Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD
Brief summary
This study is primarily a safety study. The primary and secondary endpoints are based on 24-hour Holter monitor assessments obtained on Day 14 relative to baseline.
Interventions
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
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 * Acceptable baseline (Visit 2) Holter monitor recording 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 * Clinically significant abnormal findings during the baseline Holter recording * Patients with a pacemaker or ICD/CRT/CRT\_D devices Other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-Hour Mean Heart Rate Post-dose | 14 days | The primary safety objective of this study was to compare the change in mean heart rate averaged over 24 hours post-dose, following twice daily dosing over 14 days with PT003 MDI, PT005 MDI, PT001 MDI or Foradil Aerolizer compared to baseline in patients with moderate to severe chronic obstructive pulmonary disease (COPD). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-Hour Mean Heart Rate for Day 1 of Treatment | 24 hours | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in Daytime Mean Heart Rate | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in Night Time Mean Heart Rate | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in 24-Hour Maximum Heart Rate | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in 24-Hour Minimum Heart Rate | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in Mean FEV1 Trough | Day 7 to Day 14 | Trough FEV1 averaged over Day 7 and Day 14 |
| Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Mean Change From Baseline in QTcF Interval | Baseline, Day 1, Day 7, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
| Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring | Baseline, Day 1, and Day 14 | The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation). |
Countries
Australia, New Zealand, United States
Participant flow
Recruitment details
Conducted at 15 sites throughout the US, Australia, and New Zealand from May 2011 - November 2011. Study participation was a maximum of 7 weeks.
Pre-assignment details
Study was a multicenter, randomized, double-blind, parallel group, chronic dosing (14 days) study; each patient was randomized to receive 1 of 4 possible treatments over the course of a 14-day treatment period
Participants by arm
| Arm | Count |
|---|---|
| FF MDI (PT005) FF MDI 9.6 mcg | 60 |
| GP MDI (PT001) GP MDI 36 mcg | 58 |
| GFF MDI (PT003) GFF MDI 36/9.6 mcg | 60 |
| Foradil® Aerolizer® Formoterol Fumarate 12 μg | 59 |
| Total | 237 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 2 |
| Overall Study | Protocol-specified criteria | 0 | 1 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | FF MDI (PT005) | GP MDI (PT001) | GFF MDI (PT003) | Foradil® Aerolizer® | Total |
|---|---|---|---|---|---|
| Age, Continuous | 64.1 Years STANDARD_DEVIATION 8.13 | 63.3 Years STANDARD_DEVIATION 7.93 | 64.3 Years STANDARD_DEVIATION 7.38 | 64.1 Years STANDARD_DEVIATION 7.91 | 64.0 Years STANDARD_DEVIATION 7.8 |
| Gender Female | 33 Participants | 32 Participants | 26 Participants | 31 Participants | 122 Participants |
| Gender Male | 27 Participants | 26 Participants | 34 Participants | 28 Participants | 115 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 60 | 4 / 58 | 2 / 60 | 5 / 59 |
| serious Total, serious adverse events | 1 / 60 | 0 / 58 | 1 / 60 | 1 / 59 |
Outcome results
Primary
Change From Baseline in 24-Hour Mean Heart Rate Post-dose
The primary safety objective of this study was to compare the change in mean heart rate averaged over 24 hours post-dose, following twice daily dosing over 14 days with PT003 MDI, PT005 MDI, PT001 MDI or Foradil Aerolizer compared to baseline in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
Time frame: 14 days
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FF MDI (PT005) | Change From Baseline in 24-Hour Mean Heart Rate Post-dose | -0.19 bpm |
| GP MDI (PT001) | Change From Baseline in 24-Hour Mean Heart Rate Post-dose | -1.84 bpm |
| GFF MDI (PT003) | Change From Baseline in 24-Hour Mean Heart Rate Post-dose | 0.40 bpm |
| Foradil® Aerolizer® | Change From Baseline in 24-Hour Mean Heart Rate Post-dose | -0.09 bpm |
Secondary
Change From Baseline in 24-Hour Maximum Heart Rate
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in 24-Hour Maximum Heart Rate | Day 1 | -4.71 bpm |
| FF MDI (PT005) | Change From Baseline in 24-Hour Maximum Heart Rate | Day 14 | 0.75 bpm |
| GP MDI (PT001) | Change From Baseline in 24-Hour Maximum Heart Rate | Day 14 | -2.21 bpm |
