PT003 MDI Cardiovascular Safety Study

• Sponsor: Pearl Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01349803
• Collaborator: (none)
• Enrollment: 237
• Locations: 20
• Arms: 4
• Duration (Months): 6
• Patients Per Site: 11.9
• Patients Per Site Per Month: 2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: PT005 MDI; Drug: PT001 MDI; Drug: PT003 MDI; Drug: Formoterol Fumarate 12 μg (Foradil® Aerolizer®)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 237 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel Group, 14-day, Multi-Center Study to Evaluate the Safety of PT003, PT005, PT001 and Foradil® Aerolizer® (12 µg, Open Label) as Evaluated by Holter Monitoring, in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PT005 MDI PT005 MDI	Drug: PT005 MDI; PT005 MDI administered as two puffs BID for 14 days
Experimental: PT001 MDI PT001 MDI	Drug: PT001 MDI; PT001 MDI administered as two puffs BID for 14 days
Experimental: PT003 MDI PT003 MDI	Drug: PT003 MDI; PT003 MDI administered as two puffs BID for 14 days
Active Comparator: Formoterol Fumarate 12 μg (Foradil® Aerolizer®) Formoterol Fumarate 12 μg (Foradil® Aerolizer®)	Drug: Formoterol Fumarate 12 μg (Foradil® Aerolizer®); Formoterol Fumarate 12 μg (Foradil® Aerolizer®) administered BID for 14 days; Other Names: Foradil® Aerolizer®

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Change From Baseline in Mean FEV1 Trough [Day 7 to Day 14]

   Trough FEV1 averaged over Day 7 and Day 14

2. 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).

3. 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).

4. 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).

5. 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).

6. 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).

7. 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).

8. 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).

9. 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).

10. 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).

11. 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).

12. 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).

13. 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).

14. 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).

15. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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/exclusion criteria as defined by the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pearl Investigative Site	Glendale	Arizona	United States
2	Pearl Investigative Site	Fullerton	California	United States
3	Pearl Investigative Site	Los Angeles	California	United States
4	Pearl Investigative Site	San Diego	California	United States
5	Pearl Investigative Site	Pensacola	Florida	United States
6	Pearl Investigative Site	Lafayette	Louisiana	United States
7	Pearl Investigative Site	North Dartmouth	Massachusetts	United States
8	Pearl Investigative Site	Livonia	Michigan	United States
9	Pearl Investigative Site	Medford	Oregon	United States
10	Pearl Investigative Site	San Antonio	Texas	United States
11	Pearl Investigative Site	Glebe	New South Wales	Australia
12	Pearl Investigative Site	Caboolture	Queensland	Australia
13	Pearl Investigative Site	Dawpark	South Australia	Australia
14	Pearl Investigative Site	Toorak Gardens	South Australia	Australia
15	Pearl Investigative Site	Heidelberg	Victoria	Australia
16	Pearl Investigative Site	Nedlands	Western Australia	Australia
17	Pearl Investigative Site	Caversham	Dunedin	New Zealand
18	Pearl Investigative Site	Private Bag	Hamilton	New Zealand
19	Pearl Investigative Site	Tauranga	North Island	New Zealand
20	Pearl Investigative Site	Newtown	Wellington	New Zealand

Sponsors and Collaborators

• Pearl Therapeutics, Inc.

Investigators

• Study Director: Colin Reisner, M.D., Pearl Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pearl Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT01349803
• Other Study ID Numbers: PT003003
• First Posted: May 9, 2011
• Last Update Posted: Jan 31, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by Pearl Therapeutics, Inc.: COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Formoterol Fumarate

Study Results

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 Detail	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

Arm/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg	GP MDI 36 mcg	GFF MDI 36/9.6 mcg	Formoterol Fumarate 12 μg
Period Title: Overall Study
STARTED	60	58	60	59
COMPLETED	59	57	57	57
NOT COMPLETED	1	1	3	2

Baseline Characteristics

Arm/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®	Total
Arm/Group Description	FF MDI 9.6 mcg	GP MDI 36 mcg	GFF MDI 36/9.6 mcg	Formoterol Fumarate 12 μg	Total of all reporting groups
Overall Participants	60	58	60	59	237
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.1 (8.13)	63.3 (7.93)	64.3 (7.38)	64.1 (7.91)	64.0 (7.80)
Gender (Count of Participants)
Female	33 55%	32 55.2%	26 43.3%	31 52.5%	122 51.5%
Male	27 45%	26 44.8%	34 56.7%	28 47.5%	115 48.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in 24-Hour Mean Heart Rate Post-dose
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg	GP MDI 36 mcg	GFF MDI 36/9.6 mcg	Formoterol Fumarate 12 μg
Measure Participants	59	57	55	55
Least Squares Mean (95% Confidence Interval) [bpm]	-0.19	-1.84	0.40	-0.09

