PT001 MDI Versus Spiriva® in Patients With Moderate to Severe COPD

• Sponsor: Pearl Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01566773
• Collaborator: (none)
• Enrollment: 140
• Locations: 10
• Arms: 8
• Duration (Months): 5
• Patients Per Site: 14
• Patients Per Site Per Month: 2.8

Study Details

Study Description

Brief Summary

The overall objective of this study is to determine an optimal dose and dosing regimen of PT001 MDI for further evaluation in later stage studies.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: PT001 MDI; Drug: Tiotropium Bromide; Drug: PT001 Placebo MDI	Phase 2

Detailed Description

The primary objective of this study is to assess efficacy relative to placebo of GP MDI in subjects with moderate to severe chronic obstructive pulmonary disease (COPD) within the range of doses evaluated in this protocol. To this end, each dose of GP MDI will be compared to placebo with respect to the primary efficacy endpoint, FEV1 AUC0-12 relative to baseline.

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double Blind (Test Products and Placebo), Chronic Dosing (14 Days), Four Period, Eight Treatment, Placebo-Controlled, Incomplete Block, Cross Over, Multi Center Study to Assess Efficacy and Safety of Six Doses of PT001 in Patients With Moderate to Severe COPD, Compared With Spiriva® Handihaler® (Tiotropium Bromide, Open Label) as An Active Control
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PT001 MDI (Dose 1)	Drug: PT001 MDI; Administered as two puffs BID for 14 days
Experimental: PT001 MDI (Dose 2)	Drug: PT001 MDI; Administered as two puffs BID for 14 days
Experimental: PT001 MDI (Dose 3)	Drug: PT001 MDI; Administered as two puffs BID for 14 days
Experimental: PT001 MDI (Dose 4)	Drug: PT001 MDI; Administered as two puffs BID for 14 days
Experimental: PT001 MDI (Dose 5)	Drug: PT001 MDI; Administered as two puffs BID for 14 days
Experimental: PT001 MDI (Dose 6)	Drug: PT001 MDI; Administered as two puffs BID for 14 days
Placebo Comparator: PT001 Placebo MDI	Drug: PT001 Placebo MDI
Active Comparator: Spiriva® Handihaler® (Tiotropium Bromide)	Drug: Tiotropium Bromide; Taken as 1 capsule containing 18 µg of tiotropium via the Handihaler DPI; Other Names: Spiriva® Handihaler®

Outcome Measures

Primary Outcome Measures

1. FEV1 AUC0-12 [Day 14 (-1 hr, -30 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 11.5 hr, 12 hr)]

   Forced expiratory volume in 1 second (FEV1) normalized area under the curve 0-12 hours (AUC0-12) following chronic dosing for 14 days.

Secondary Outcome Measures

1. Peak Change From Baseline in FEV1 [Day 1]

   Highest value of FEV1 post dose on day 1

2. Time to Onset of Action (>10% Improvement in FEV1) on Day 1 [Day 1 (15 min, 30 min, 1 hr, 2 hrs, no onset within 2 hrs)]

   Time to Onset of Action (>10% Improvement in FEV1) on Day 1.

3. Percentage of Subjects Achieving at Least 12% Improvement in FEV1 [Day 1]

   Percentage of subjects achieving at least 12% improvement in FEV1.

4. Peak Change From Baseline in Inspiratory Capacity (IC) [Day 1 (1 hr and 2 hr post-dose )]

   Peak change in Inspiratory Capacity (IC) mean of 1 and 2 hour post-dose assessments minus the baseline

5. Change From Baseline in Morning Pre-dose Trough FEV1 [Day 7 (average of the 60 and 30-minute pre-dose values on Treatment Day 7 minus the baseline)]

   Change from baseline in morning pre-dose trough FEV1 (average of the 60 and 30-minute pre-dose values on Treatment Day 7 minus the baseline)