| GP MDI (PT001) | Change From Baseline in 24-Hour Maximum Heart Rate | Day 1 | -1.88 bpm |
| GFF MDI (PT003) | Change From Baseline in 24-Hour Maximum Heart Rate | Day 1 | -1.91 bpm |
| GFF MDI (PT003) | Change From Baseline in 24-Hour Maximum Heart Rate | Day 14 | -0.06 bpm |
| Foradil® Aerolizer® | Change From Baseline in 24-Hour Maximum Heart Rate | Day 1 | 0.31 bpm |
| Foradil® Aerolizer® | Change From Baseline in 24-Hour Maximum Heart Rate | Day 14 | -1.13 bpm |
Secondary
Change From Baseline in 24-Hour Mean Heart Rate for Day 1 of Treatment
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: 24 hours
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FF MDI (PT005) | Change From Baseline in 24-Hour Mean Heart Rate for Day 1 of Treatment | 0.56 bpm |
| GP MDI (PT001) | Change From Baseline in 24-Hour Mean Heart Rate for Day 1 of Treatment | -0.44 bpm |
| GFF MDI (PT003) | Change From Baseline in 24-Hour Mean Heart Rate for Day 1 of Treatment | 0.92 bpm |
| Foradil® Aerolizer® | Change From Baseline in 24-Hour Mean Heart Rate for Day 1 of Treatment | 0.31 bpm |
Secondary
Change From Baseline in 24-Hour Minimum Heart Rate
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in 24-Hour Minimum Heart Rate | Day 1 | 0.05 bpm |
| FF MDI (PT005) | Change From Baseline in 24-Hour Minimum Heart Rate | Day 14 | -0.79 bpm |
| GP MDI (PT001) | Change From Baseline in 24-Hour Minimum Heart Rate | Day 14 | -1.92 bpm |
| GP MDI (PT001) | Change From Baseline in 24-Hour Minimum Heart Rate | Day 1 | -0.03 bpm |
| GFF MDI (PT003) | Change From Baseline in 24-Hour Minimum Heart Rate | Day 1 | 0.50 bpm |
| GFF MDI (PT003) | Change From Baseline in 24-Hour Minimum Heart Rate | Day 14 | -0.21 bpm |
| Foradil® Aerolizer® | Change From Baseline in 24-Hour Minimum Heart Rate | Day 1 | 0.45 bpm |
| Foradil® Aerolizer® | Change From Baseline in 24-Hour Minimum Heart Rate | Day 14 | 0.88 bpm |
Secondary
Change From Baseline in Daytime Mean Heart Rate
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in Daytime Mean Heart Rate | Day 1 | 0.00 bpm |
| FF MDI (PT005) | Change From Baseline in Daytime Mean Heart Rate | Day 14 | -1.22 bpm |
| GP MDI (PT001) | Change From Baseline in Daytime Mean Heart Rate | Day 14 | -2.00 bpm |
| GP MDI (PT001) | Change From Baseline in Daytime Mean Heart Rate | Day 1 | -0.52 bpm |
| GFF MDI (PT003) | Change From Baseline in Daytime Mean Heart Rate | Day 1 | 0.16 bpm |
| GFF MDI (PT003) | Change From Baseline in Daytime Mean Heart Rate | Day 14 | -0.40 bpm |
| Foradil® Aerolizer® | Change From Baseline in Daytime Mean Heart Rate | Day 1 | -0.17 bpm |
| Foradil® Aerolizer® | Change From Baseline in Daytime Mean Heart Rate | Day 14 | -0.54 bpm |
Secondary
Change From Baseline in Mean FEV1 Trough
Trough FEV1 averaged over Day 7 and Day 14
Time frame: Day 7 to Day 14
Population: MITT - patients from the ITT population who completed at least one evaluable FEV1 spirometry assessment for baseline (pre-dose on Day 1) and had an evaluable FEV1 spirometry assessment on at least one of the following: Day 7 pre-dose or Day 14 pre-dose (or both).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FF MDI (PT005) | Change From Baseline in Mean FEV1 Trough | 0.091 Liters |
| GP MDI (PT001) | Change From Baseline in Mean FEV1 Trough | 0.126 Liters |
| GFF MDI (PT003) | Change From Baseline in Mean FEV1 Trough | 0.251 Liters |
| Foradil® Aerolizer® | Change From Baseline in Mean FEV1 Trough | 0.124 Liters |
Secondary
Change From Baseline in Night Time Mean Heart Rate
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in Night Time Mean Heart Rate | Day 1 | 3.05 bpm |
| FF MDI (PT005) | Change From Baseline in Night Time Mean Heart Rate | Day 14 | 0.04 bpm |
| GP MDI (PT001) | Change From Baseline in Night Time Mean Heart Rate | Day 14 | -0.88 bpm |
| GP MDI (PT001) | Change From Baseline in Night Time Mean Heart Rate | Day 1 | -0.54 bpm |
| GFF MDI (PT003) | Change From Baseline in Night Time Mean Heart Rate | Day 1 | 2.95 bpm |
| GFF MDI (PT003) | Change From Baseline in Night Time Mean Heart Rate | Day 14 | 0.11 bpm |
| Foradil® Aerolizer® | Change From Baseline in Night Time Mean Heart Rate | Day 1 | 0.70 bpm |
| Foradil® Aerolizer® | Change From Baseline in Night Time Mean Heart Rate | Day 14 | 1.05 bpm |
Secondary
Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring | Day 1 | 1.31 Ventricular events / hour | Standard Error 1.605 |
| FF MDI (PT005) | Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring | Day 14 | 3.09 Ventricular events / hour | Standard Error 4.092 |
