Study to evaluate single inhaled doses of PT001, PT003, PT005 and PT001 Plus PT005 in healthy subjects

Study identifier:PT0030901

ClinicalTrials.gov identifier:NCT00893971

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A randomized, double-blind, single dose, four-period, four-treatment, cross-over study evaluating the safety of PT001, PT003, PT005 administered individually and PT001 + PT005 delivered together in separate inhalers in healthy subjects

Medical condition

Healthy Volunteers

Phase

Phase 1

Healthy volunteers

Yes

Study drug

PT001, PT005, PT003, PT001 + PT005

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 55 Years

Date

Study Start Date: 01 May 2009

Primary Completion Date: 01 Jul 2009

Study Completion Date: 01 Jul 2009

Study design

Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Crossover Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 May 2016 by Pearl Therapeutics, Inc.

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

- Provide signed written informed consent
- 18-55 years of age
- Healthy subjects confirmed by medical history, physical examination, vital signs, pulmonary function tests, electrocardiogram and clinical laboratory tests
- Female subjects of child-bearing potential who are sexually active must be willing to undergo a pregnancy test and agree to use two forms of contraception
- Body mass index (BMI) between 18.5 and 30, inclusive
- Non-smokers for at least 6 months prior to screening
- Pulmonary function tests within normal limits
- Willing to remain at the study center for at least 12-24 hours on each test day
- Venous access in both arms to allow collection of numerous blood samples

Exclusion Criteria

- Women who are pregnant or lactating
- Clinically significant medical conditions
- Viral illness within the last 30 days
- Symptomatic prostatic hypertrophy or bladder neck obstruction
- Known narrow-angle glaucoma
- History of bowel obstruction
- Clinically significant abnormal electrocardiogram
- Positive Hepatitis B surface antigen or positive Hepatitis C antibody
- Positive screening test for HIV antibodies
- History of hypersensitivity to any beta2-agonists, anticholinergics, or any component of the MDI
- Known or suspected history of alcohol or drug abuse within the last 2-years
- Greater than normal alcohol consumption
- Ingestion of any poppy seeds within the 48 hours prior to the screening
- Ingestion of any poppy seeds within the 48 hours prior to, or any alcohol, xanthines or grapefruit-containing foods or beverages within the 24 hours prior to, or during, each confinement
- Positive breath alcohol result
- Positive urine drug screen
- Use of any beta2-agonists,or anticholinergics prior to the recruitment interview
- Lower respiratory tract infections requiring antibiotics in the previous 6 weeks
- Use of any other prescription medication
- Use of any over the counter product, herbal product, diet aid, hormone supplement
- Donation > 450 ml of blood within 8 weeks of first treatment dose
- Clinically significant vital sign abnormality
- Clinically significant biochemical, hematological or urinalysis abnormality
- Affiliations with investigator site
- Treatment with investigational study drug or participation in another clinical trial or study within the last 30 days or 5 half lives prior to screening, whichever is longer

Location

Dr Joanne Marjason

Herston, Queensland, Australia, 4006

Arms	Assigned Interventions
Experimental: 1 Inhaled PT001 18 μg	Drug: PT001 Inhaled PT001, single dose
Experimental: 2 Inhaled PT005 2.4 μg	Drug: PT005 Inhaled PT005, single dose
Experimental: 3 Inhaled PT003 (PT001 18 μg / 2.4 μg PT005)	Drug: PT003 Inhaled PT003, single dose
Experimental: 4 PT001 18 μg + PT005 2.4 μg	Drug: PT001 + PT005 Inhaled PT001 + PT005, single dose

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Conducted at a single site in Australia from May 2009 through July 2009. Study participation was a maximum of 7 weeks.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
This was a single-center, randomized, double-blind, single-dose, 4-period, 4-treatment, crossover study evaluating a single administration of inhaled treatment (PT001, PT003, PT005 and PT001+PT005 delivered from separate inhalers as a loose combination).