6. Peak Change From Baseline in FEV1 [Day 7]

   Peak change from baseline in FEV1 (defined as the change at the highest value of FEV1 post-dose minus the baseline)

7. Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC) [Day 7]

   Change from baseline in morning pre-dose trough IC (average of the 60 and 30-minute pre-dose assessments minus the baseline)

8. Peak Change From Baseline in IC [Day 7 (mean of 1 hr and 2 hr post-dose assessments)]

   Peak change from baseline in IC (mean of 1 hr and 2 hr post-dose assessments)

9. Change From Baseline in Mean Morning Pre-dose Daily PEFR [Day 7 (60 minutes pre-dose, 30 minutes pre-dose)]

   Change from baseline in mean morning pre-dose daily PEFR (peak expiratory flow rate) taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (excluding reading taken pre-dose on Visit 2 [Treatment Day 1])

10. Change From Baseline in Morning Post-dose Daily PEFR [Day 7 (30 minutes post-dose)]

    Change from baseline in morning post-dose daily PEFR (peak expiratory flow rate) taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (excluding reading taken pre-dose on Visit 2 [Treatment Day 1])

11. Change From Baseline in Mean Evening Pre-dose PEFR [Day 7]

    Change from baseline in mean evening pre-dose daily peak flow readings taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (subjects taking Spiriva performed a single evening assessment)

12. Change From Baseline in Mean Evening Post-dose PEFR [Day 7]

    Change from baseline in mean evening post-dose daily peak flow readings taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (subjects taking Spiriva performed a single evening assessment)

13. Mean Number of Puffs of Rescue Medication [Day 7]

    Mean number of puffs of rescue medication recorded in subject diaries during each treatment period and by treatment and numbers of days treated

14. Change From Baseline in Morning Pre-dose Trough FEV1 [Day 14 (average of the 60 and 30-minute pre-dose values on Treatment Day 14 minus the baseline)]

    Change from baseline in morning pre-dose trough FEV1 (average of the 60 and 30-minute pre-dose values on Treatment Day 14 minus the baseline)

15. Peak Change From Baseline in FEV1 [Day 14]

    Peak change from baseline in FEV1 (defined as the change at the highest value of FEV1 post-dose minus the baseline)

16. Change From Baseline for Mean Morning Pre-dose Trough IC [Day 14 (average of the 60 and 30-minute pre-dose assessments minus the baseline)]

    Change from baseline for mean morning pre-dose trough IC (average of the 60 and 30-minute pre-dose assessments minus the baseline)

17. Peak Change From Baseline in IC [Day 14 (mean of 1 and 2 hour post-dose assessments minus the baseline)]

    Peak change from baseline in IC (mean of 1 and 2 hour post-dose assessments minus the baseline)

18. Change From Baseline in 12-hour Post-dose Trough FEV1 [Day 14 (Baseline, 11.5 and 12 hours post dose)]

    12-hour post-dose trough FEV1 was defined as the mean of the FEV1 assessments taken at 11.5 and 12 hours post-dose minus the baseline

19. Change From Baseline in Mean Morning Pre-dose Daily PEFR [Baseline, Treatment Day 1 and every day, to the end of the 14-Day Treatment period before dosing, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)]

    Change from baseline in mean morning pre-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (mean reading excluded reading taken pre-dose on Visit 2 [Treatment 1 Day 1]

20. Change From Baseline in Mean Morning Post-dose Daily PEFR [Baseline, Treatment Day 1 and every day, to the end of the 14-Day Treatment period 30 minutes post dosing, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)]

    Change from baseline in mean morning post-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (mean reading excluded reading taken pre-dose on Visit 2 [Treatment 1 Day 1]

21. Change From Baseline in Mean Evening Pre-dose Daily PEFR [Treatment Day 1 to the end of the 14-Day Treatment, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)]

    Change from baseline in mean evening pre-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (subjects taking Spiriva performed a single evening assessment)