| GP MDI (PT001) | Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring | Day 14 | 0.62 Ventricular events / hour | Standard Error 1.088 |
| GP MDI (PT001) | Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring | Day 1 | 0.56 Ventricular events / hour | Standard Error 0.853 |
| GFF MDI (PT003) | Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring | Day 1 | 1.59 Ventricular events / hour | Standard Error 1.879 |
| GFF MDI (PT003) | Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring | Day 14 | -0.10 Ventricular events / hour | Standard Error 0.541 |
| Foradil® Aerolizer® | Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring | Day 1 | 0.45 Ventricular events / hour | Standard Error 0.58 |
| Foradil® Aerolizer® | Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring | Day 14 | -0.54 Ventricular events / hour | Standard Error 0.424 |
Secondary
Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 1 | -0.04 Bradycardia episodes / hour | Standard Error 0.139 |
| FF MDI (PT005) | Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 14 | -0.02 Bradycardia episodes / hour | Standard Error 0.111 |
| GP MDI (PT001) | Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 14 | 0.40 Bradycardia episodes / hour | Standard Error 0.21 |
| GP MDI (PT001) | Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 1 | -0.02 Bradycardia episodes / hour | Standard Error 0.083 |
| GFF MDI (PT003) | Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 1 | 0.11 Bradycardia episodes / hour | Standard Error 0.193 |
| GFF MDI (PT003) | Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 14 | 0.27 Bradycardia episodes / hour | Standard Error 0.283 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 1 | 0.03 Bradycardia episodes / hour | Standard Error 0.036 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 14 | 0.13 Bradycardia episodes / hour | Standard Error 0.132 |
Secondary
Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring | Day 1 | 7.72 Supraventricular events / hour | Standard Error 6.971 |
| FF MDI (PT005) | Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring | Day 14 | 3.61 Supraventricular events / hour | Standard Error 5.179 |
| GP MDI (PT001) | Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring | Day 14 | -9.29 Supraventricular events / hour | Standard Error 9.398 |
| GP MDI (PT001) | Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring | Day 1 | 0.74 Supraventricular events / hour | Standard Error 0.804 |
| GFF MDI (PT003) | Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring | Day 1 | -4.55 Supraventricular events / hour | Standard Error 5.947 |
| GFF MDI (PT003) | Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring | Day 14 | 3.61 Supraventricular events / hour | Standard Error 5.179 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring | Day 1 | 15.36 Supraventricular events / hour | Standard Error 16.359 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring | Day 14 | 5.81 Supraventricular events / hour | Standard Error 11.32 |
Secondary
Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 1 | 0.03 Supraventricular couplets / hour | Standard Error 0.034 |
| FF MDI (PT005) | Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 14 | 0.01 Supraventricular couplets / hour | Standard Error 0.025 |
| GP MDI (PT001) | Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 14 | 0.00 Supraventricular couplets / hour | Standard Error 0.017 |
| GP MDI (PT001) | Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 1 | 0.01 Supraventricular couplets / hour | Standard Error 0.021 |
| GFF MDI (PT003) | Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 1 | 0.05 Supraventricular couplets / hour | Standard Error 0.019 |
| GFF MDI (PT003) | Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 14 | 0.00 Supraventricular couplets / hour | Standard Error 0.018 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 1 | 0.04 Supraventricular couplets / hour | Standard Error 0.065 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 14 | -0.02 Supraventricular couplets / hour | Standard Error 0.02 |
Secondary
Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring | Day 1 | 0.00 Supraventricular runs / hour | Standard Error 0.014 |
| FF MDI (PT005) | Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring | Day 14 | 0.01 Supraventricular runs / hour | Standard Error 0.013 |
| GP MDI (PT001) | Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring | Day 14 | 0.02 Supraventricular runs / hour | Standard Error 0.015 |
| GP MDI (PT001) | Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring | Day 1 | 0.02 Supraventricular runs / hour | Standard Error 0.011 |
