 30 Minutes, Time to Onset of Action Determination
Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment.
Time frame: Day 1 - 30 Minutes
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | FEV1 on Day 1, 30 Minutes, Time to Onset of Action Determination | 0.207 Liter |
| BFF MDI 160/9.6 μg | FEV1 on Day 1, 30 Minutes, Time to Onset of Action Determination | 0.207 Liter |
| FF MDI 9.6 μg | FEV1 on Day 1, 30 Minutes, Time to Onset of Action Determination | 0.215 Liter |
| BD MDI 320 ug | FEV1 on Day 1, 30 Minutes, Time to Onset of Action Determination | 0.047 Liter |
| Symbicort TBH 400/12 ug | FEV1 on Day 1, 30 Minutes, Time to Onset of Action Determination | 0.190 Liter |
Secondary
FEV1 on Day 1, 4 Hours, Time to Onset of Action Determination
Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment.
Time frame: Day 1 - 4 Hours
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | FEV1 on Day 1, 4 Hours, Time to Onset of Action Determination | 0.230 Liter |
| BFF MDI 160/9.6 μg | FEV1 on Day 1, 4 Hours, Time to Onset of Action Determination | 0.215 Liter |
| FF MDI 9.6 μg | FEV1 on Day 1, 4 Hours, Time to Onset of Action Determination | 0.212 Liter |
| BD MDI 320 ug | FEV1 on Day 1, 4 Hours, Time to Onset of Action Determination | 0.073 Liter |
| Symbicort TBH 400/12 ug | FEV1 on Day 1, 4 Hours, Time to Onset of Action Determination | 0.209 Liter |
Secondary
FEV1 on Day 1, 5 Minutes, Time to Onset of Action Determination
Time to onset of action Day 1 was evaluated by calculating change from baseline in FEV1 at each post-dose timepoint (5min, 15min, 30min, 1hr, 2hr, and 4hr), then comparing each treatment to BD MDI 320 ug. The first timepoint a statistically significant difference from BD MDI 320 ug of ≥100mL was determined to be time of onset for that treatment.
Time frame: Day 1 - 5 Minutes
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | FEV1 on Day 1, 5 Minutes, Time to Onset of Action Determination | 0.157 Liter |
| BFF MDI 160/9.6 μg | FEV1 on Day 1, 5 Minutes, Time to Onset of Action Determination | 0.151 Liter |
| FF MDI 9.6 μg | FEV1 on Day 1, 5 Minutes, Time to Onset of Action Determination | 0.160 Liter |
| BD MDI 320 ug | FEV1 on Day 1, 5 Minutes, Time to Onset of Action Determination | 0.025 Liter |
| Symbicort TBH 400/12 ug | FEV1 on Day 1, 5 Minutes, Time to Onset of Action Determination | 0.131 Liter |
Secondary
Peak Change From Baseline in FEV1 at Week 24 (BFF MDI vs BD MDI)
Peak change from baseline in FEV1 (Forced Expiratory Volume in 1 second) at Week 24 (BFF MDI vs BD MDI)
Time frame: at Week 24
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | Peak Change From Baseline in FEV1 at Week 24 (BFF MDI vs BD MDI) | 0.272 Liter |
| BFF MDI 160/9.6 μg | Peak Change From Baseline in FEV1 at Week 24 (BFF MDI vs BD MDI) | 0.258 Liter |
| FF MDI 9.6 μg | Peak Change From Baseline in FEV1 at Week 24 (BFF MDI vs BD MDI) | 0.243 Liter |
| BD MDI 320 ug | Peak Change From Baseline in FEV1 at Week 24 (BFF MDI vs BD MDI) | 0.116 Liter |
| Symbicort TBH 400/12 ug | Peak Change From Baseline in FEV1 at Week 24 (BFF MDI vs BD MDI) | 0.267 Liter |
Secondary
Percentage of Subjects Achieving an MCID (Minimal Clinically Important Difference) of 4 Units or More in SGRQ at Week 24
The SGRQ (St. George's Respiratory Questionnaire) is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of BFF MDI, FF MDI, BD MDI, & Symbicort TBH on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life.