Reporting Groups

	Description
All Subjects	Any treatment arm

Participant Flow: Overall Study

	All Subjects
STARTED	16
COMPLETED	13
NOT COMPLETED	3
Physician Decision	3

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

All randomized subjects

Reporting Groups

	Description
All subjects	Any treatment arm

Baseline Measures

	All subjects
Number of Participants [units: Participants]	16
Age Continuous [units: Years] Mean ± Standard Deviation	27.4 ± 10.1
Gender, Male/Female [units: Participants]
Female	11
Male	5

Outcome Measures

1. Primary Outcome Measure: Symptoms of dry mouth [ Time Frame: 12 hours ]

Measure Type	Primary
Measure Name	Symptoms of dry mouth
Measure Description	Number of participants reporting dry mouth at 12 hours post-dose
Time Frame	12 hours
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups

	Description
Placebo + PT001	Placebo + Glycopyrrolate MDI (72 mcg)
Placebo + PT005	Placebo + Formoterol Fumarate 9.6 mcg
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Measured Values

	Placebo + PT001	Placebo + PT005	PT001 + PT005	Placebo + PT003
Number of Participants Analyzed [units:participants]	15	13	16	15
Symptoms of dry mouth [units: Participants]
Immediately pre-dose	3	1	3	1
30 minutes post-dose	4	3	4	5
1-hour post-dose	3	2	3	3
2-hours post-dose	3	1	3	1
4-hours post-dose	1	1	3	0
6-hours post-dose	1	1	2	NA^[1]
8-hours post-dose	1	1	2	NA^[2]
12-hours post-dose	1	1	2	NA^[3]

[1]	If dry mouth was not present after the 2-hour time point, no further assessment was required
[2]	If dry mouth was not present after the 2-hour time point, no further assessment was required
[3]	If dry mouth was not present after the 2-hour time point, no further assessment was required

No statistical analysis provided for Symptoms of dry mouth

2. Primary Outcome Measure: Symptoms of tremor [ Time Frame: 12 hours ]

Measure Type	Primary
Measure Name	Symptoms of tremor
Measure Description	Number of participants reporting tremor at 12 hours post-dose
Time Frame	12 hours
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups

	Description
Placebo + PT001	Placebo + Glycopyrrolate MDI (72 mcg)
Placebo + PT005	Placebo + Formoterol Fumarate 9.6 mcg
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Measured Values

	Placebo + PT001	Placebo + PT005	PT001 + PT005	Placebo + PT003
Number of Participants Analyzed [units:participants]	15	13	16	15
Symptoms of tremor [units: Participants]
Immediately pre-dose	0	0	0	0
30-minutes post-dose	0	0	0	0
1-hour post-dose	0	0	0	0
2-hours post-dose	0	0	1	0
4-hours post-dose	NA^[1]	1	1	NA^[2]
6-hours post-dose	NA^[3]	0	NA^[4]	NA^[5]
8-hours post-dose	NA^[6]	NA^[7]	NA^[8]	NA^[9]

[1]	If no tremor was present up to the 2-hour time point, no further assessment was required
[2]	If no tremor was present up to the 2-hour time point, no further assessment was required
[3]	If no tremor was present up to the 2-hour time point, no further assessment was required
[4]	If no tremor was present at the next 2-hour time point, no further assessment was required
[5]	If no tremor was present up to the 2-hour time point, no further assessment was required
[6]	If no tremor was present up to the 2-hour time point, no further assessment was required
[7]	If no tremor was present at the next 2-hour time point, no further assessment was required
[8]	If no tremor was present at the next 2-hour time point, no further assessment was required
[9]	If no tremor was present up to the 2-hour time point, no further assessment was required

No statistical analysis provided for Symptoms of tremor

3. Primary Outcome Measure: Blood chemistry change from baseline [ Time Frame: 12/24 hours ]

Measure Type	Primary
Measure Name	Blood chemistry change from baseline
Measure Description	Series of 11 blood chemistries assessed throughout the study
Time Frame	12/24 hours
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups

	Description
Placebo + PT001	Placebo + Glycopyrrolate MDI (72 mcg)
Placebo + PT005	Placebo + Formoterol Fumarate 9.6 mcg
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Measured Values