| GFF MDI (PT003) | Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring | Day 1 | 0.01 Supraventricular runs / hour | Standard Error 0.011 |
| GFF MDI (PT003) | Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring | Day 14 | 0.00 Supraventricular runs / hour | Standard Error 0.012 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring | Day 1 | 0.01 Supraventricular runs / hour | Standard Error 0.01 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring | Day 14 | 0.01 Supraventricular runs / hour | Standard Error 0.014 |
Secondary
Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 1 | -0.16 Tachycardia episodes / hour | Standard Error 0.17 |
| FF MDI (PT005) | Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 14 | -0.23 Tachycardia episodes / hour | Standard Error 0.146 |
| GP MDI (PT001) | Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 14 | -0.34 Tachycardia episodes / hour | Standard Error 0.229 |
| GP MDI (PT001) | Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 1 | -0.24 Tachycardia episodes / hour | Standard Error 0.209 |
| GFF MDI (PT003) | Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 1 | -0.02 Tachycardia episodes / hour | Standard Error 0.16 |
| GFF MDI (PT003) | Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 14 | 0.22 Tachycardia episodes / hour | Standard Error 0.154 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 1 | -0.09 Tachycardia episodes / hour | Standard Error 0.197 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring | Day 14 | -0.01 Tachycardia episodes / hour | Standard Error 0.206 |
Secondary
Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 1 | 0.09 Ventricular couplets / hour | Standard Error 0.071 |
| FF MDI (PT005) | Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 14 | 0.02 Ventricular couplets / hour | Standard Error 0.021 |
| GP MDI (PT001) | Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 14 | 0.00 Ventricular couplets / hour | Standard Error 0.009 |
| GP MDI (PT001) | Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 1 | 0.00 Ventricular couplets / hour | Standard Error 0.005 |
| GFF MDI (PT003) | Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 1 | 0.00 Ventricular couplets / hour | Standard Error 0.009 |
| GFF MDI (PT003) | Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 14 | -0.03 Ventricular couplets / hour | Standard Error 0.033 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 1 | 0.00 Ventricular couplets / hour | Standard Error 0.005 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring | Day 14 | -0.01 Ventricular couplets / hour | Standard Error 0.004 |
Secondary
Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, and Day 14
Population: Safety Holter Monitoring Population: a sub-set of the safety population that had at least 18 hours of Holter monitoring data at Screening and at Day 1 and/or Day 14. Exclusions from this population were identified prior to database lock and unblinding.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FF MDI (PT005) | Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring | Day 1 | -0.003 Ventricular runs / hour | Standard Error 0.0024 |
| FF MDI (PT005) | Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring | Day 14 | -0.004 Ventricular runs / hour | Standard Error 0.0021 |
| GP MDI (PT001) | Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring | Day 14 | 0.001 Ventricular runs / hour | Standard Error 0.0029 |
| GP MDI (PT001) | Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring | Day 1 | -0.001 Ventricular runs / hour | Standard Error 0.0017 |
| GFF MDI (PT003) | Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring | Day 1 | 0.001 Ventricular runs / hour | Standard Error 0.0019 |
| GFF MDI (PT003) | Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring | Day 14 | 0.001 Ventricular runs / hour | Standard Error 0.0013 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring | Day 1 | -0.003 Ventricular runs / hour | Standard Error 0.004 |
| Foradil® Aerolizer® | Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring | Day 14 | -0.004 Ventricular runs / hour | Standard Error 0.0037 |
Secondary
Mean Change From Baseline in QTcF Interval
The secondary objectives of the study was to further characterize cardiovascular safety parameters of all treatment groups including the maximum 24-hour heart rate, mean night-time and day-time heart rate, ventricular ectopic events, ventricular couplets, ventricular runs, the number of supraventricular runs, and sustained ventricular tachycardia (VT), supraventricular ectopic events, and other clinically relevant arrhythmias (such as atrial fibrillation).