Time frame: at Week 24
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BFF MDI 320/9.6 μg | Percentage of Subjects Achieving an MCID (Minimal Clinically Important Difference) of 4 Units or More in SGRQ at Week 24 | 48.12 Percentage of Subjects |
| BFF MDI 160/9.6 μg | Percentage of Subjects Achieving an MCID (Minimal Clinically Important Difference) of 4 Units or More in SGRQ at Week 24 | 47.22 Percentage of Subjects |
| FF MDI 9.6 μg | Percentage of Subjects Achieving an MCID (Minimal Clinically Important Difference) of 4 Units or More in SGRQ at Week 24 | 41.59 Percentage of Subjects |
| BD MDI 320 ug | Percentage of Subjects Achieving an MCID (Minimal Clinically Important Difference) of 4 Units or More in SGRQ at Week 24 | 43.62 Percentage of Subjects |
| Symbicort TBH 400/12 ug | Percentage of Subjects Achieving an MCID (Minimal Clinically Important Difference) of 4 Units or More in SGRQ at Week 24 | 53.78 Percentage of Subjects |
Secondary
Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI).
Time to first moderate or severe COPD (Chronic Obstructive Pulmonary Disease) exacerbation (BFF MDI vs FF MDI).
Time frame: over 24 Weeks (timepoints of 4, 12 & 20 weeks)
Population: mITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BFF MDI 320/9.6 μg | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 4 Weeks | 3.2 Percentage of Participants |
| BFF MDI 320/9.6 μg | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 20 Weeks | 14.4 Percentage of Participants |
| BFF MDI 320/9.6 μg | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 12 Weeks | 9.8 Percentage of Participants |
| BFF MDI 160/9.6 μg | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 12 Weeks | 9.9 Percentage of Participants |
| BFF MDI 160/9.6 μg | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 4 Weeks | 3.3 Percentage of Participants |
| BFF MDI 160/9.6 μg | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 20 Weeks | 18.5 Percentage of Participants |
| FF MDI 9.6 μg | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 12 Weeks | 15.0 Percentage of Participants |
| FF MDI 9.6 μg | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 4 Weeks | 5.5 Percentage of Participants |
| FF MDI 9.6 μg | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 20 Weeks | 20.5 Percentage of Participants |
| BD MDI 320 ug | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 4 Weeks | 7.0 Percentage of Participants |
| BD MDI 320 ug | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 20 Weeks | 17.7 Percentage of Participants |
| BD MDI 320 ug | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 12 Weeks | 14.9 Percentage of Participants |
| Symbicort TBH 400/12 ug | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 12 Weeks | 8.6 Percentage of Participants |
| Symbicort TBH 400/12 ug | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 4 Weeks | 1.8 Percentage of Participants |
| Symbicort TBH 400/12 ug | Time to First Moderate or Severe COPD Exacerbation (BFF MDI vs FF MDI). | Percentage of Subjects to Exacerbate at 20 Weeks | 13.1 Percentage of Participants |
Other Pre-specified
Substudy: 12-hour PFT Endpoint FEV1 AUC0-12
Substudy: 12-hour PFT (Pulmonary Function Test) endpoint FEV1 (Forced Expiratory Volume) AUC0-12 (Area under the Curve 0-12). Changes from baseline in FEV1 AUC0-12 were normalized by taking the area under the curve value and dividing by the length of time under consideration. This normalization represents a weighted average of the change from baseline in FEV1 over the 12-hour period.
Time frame: at Week 12
Population: mITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BFF MDI 320/9.6 μg | Substudy: 12-hour PFT Endpoint FEV1 AUC0-12 | 0.135 Liter |
| BFF MDI 160/9.6 μg | Substudy: 12-hour PFT Endpoint FEV1 AUC0-12 | 0.124 Liter |
| FF MDI 9.6 μg | Substudy: 12-hour PFT Endpoint FEV1 AUC0-12 | 0.117 Liter |
| BD MDI 320 ug | Substudy: 12-hour PFT Endpoint FEV1 AUC0-12 | 0.024 Liter |