22. Change From Baseline in Mean Evening Post-dose Daily PEFR [Through the end of the 14-Day Treatment]

    Change from baseline in mean evening post-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (subjects taking Spiriva performed a single evening assessment)

23. Mean Number of Puffs of Rescue Medication (End of Treatment) [Day 14 (End of treatment)]

    Mean number of puffs of rescue medication recorded in subject diaries during each treatment period and by treatment and numbers of days treated

24. Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 [Day 1 through Day 14]

    Change from Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Signed written informed consent

• 40 - 80 years of age

• Clinical history of COPD with airflow limitation that is not fully reversible

• Females of non-child bearing potential or females of child bearing potential with negative pregnancy test; and acceptable contraceptive methods

• Current/former smokers with at least a 10 pack-year history of cigarette smoking

• A measured post- bronchodilator FEV1/FVC ratio of < or = 0.70

• A measured post- bronchodilator FEV1 > or = 750ml or 30% predicted and < or = 80% of predicted normal values

• Able to change COPD treatment as required by protocol

Exclusion Criteria:

• Women who are pregnant or lactating

• Primary diagnosis of asthma

• Alpha-1 antitrypsin deficiency as the cause of COPD

• Active pulmonary diseases

• Prior lung volume reduction surgery

• Abnormal chest X-ray (or CT scan) not due to the presence of COPD

• Hospitalized due to poorly controlled COPD within 3 months of Screening

• Clinically significant medical conditions that preclude participation in the study (e.g. clinically significant abnormal ECG, uncontrolled hypertension, glaucoma, symptomatic prostatic hypertrophy)

• Cancer that has not been in complete remission for at least 5 years

• Treatment with investigational study drug or participation in another clinical trial or study within the last 30 days or 5 half lives

Other inclusion/exclusion criteria as defined in the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pearl Investigative Site	Fullerton	California	United States	92835
2	Pearl Investigative Site	Clearwater	Florida	United States	33765
3	Pearl Investigative Site	Panama City	Florida	United States	32405
4	Pearl Investigative Site	Tampa	Florida	United States	33603
5	Pearl Investigative Site	Winter Park	Florida	United States	32789
6	Pearl Investigative Site	Charlotte	North Carolina	United States	28207
7	Pearl Investigative Site	Medford	Oregon	United States	97504
8	Pearl Investigative Site	Spartanburg	South Carolina	United States	29303
9	Pearl Investigative Site	Longview	Texas	United States	75605
10	Pearl Investigative Site	Richmond	Virginia	United States	23225

Sponsors and Collaborators

• Pearl Therapeutics, Inc.

Investigators

• Study Director: Colin Reisner, MD, Pearl Therapeutics, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• protocol-pt001003_FINAL_Redacted

Publications

None provided.

• Responsible Party: Pearl Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT01566773
• Other Study ID Numbers: PT001003
• First Posted: Mar 29, 2012
• Last Update Posted: Oct 12, 2017
• Last Verified: Oct 1, 2017

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

Study Results

Participant Flow

Recruitment Details	The study was conducted at 10 sites in the US from April 2012 to August 2012. Study participation maximum of 26 weeks.
Pre-assignment Detail	A randomized, double-blind,chronic dosing, four-period, eight-treatment, placebo-controlled, incomplete block, crossover, multicenter study.

Arm/Group Title	All Subjects
Arm/Group Description
Period Title: Overall Study
STARTED	140
GP MDI 18 µg BID	64
GP MDI 9 µg BID	64
GP MDI 4.6 µg BID	62
GP MDI 2.4 µg BID	64
GP MDI 1.2 µg BID	57
GP MDI 0.6 µg BID	59
Placebo MDI	62
Spiriva® Handihaler®	62
COMPLETED	110
NOT COMPLETED	30

Baseline Characteristics

Arm/Group Title	All Subjects
Arm/Group Description	All Subjects
Overall Participants	140
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.3 (8.4)
Sex: Female, Male (Count of Participants)
Female	65 46.4%
Male	75 53.6%