Time frame: Baseline, Day 1, Day 7, and Day 14
Population: Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FF MDI (PT005) | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 30 minutes | 1.53 msec | Standard Deviation 11.238 |
| FF MDI (PT005) | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 2 hours | 1.75 msec | Standard Deviation 13.861 |
| FF MDI (PT005) | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 24 hours | -0.09 msec | Standard Deviation 13.309 |
| FF MDI (PT005) | Mean Change From Baseline in QTcF Interval | Day 7: Pre-dose | -1.80 msec | Standard Deviation 10.362 |
| FF MDI (PT005) | Mean Change From Baseline in QTcF Interval | Day 14: Pre-dose | -0.59 msec | Standard Deviation 12.523 |
| FF MDI (PT005) | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 30 minutes | 1.21 msec | Standard Deviation 13.35 |
| FF MDI (PT005) | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 2 hours | 0.44 msec | Standard Deviation 12.521 |
| FF MDI (PT005) | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 24 hours | -1.32 msec | Standard Deviation 12.738 |
| GP MDI (PT001) | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 30 minutes | 4.10 msec | Standard Deviation 17.202 |
| GP MDI (PT001) | Mean Change From Baseline in QTcF Interval | Day 14: Pre-dose | 1.79 msec | Standard Deviation 13.028 |
| GP MDI (PT001) | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 2 hours | 3.57 msec | Standard Deviation 12.866 |
| GP MDI (PT001) | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 24 hours | -0.05 msec | Standard Deviation 13.794 |
| GP MDI (PT001) | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 2 hours | 6.02 msec | Standard Deviation 16.774 |
| GP MDI (PT001) | Mean Change From Baseline in QTcF Interval | Day 7: Pre-dose | 1.40 msec | Standard Deviation 14.713 |
| GP MDI (PT001) | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 24 hours | 1.23 msec | Standard Deviation 16.142 |
| GP MDI (PT001) | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 30 minutes | 4.67 msec | Standard Deviation 12.548 |
| GFF MDI (PT003) | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 2 hours | 5.01 msec | Standard Deviation 14.861 |
| GFF MDI (PT003) | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 24 hours | -1.43 msec | Standard Deviation 12.724 |
| GFF MDI (PT003) | Mean Change From Baseline in QTcF Interval | Day 7: Pre-dose | 1.06 msec | Standard Deviation 12.151 |
| GFF MDI (PT003) | Mean Change From Baseline in QTcF Interval | Day 14: Pre-dose | -0.42 msec | Standard Deviation 11.91 |
| GFF MDI (PT003) | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 30 minutes | 2.23 msec | Standard Deviation 13.194 |
| GFF MDI (PT003) | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 24 hours | -1.93 msec | Standard Deviation 11.269 |
| GFF MDI (PT003) | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 30 minutes | 3.27 msec | Standard Deviation 9.223 |
| GFF MDI (PT003) | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 2 hours | 1.62 msec | Standard Deviation 13.785 |
| Foradil® Aerolizer® | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 24 hours | 0.36 msec | Standard Deviation 10.989 |
| Foradil® Aerolizer® | Mean Change From Baseline in QTcF Interval | Day 7: Pre-dose | 3.85 msec | Standard Deviation 12.599 |
| Foradil® Aerolizer® | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 2 hours | 5.25 msec | Standard Deviation 11.709 |
| Foradil® Aerolizer® | Mean Change From Baseline in QTcF Interval | Day 1: Post-dose 30 minutes | 3.71 msec | Standard Deviation 9.816 |
| Foradil® Aerolizer® | Mean Change From Baseline in QTcF Interval | Day 14: Pre-dose | 1.53 msec | Standard Deviation 14.085 |
| Foradil® Aerolizer® | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 24 hours | 1.44 msec | Standard Deviation 16.086 |
| Foradil® Aerolizer® | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 2 hours | 3.98 msec | Standard Deviation 14.135 |
| Foradil® Aerolizer® | Mean Change From Baseline in QTcF Interval | Day 14: Post-dose 30 minutes | 1.20 msec | Standard Deviation 14.458 |