	Placebo + PT001	Placebo + PT005	PT001 + PT005	Placebo + PT003
Number of Participants Analyzed [units:participants]	15	13	16	15
Blood chemistry change from baseline [units: Various] Mean (Full Range)
Sodium (mmol/L)	0.76 (-3 to 4)	0.78 (-1 to 3)	0.35 (-2 to 6)	0.6 (-2 to 3)
Chloride (mmol/L)	-1.29 (-7 to 2)	-0.4 (-4 to 4)	-0.75 (-5 to 6)	-1.2 (-3 to 0)
Urea (mmol/L)	0.12 (-0.9 to 1.4)	-0.05 (-1.3 to 1.8)	-0.11 (-2.6 to 1.5)	-0.33 (-3.3 to 1.1)
Creatinine (micomol/L)	2.19 (-11 to 11)	1.45 (-15 to 12)	0.44 (-14 to 11)	-0.8 (-13 to 11)
Calcium (mmol/L)	-0.01 (-0.1 to 0.08)	-0.04 (-0.2 to 0.06)	-0.03 (-0.21 to 0.08)	-0.01 (-0.11 to 0.09)
Bilirubin (micromol/L)	-1.4 (-6 to 3)	-2.18 (-5 to 0)	-2.32 (-6 to 1)	-2.07 (-10 to 2)
ALP (U/L)	2.99 (-3 to 10)	3.59 (-3 to 12)	1.39 (-9 to 9)	2 (-9 to 11)
ALT (U/L)	0.07 (-6 to 5)	-1.21 (-8 to 4)	-0.41 (-5 to 5)	-0.33 (-5 to 6)
AST (U/L)	-0.83 (-10 to 7)	0.25 (-5 to 6)	-2.91 (-14 to 4)	-1.67 (-10 to 4)
Bicarbonate (mmol/L)	0.64 (-2 to 4)	0.05 (-4 to 2)	0.44 (-5 to 6)	0.47 (-5 to 3)
Glucose (mmol/L)	-0.17 (-2.5 to 1.1)	-0.34 (-2.4 to 1.2)	-0.34 (-2 to 1.1)	0.45 (-1.9 to 2.5)

No statistical analysis provided for Blood chemistry change from baseline

4. Primary Outcome Measure: Hematology change from baseline [ Time Frame: 12/24 hours ]

Measure Type	Primary
Measure Name	Hematology change from baseline
Measure Description	Hematology assessments taken throughout the study
Time Frame	12/24 hours
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups

	Description
Placebo + PT001	Placebo + Glycopyrrolate MDI (72 mcg)
Placebo + PT005	Placebo + Formoterol Fumarate 9.6 mcg
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Measured Values

	Placebo + PT001	Placebo + PT005	PT001 + PT005	Placebo + PT003
Number of Participants Analyzed [units:participants]	15	13	15	15
Hematology change from baseline [units: Various] Mean (Full Range)
Hemoglobin (g/L)	2.45 (-24 to 11)	2.95 (-6 to 10)	1.73 (-4 to 10)	3.33 (-9 to 9)
Hematocrit	0.01 (-0.07 to 0.03)	0.01 (-0.02 to 0.04)	0.01 (-0.02 to 0.03)	0.01 (-0.02 to 0.04)
WCC (x10^9/L)	17.93 (-13 to 39)	20.61 (-1 to 55)	10.8 (-31 to 43)	20.33 (-17 to 54)
Platelets (x10^9/L)	1.08 (-1 to 3)	0.88 (-1 to 3)	0.93 (0 to 3)	0.67 (-4 to 3)

No statistical analysis provided for Hematology change from baseline

5. Primary Outcome Measure: Heart rate change from baseline [ Time Frame: 12 hours ]

Measure Type	Primary
Measure Name	Heart rate change from baseline
Measure Description	Change from baseline for heart rate 12-hours post-dose
Time Frame	12 hours
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups

	Description
Placebo + PT001	Placebo + Glycopyrrolate MDI (72 mcg)
Placebo + PT005	Placebo + Formoterol Fumarate 9.6 mcg
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Measured Values

	Placebo + PT001	Placebo + PT005	PT001 + PT005	Placebo + PT003
Number of Participants Analyzed [units:participants]	15	13	16	15
Heart rate change from baseline [units: Various] Mean (Full Range)
Heart rate (bpm)	2.0 (-7 to 13)	4.4 (-12 to 21)	2.9 (-3 to 11)	1.8 (-13 to 19)
Systolic blood pressure (mmHg)	3.3 (-14 to 18)	1.0 (-20 to 14)	0.1 (-9 to 14)	0.4 (-8 to 13)
Diastolic blood pressure (mmHg)	6.3 (-8 to 24)	1.5 (-13 to 10)	0.6 (-12 to 12)	1.6 (-14 to 28)
SpO2 (%)	0.2 (-2 to 2)	0.1 (-1 to 3)	-0.1 (-2 to 1)	0.1 (-1 to 2)