Outcome Measures

1. Primary Outcome

Title	FEV1 AUC0-12
Description	Forced expiratory volume in 1 second (FEV1) normalized area under the curve 0-12 hours (AUC0-12) following chronic dosing for 14 days.
Time Frame	Day 14 (-1 hr, -30 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 11.5 hr, 12 hr)

Outcome Measure Data

Analysis Population Description

MITT (Modified Intent to Treat) Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	58	59	60	53	54	52	55
Least Squares Mean (95% Confidence Interval) [Liter]	1.448	1.416	1.432	1.416	1.386	1.353	1.290	1.514

2. Secondary Outcome

Title	Peak Change From Baseline in FEV1
Description	Highest value of FEV1 post dose on day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	59	59	60	59	55	55	60	57
Least Squares Mean (95% Confidence Interval) [mL]	231	226	165	170	136	107	57	270

3. Secondary Outcome

Title	Time to Onset of Action (>10% Improvement in FEV1) on Day 1
Description	Time to Onset of Action (>10% Improvement in FEV1) on Day 1.
Time Frame	Day 1 (15 min, 30 min, 1 hr, 2 hrs, no onset within 2 hrs)

Outcome Measure Data

Analysis Population Description

MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	55	56	57	58	50	54	55	54
15 minutes	29 20.7%	30 NaN	14 NaN	21 NaN	18 NaN	7 NaN	4 NaN	39 NaN
30 minutes	22 15.7%	11 NaN	9 NaN	16 NaN	12 NaN	9 NaN	7 NaN	15 NaN
1 hour	26 18.6%	11 NaN	11 NaN	10 NaN	10 NaN	17 NaN	9 NaN	15 NaN
2 hours	0 0%	16 NaN	11 NaN	7 NaN	10 NaN	7 NaN	2 NaN	11 NaN
No onset within 2 hours	24 17.1%	32 NaN	56 NaN	47 NaN	50 NaN	59 NaN	78 NaN	20 NaN

4. Secondary Outcome

Title	Percentage of Subjects Achieving at Least 12% Improvement in FEV1
Description	Percentage of subjects achieving at least 12% improvement in FEV1.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	56	58	60	52	56	56
Number [Percentage of participants]	70 50%	59 NaN	40 NaN	47 NaN	40 NaN	31 NaN	71 NaN

5. Secondary Outcome

Title	Peak Change From Baseline in Inspiratory Capacity (IC)
Description	Peak change in Inspiratory Capacity (IC) mean of 1 and 2 hour post-dose assessments minus the baseline
Time Frame	Day 1 (1 hr and 2 hr post-dose )

Outcome Measure Data

Analysis Population Description

MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	59	59	61	60	55	54	60	56
Least Squares Mean (95% Confidence Interval) [mL]	234	263	151	183	126	82	80	343

6. Secondary Outcome

Title	Change From Baseline in Morning Pre-dose Trough FEV1
Description	Change from baseline in morning pre-dose trough FEV1 (average of the 60 and 30-minute pre-dose values on Treatment Day 7 minus the baseline)
Time Frame	Day 7 (average of the 60 and 30-minute pre-dose values on Treatment Day 7 minus the baseline)

Outcome Measure Data

Analysis Population Description

MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	59	60	60	55	55	58	57
Least Squares Mean (95% Confidence Interval) [mL]	88	90	109	96	43	23	10	156

7. Secondary Outcome

Title	Peak Change From Baseline in FEV1
Description	Peak change from baseline in FEV1 (defined as the change at the highest value of FEV1 post-dose minus the baseline)
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	59	59	59	55	54	58	57
Least Squares Mean (95% Confidence Interval) [mL]	286	269	266	235	225	166	114	366

8. Secondary Outcome

Title	Change From Baseline in Morning Pre-dose Trough Inspiratory Capacity (IC)
Description	Change from baseline in morning pre-dose trough IC (average of the 60 and 30-minute pre-dose assessments minus the baseline)
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	59	60	60	55	54	58	56
Least Squares Mean (95% Confidence Interval) [mL]	137	57	101	142	73	54	62	184

9. Secondary Outcome

Title	Peak Change From Baseline in IC
Description	Peak change from baseline in IC (mean of 1 hr and 2 hr post-dose assessments)
Time Frame	Day 7 (mean of 1 hr and 2 hr post-dose assessments)

Outcome Measure Data

Analysis Population Description

MITT Population: Subjects who completed at least 2 treatment periods with minimally 2 hours post-dosing on Day 14 for each of the treatment periods.