2. Secondary Outcome

Title	Change From Baseline in Mean FEV1 Trough
Description	Trough FEV1 averaged over Day 7 and Day 14
Time Frame	Day 7 to Day 14

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg	GP MDI 36 mcg	GFF MDI 36/9.6 mcg	Formoterol Fumarate 12 μg
Measure Participants	57	49	53	55
Least Squares Mean (95% Confidence Interval) [Liters]	0.091	0.126	0.251	0.124

3. Secondary Outcome

Title	Change From Baseline in 24-Hour Mean Heart Rate for Day 1 of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg	GP MDI 36 mcg	GFF MDI 36/9.6 mcg	Formoterol Fumarate 12 μg
Measure Participants	60	58	57	57
Least Squares Mean (95% Confidence Interval) [bpm]	0.56	-0.44	0.92	0.31

4. Secondary Outcome

Title	Change From Baseline in Daytime Mean Heart Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=59 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	59	58	57	57
Day 1	0.00	-0.52	0.16	-0.17
Day 14	-1.22	-2.00	-0.40	-0.54

5. Secondary Outcome

Title	Change From Baseline in Night Time Mean Heart Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=59 Day 14: N=58	GP MDI 36 mcg Day 1: N=57 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=55 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	59	57	55	57
Day 1	3.05	-0.54	2.95	0.70
Day 14	0.04	-0.88	0.11	1.05

6. Secondary Outcome

Title	Change From Baseline in 24-Hour Maximum Heart Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=60 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	60	58	57	57
Day 1	-4.71	-1.88	-1.91	0.31
Day 14	0.75	-2.21	-0.06	-1.13

7. Secondary Outcome

Title	Change From Baseline in 24-Hour Minimum Heart Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=60 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	60	58	57	57
Day 1	0.05	-0.03	0.50	0.45
Day 14	-0.79	-1.92	-0.21	0.88

8. Secondary Outcome

Title	Change From Baseline in Number of Isolated Ventricular Events Recorded During 24-Hour Holter Monitoring
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=60 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	60	58	57	57
Day 1	1.31 (1.605)	0.56 (0.853)	1.59 (1.879)	0.45 (0.580)
Day 14	3.09 (4.092)	0.62 (1.088)	-0.10 (0.541)	-0.54 (0.424)

9. Secondary Outcome

Title	Change From Baseline in the Number of Ventricular Couplets Recorded During 24-Hour Holter Monitoring
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=60 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	60	58	57	57
Day 1	0.09 (0.071)	0.00 (0.005)	0.00 (0.009)	0.00 (0.005)
Day 14	0.02 (0.021)	0.00 (0.009)	-0.03 (0.033)	-0.01 (0.004)

10. Secondary Outcome

Title	Change From Baseline in the Number of Ventricular Runs Recorded During 24-Hour Holter Monitoring
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=60 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	60	58	57	57
Day 1	-0.003 (0.0024)	-0.001 (0.0017)	0.001 (0.0019)	-0.003 (0.0040)
Day 14	-0.004 (0.0021)	0.001 (0.0029)	0.001 (0.0013)	-0.004 (0.0037)

11. Secondary Outcome

Title	Change From Baseline in the Number of Isolated Supraventricular Events Recorded During 24-Hour Holter Monitoring
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=60 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	60	58	57	57
Day 1	7.72 (6.971)	0.74 (0.804)	-4.55 (5.947)	15.36 (16.359)
Day 14	3.61 (5.179)	-9.29 (9.398)	3.61 (5.179)	5.81 (11.320)

12. Secondary Outcome

Title	Change From Baseline in the Number of Supraventricular Couplets Recorded During 24-Hour Holter Monitoring
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=60 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	60	58	57	57
Day 1	0.03 (0.034)	0.01 (0.021)	0.05 (0.019)	0.04 (0.065)
Day 14	0.01 (0.025)	0.00 (0.017)	0.00 (0.018)	-0.02 (0.020)

13. Secondary Outcome

Title	Change From Baseline in the Number of Supraventricular Runs Recorded During 24-Hour Holter Monitoring
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=60 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	60	58	57	57
Day 1	0.00 (0.014)	0.02 (0.011)	0.01 (0.011)	0.01 (0.010)
Day 14	0.01 (0.013)	0.02 (0.015)	0.00 (0.012)	0.01 (0.014)