No statistical analysis provided for Heart rate change from baseline

6. Primary Outcome Measure: ECG change from baseline [ Time Frame: 12 hours ]

Measure Type	Primary
Measure Name	ECG change from baseline
Measure Description	Change from baseline for ECG parameters 12-hours post-dose
Time Frame	12 hours
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups

	Description
Placebo + PT001	Placebo + Glycopyrrolate MDI (72 mcg)
Placebo + PT005	Placebo + Formoterol Fumarate 9.6 mcg
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Measured Values

	Placebo + PT001	Placebo + PT005	PT001 + PT005	Placebo + PT003
Number of Participants Analyzed [units:participants]	15	13	16	15
ECG change from baseline [units: Various] Mean (Full Range)
Ventricular rate (bpm)	1.5 (-7 to 9)	4.7 (-18 to 22)	5.2 (-4 to 25)	4.0 (-9 to 13)
PR interval (ms)	-11.0 (-126 to 10)	-8.3 (-20 to 2)	-5.3 (-24 to 24)	-10.4 (-34 to 14)
QRS duration (ms)	-3.0 (-10 to 4)	-5.4 (-18 to 10)	0.4 (-10 to 42)	-2.0 (-12 to 10)
QT interval (ms)	-8.6 (-32 to 4)	-9.4 (-42 to 20)	-10.1 (-60 to 16)	-12.8 (-26 to 10)
QTcB (ms)	-3.7 (-24 to 18)	5.3 (-36 to 41)	5.4 (-17 to 39)	-2.1 (-26 to 31)
QTcF (ms)	-5.1 (-25 to 12)	0.0 (-19 to 16)	-0.1 (-23 to 21)	-5.9 (-18 to 24)

No statistical analysis provided for ECG change from baseline

7. Primary Outcome Measure: Spirometry change from baseline [ Time Frame: 12 hours ]

Measure Type	Primary
Measure Name	Spirometry change from baseline
Measure Description	Change from baseline for spirometery measures 12-hours post-dose
Time Frame	12 hours
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups

	Description
Placebo + PT001	Placebo + Glycopyrrolate MDI (72 mcg)
Placebo + PT005	Placebo + Formoterol Fumarate 9.6 mcg
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Measured Values

	Placebo + PT001	Placebo + PT005	PT001 + PT005	Placebo + PT003
Number of Participants Analyzed [units:participants]	15	13	16	15
Spirometry change from baseline [units: Various] Mean (Full Range)
FEV1 (L)	0.260 (-0.28 to 0.49)	0.148 (-0.53 to 0.43)	0.202 (-0.27 to 0.71)	0.195 (-0.33 to 0.49)
FEV1 % predicted	7.2 (-8 to 12)	4.5 (-12 to 12)	5.2 (-8 to 15)	5.0 (-7 to 15)
FVC (L)	0.145 (-0.51 to 0.47)	0.0 (-0.82 to 0.44)	0.082 (-0.49 to 0.53)	0.045 (-0.64 to 0.50)
FEV / FVC (%)	3.0 (-4 to 10)	3.4 (0 to 7)	3.2 (-4 to 9)	3.6 (1 to 8)
PEFR (L/min)	40.4 (0 to 93)	32.1 (-120 to 150)	40.1 (-63 to 135)	31.6 (-99 to 102)

No statistical analysis provided for Spirometry change from baseline

8. Secondary Outcome Measure: Plasma glycopyrrolate PK parameters [ Time Frame: 12 hours ]

Measure Type	Secondary
Measure Name	Plasma glycopyrrolate PK parameters
Measure Description	Various pharmacokinetic parameters for plasma glycopyrrolate
Time Frame	12 hours
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK evaluable subjects

Reporting Groups

	Description
Placebo + PT001	Placebo + Glycopyrrolate MDI (72 mcg)
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Measured Values