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	59	60	60	55	54	58	56
Least Squares Mean (95% Confidence Interval) [mL]	302	234	254	312	195	159	99	390

10. Secondary Outcome

Title	Change From Baseline in Mean Morning Pre-dose Daily PEFR
Description	Change from baseline in mean morning pre-dose daily PEFR (peak expiratory flow rate) taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (excluding reading taken pre-dose on Visit 2 [Treatment Day 1])
Time Frame	Day 7 (60 minutes pre-dose, 30 minutes pre-dose)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	58	59	59	55	55	59	56
Least Squares Mean (95% Confidence Interval) [L/min]	8.0	3.2	0.2	2.4	-2.4	-2.5	-7.2	12.7

11. Secondary Outcome

Title	Change From Baseline in Morning Post-dose Daily PEFR
Description	Change from baseline in morning post-dose daily PEFR (peak expiratory flow rate) taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (excluding reading taken pre-dose on Visit 2 [Treatment Day 1])
Time Frame	Day 7 (30 minutes post-dose)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	58	59	59	55	55	59	56
Least Squares Mean (95% Confidence Interval) [L/min]	32.3	23.9	17.2	18.3	14.3	13.7	4.5	38.0

12. Secondary Outcome

Title	Change From Baseline in Mean Evening Pre-dose PEFR
Description	Change from baseline in mean evening pre-dose daily peak flow readings taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (subjects taking Spiriva performed a single evening assessment)
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.
Measure Participants	58	58	59	59	55	55	59
Least Squares Mean (95% Confidence Interval) [L/min]	15.8	12.6	4.7	11.2	7.5	5.9	3.3

13. Secondary Outcome

Title	Change From Baseline in Mean Evening Post-dose PEFR
Description	Change from baseline in mean evening post-dose daily peak flow readings taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (subjects taking Spiriva performed a single evening assessment)
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva Respimat
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva Respimat 18 µg
Measure Participants	58	58	59	59	55	55	59	55
Least Squares Mean (95% Confidence Interval) [L/min]	42.2	30.3	21.6	24.3	20.2	22.1	11.0	35.6

14. Secondary Outcome

Title	Mean Number of Puffs of Rescue Medication
Description	Mean number of puffs of rescue medication recorded in subject diaries during each treatment period and by treatment and numbers of days treated
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	59	59	61	60	55	55	60	58
Mean (95% Confidence Interval) [Puffs]	0.9	1.3	1.2	1.2	1.5	1.6	2.0	0.9

15. Secondary Outcome

Title	Change From Baseline in Morning Pre-dose Trough FEV1
Description	Change from baseline in morning pre-dose trough FEV1 (average of the 60 and 30-minute pre-dose values on Treatment Day 14 minus the baseline)
Time Frame	Day 14 (average of the 60 and 30-minute pre-dose values on Treatment Day 14 minus the baseline)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	59	60	59	55	55	56	57
Least Squares Mean (95% Confidence Interval) [mL]	89	80	67	77	68	29	-8	126

16. Secondary Outcome

Title	Peak Change From Baseline in FEV1
Description	Peak change from baseline in FEV1 (defined as the change at the highest value of FEV1 post-dose minus the baseline)
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	59	60	60	54	54	54	57
Least Squares Mean (95% Confidence Interval) [mL]	288	288	287	261	246	188	130	361