14. Secondary Outcome

Title	Change From Baseline in the Number of Bradycardia Episodes Recorded During 24-Hour Holter Monitoring
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=60 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	60	58	57	57
Day 1	-0.04 (0.139)	-0.02 (0.083)	0.11 (0.193)	0.03 (0.036)
Day 14	-0.02 (0.111)	0.40 (0.210)	0.27 (0.283)	0.13 (0.132)

15. Secondary Outcome

Title	Change From Baseline in the Number of Tachycardia Episodes Recorded During 24-Hour Holter Monitoring
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg Day 1: N=60 Day 14: N=59	GP MDI 36 mcg Day 1: N=58 Day 14: N=57	GFF MDI 36/9.6 mcg Day 1: N=57 Day 14: N=55	Formoterol Fumarate 12 μg Day 1: N=57 Day 14: N=55
Measure Participants	60	58	57	57
Day 1	-0.16 (0.170)	-0.24 (0.209)	-0.02 (0.160)	-0.09 (0.197)
Day 14	-0.23 (0.146)	-0.34 (0.229)	0.22 (0.154)	-0.01 (0.206)

16. Secondary Outcome

Title	Mean Change From Baseline in QTcF Interval
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	FF MDI (PT005)	GP MDI (PT001)	GFF MDI (PT003)	Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg	GP MDI 36 mcg	GFF MDI 36/9.6 mcg	Formoterol Fumarate 12 μg
Measure Participants	60	58	60	59
Day 1: Post-dose 30 minutes	1.53 (11.238)	4.67 (12.548)	3.27 (9.223)	3.71 (9.816)
Day 1: Post-dose 2 hours	1.75 (13.861)	3.57 (12.866)	1.62 (13.785)	5.25 (11.709)
Day 1: Post-dose 24 hours	-0.09 (13.309)	1.23 (16.142)	-1.43 (12.724)	0.36 (10.989)
Day 7: Pre-dose	-1.80 (10.362)	1.40 (14.713)	1.06 (12.151)	3.85 (12.599)
Day 14: Pre-dose	-0.59 (12.523)	1.79 (13.028)	-0.42 (11.910)	1.53 (14.085)
Day 14: Post-dose 30 minutes	1.21 (13.350)	4.10 (17.202)	2.23 (13.194)	1.20 (14.458)
Day 14: Post-dose 2 hours	0.44 (12.521)	6.02 (16.774)	5.01 (14.861)	3.98 (14.135)
Day 14: Post-dose 24 hours	-1.32 (12.738)	-0.05 (13.794)	-1.93 (11.269)	1.44 (16.086)

Adverse Events

Time Frame	Adverse events (AEs) and Serious Adverse Events (SAEs) were collected from the time the subject signs the informed consent form up to 14 days following the last dose of study drug.
Adverse Event Reporting Description	All patients who were randomized to a treatment, received at least one dose of the study treatment, and had any safety data after starting study treatment. A patient who used a study treatment, but took less than one full dose qualified for this population.
Arm/Group Title	FF MDI (PT005)		GP MDI (PT001)		GFF MDI (PT003)		Foradil® Aerolizer®
Arm/Group Description	FF MDI 9.6 mcg		GP MDI 36 mcg		GFF MDI 36/9.6 mcg		Formoterol Fumarate 12 μg
All Cause Mortality
	FF MDI (PT005)		GP MDI (PT001)		GFF MDI (PT003)		Foradil® Aerolizer®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	FF MDI (PT005)		GP MDI (PT001)		GFF MDI (PT003)		Foradil® Aerolizer®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/60 (1.7%)		0/58 (0%)		1/60 (1.7%)		1/59 (1.7%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/60 (1.7%)	1	0/58 (0%)	0	1/60 (1.7%)	1	1/59 (1.7%)	1
Other (Not Including Serious) Adverse Events
	FF MDI (PT005)		GP MDI (PT001)		GFF MDI (PT003)		Foradil® Aerolizer®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/60 (10%)		4/58 (6.9%)		2/60 (3.3%)		5/59 (8.5%)
Infections and infestations
Nasopharyngitis	0/60 (0%)	0	1/58 (1.7%)	1	1/60 (1.7%)	1	3/59 (5.1%)	3
Nervous system disorders
Tremor	4/60 (6.7%)	5	0/58 (0%)	0	1/60 (1.7%)	1	1/59 (1.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/60 (3.3%)	2	3/58 (5.2%)	3	0/60 (0%)	0	1/59 (1.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Drafts of any and all publications or presentations of this study must be submitted at least 30 days prior to submission for publication or presentation to Pearl Therapeutics for review, approval, and to ensure consistency. Pearl Therapeutics has the right to request appropriate modification to correct facts and to represent its opinions, or the opinions of the publication committee, if these differ with the proposed publication.