17. Secondary Outcome

Title	Change From Baseline for Mean Morning Pre-dose Trough IC
Description	Change from baseline for mean morning pre-dose trough IC (average of the 60 and 30-minute pre-dose assessments minus the baseline)
Time Frame	Day 14 (average of the 60 and 30-minute pre-dose assessments minus the baseline)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	59	60	60	55	54	56	56
Least Squares Mean (95% Confidence Interval) [mL]	94	45	64	104	69	34	9	138

18. Secondary Outcome

Title	Peak Change From Baseline in IC
Description	Peak change from baseline in IC (mean of 1 and 2 hour post-dose assessments minus the baseline)
Time Frame	Day 14 (mean of 1 and 2 hour post-dose assessments minus the baseline)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	59	60	60	54	54	56	56
Least Squares Mean (95% Confidence Interval) [mL]	280	259	288	226	261	172	77	284

19. Secondary Outcome

Title	Change From Baseline in 12-hour Post-dose Trough FEV1
Description	12-hour post-dose trough FEV1 was defined as the mean of the FEV1 assessments taken at 11.5 and 12 hours post-dose minus the baseline
Time Frame	Day 14 (Baseline, 11.5 and 12 hours post dose)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	58	59	60	53	55	54	56
Least Squares Mean (95% Confidence Interval) [mL]	116	69	99	112	66	55	1	164

20. Secondary Outcome

Title	Change From Baseline in Mean Morning Pre-dose Daily PEFR
Description	Change from baseline in mean morning pre-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (mean reading excluded reading taken pre-dose on Visit 2 [Treatment 1 Day 1]
Time Frame	Baseline, Treatment Day 1 and every day, to the end of the 14-Day Treatment period before dosing, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	57	58	59	59	55	55	58	56
Least Squares Mean (95% Confidence Interval) [L/min]	8.6	6.2	2.0	4.4	0.3	-0.5	-6.3	14.8

21. Secondary Outcome

Title	Change From Baseline in Mean Morning Post-dose Daily PEFR
Description	Change from baseline in mean morning post-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (mean reading excluded reading taken pre-dose on Visit 2 [Treatment 1 Day 1]
Time Frame	Baseline, Treatment Day 1 and every day, to the end of the 14-Day Treatment period 30 minutes post dosing, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	57	58	59	59	55	55	58	56
Least Squares Mean (95% Confidence Interval) [L/min]	33.5	26.7	20.2	20.3	14.8	14.3	5.3	39.8

22. Secondary Outcome

Title	Change From Baseline in Mean Evening Pre-dose Daily PEFR
Description	Change from baseline in mean evening pre-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (subjects taking Spiriva performed a single evening assessment)
Time Frame	Treatment Day 1 to the end of the 14-Day Treatment, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.
Measure Participants	57	58	59	59	55	55	58
Least Squares Mean (95% Confidence Interval) [L/min]	15.7	14.9	7.2	11.7	5.0	6.9	5.7

23. Secondary Outcome

Title	Change From Baseline in Mean Evening Post-dose Daily PEFR
Description	Change from baseline in mean evening post-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (subjects taking Spiriva performed a single evening assessment)
Time Frame	Through the end of the 14-Day Treatment

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	57	58	59	59	55	55	58	56
Least Squares Mean (95% Confidence Interval) [L/min]	41.4	32.7	24.7	27.0	19.4	22.7	13.5	35.9

24. Secondary Outcome

Title	Mean Number of Puffs of Rescue Medication (End of Treatment)
Description	Mean number of puffs of rescue medication recorded in subject diaries during each treatment period and by treatment and numbers of days treated
Time Frame	Day 14 (End of treatment)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	59	59	61	60	55	55	68	58
Mean (95% Confidence Interval) [Puffs]	0.85	1.25	1.19	1.11	1.43	1.57	1.92	0.87

25. Secondary Outcome

Title	Change From Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14
Description	Change from Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14
Time Frame	Day 1 through Day 14

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	GP MDI 18 µg BID	GP MDI 9 µg BID	GP MDI 4.6 µg BID	GP MDI 2.4 µg BID	GP MDI 1.2 µg BID	GP MDI 0.6 µg BID	Placebo MDI	Spiriva® Handihaler®
Arm/Group Description	GP MDI 18 µg BID.	GP MDI 9 µg BID.	GP MDI 4.6 µg BID.	GP MDI 2.4 µg BID.	GP MDI 1.2 µg BID.	GP MDI 0.6 µg BID.	Placebo MDI.	Spiriva® Handihaler® (Tiotropium Bromide).
Measure Participants	58	59	60	59	55	55	56	57
Least Squares Mean (95% Confidence Interval) [Liter]	0.088	0.087	0.090	0.086	0.056	0.023	0.001	0.141

Adverse Events

Time Frame	All of the adverse events (AEs) reported during the study were captured after signing informed consent through the 7-14 day follow up period.
Arm/Group Title	GP MDI 18 µg BID		GP MDI 9 µg BID		GP MDI 4.6 µg BID		GP MDI 2.4 µg BID		GP MDI 1.2 µg BID		GP MDI 0.6 µg BID		Placebo MDI		Spiriva 18 µg
Arm/Group Description	GP MDI 18 µg BID.		GP MDI 9 µg BID.		GP MDI 4.6 µg BID.		GP MDI 2.4 µg BID.		GP MDI 1.2 µg BID.		GP MDI 0.6 µg BID.		Placebo MDI.		Spiriva 18 µg
All Cause Mortality
	GP MDI 18 µg BID		GP MDI 9 µg BID		GP MDI 4.6 µg BID		GP MDI 2.4 µg BID		GP MDI 1.2 µg BID		GP MDI 0.6 µg BID		Placebo MDI		Spiriva 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	GP MDI 18 µg BID		GP MDI 9 µg BID		GP MDI 4.6 µg BID		GP MDI 2.4 µg BID		GP MDI 1.2 µg BID		GP MDI 0.6 µg BID		Placebo MDI		Spiriva 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		1/64 (1.6%)		0/62 (0%)		1/64 (1.6%)		0/57 (0%)		1/59 (1.7%)		1/62 (1.6%)		1/62 (1.6%)
Cardiac disorders
Acute myocardial infarction	0/64 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/64 (0%)	0	0/57 (0%)	0	0/59 (0%)	0	0/62 (0%)	0	1/62 (1.6%)	1
Infections and infestations
Pneumonia	0/64 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	1/64 (1.6%)	1	0/57 (0%)	0	0/59 (0%)	0	0/62 (0%)	0	0/62 (0%)	0
Reproductive system and breast disorders
Prostatitis	0/64 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/64 (0%)	0	0/57 (0%)	0	1/59 (1.7%)	1	0/62 (0%)	0	0/62 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	0/64 (0%)	0	1/64 (1.6%)	1	0/62 (0%)	0	0/64 (0%)	0	0/57 (0%)	0	0/59 (0%)	0	1/62 (1.6%)	1	0/62 (0%)	0
Other (Not Including Serious) Adverse Events
	GP MDI 18 µg BID		GP MDI 9 µg BID		GP MDI 4.6 µg BID		GP MDI 2.4 µg BID		GP MDI 1.2 µg BID		GP MDI 0.6 µg BID		Placebo MDI		Spiriva 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/64 (3.1%)		3/64 (4.7%)		3/62 (4.8%)		6/64 (9.4%)		3/57 (5.3%)		4/59 (6.8%)		3/62 (4.8%)		6/62 (9.7%)
Gastrointestinal disorders
Dry mouth	2/64 (3.1%)	4	3/64 (4.7%)	3	3/62 (4.8%)	3	6/64 (9.4%)	7	3/57 (5.3%)	3	4/59 (6.8%)	5	3/62 (4.8%)	3	6/62 (9.7%)	7

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.