	Placebo + PT001	PT001 + PT005	Placebo + PT003
Number of Participants Analyzed [units:participants]	12	12	12
Plasma glycopyrrolate PK parameters [units: Various] Mean (Standard Deviation)
*AUC0-tlast (hpg/mL)**	156.6 (76.7)	100.1 (43.1)	78.4 (36.2)
*AUC-12 (hpg/mL)**	156.7 (76.5)	100.6 (42.4)	80.1 (34.9)
Tmax (h)	0.16 (0.14)	0.07 (0.06)	0.06 (0.03)
Cmax (pg/mL)	61.3 (40.9)	77.8 (72.0)	44.4 (18.3)
ke (1/h)	0.143 (0.047)	0.147 (0.042)	0.155 (0.059)
t1/2 (h)	5.34 (1.78)	5.12 (1.61)	5.12 (2.07)
*AUC0-inf (hpg/mL)**	172.4 (88.6)	137.2 (55.4)	100.8 (50.5)

No statistical analysis provided for Plasma glycopyrrolate PK parameters

9. Secondary Outcome Measure: Plasma formoterol fumarate PK parameters [ Time Frame: 12 hours ]

Measure Type	Secondary
Measure Name	Plasma formoterol fumarate PK parameters
Measure Description	Various pharmacokinetic parameters for plasma formoterol fumarate
Time Frame	12 hours
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK evaluable subjects

Reporting Groups

	Description
Placebo + PT005	Placebo + Formoterol Fumarate 9.6 mcg
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Measured Values

	Placebo + PT005	PT001 + PT005	Placebo + PT003
Number of Participants Analyzed [units:participants]	11	11	11
Plasma formoterol fumarate PK parameters [units: Various] Mean (Standard Deviation)
*AUC0-tlast (hpg/mL)**	47.9 (12.3)	61.2 (16.5)	57.9 (16.3)
*AUC0-12 (hpg/mL)**	48.1 (12.2)	61.2 (16.6)	57.8 (16.2)
Tmax (h)	0.28 (0.31)	0.27 (0.59)	0.43 (0.46)
Cmax (pg/mL)	10.4 (3.8)	13.2 (4.5)	11.9 (4.0)
ke (1/h)	0.142 (0.035)	0.135 (0.025)	0.126 (0.032)
t1/2 (h)	5.12 (1.10)	5.28 (1.02)	5.80 (1.32)
*AUC0-inf (hpg/mL)**	56.1 (8.3)	76.4 (18.5)	67.0 (12.8)

No statistical analysis provided for Plasma formoterol fumarate PK parameters

Serious Adverse Events

Time Frame	SAEs and AEs were collected throughout study participation
Additional Description	Safety population included all participants who received investigational drug; participants were included in safety population according to the investigational drug they were receiving at the time of the event

Reporting Groups

	Description
Placebo + PT001	Placebo + Glycopyrrolate MDI (72 mcg)
Placebo + PT005	Placebo + Formoterol Fumarate 9.6 mcg
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Serious Adverse Events

	Placebo + PT001	Placebo + PT005	PT001 + PT005	Placebo + PT003
Total, serious adverse events
# participants affected / at risk	0/15 (0.00%)	0/13 (0.00%)	0/16 (0.00%)	0/15 (0.00%)

Other Adverse Events

Time Frame	SAEs and AEs were collected throughout study participation
Additional Description	Safety population included all participants who received investigational drug; participants were included in safety population according to the investigational drug they were receiving at the time of the event

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Placebo + PT001	Placebo + Glycopyrrolate MDI (72 mcg)
Placebo + PT005	Placebo + Formoterol Fumarate 9.6 mcg
PT001 + PT005	Glycopyrrolate 72 mcg + Formoterol Fumarate 9.6 mcg (taken in any order)
Placebo + PT003	Placebo + Glycopyrrolate 72 mcg / Formoterol Fumarate 9.6 mcg

Other Adverse Events

Placebo + PT001

Placebo + PT005

PT001 + PT005

Placebo + PT003

Total, other (not including serious) adverse events

# participants affected / at risk

7/15 (46.67%)

6/13 (46.15%)

8/16 (50.00%)

9/15 (60.00%)

Eye disorders

Dry eye¹,^†

# participants affected / at risk

1/15 (6.67%)

1/13 (7.69%)

0/16 (0.00%)

1/15 (6.67%)

# events

Gastrointestinal disorders

Dry mouth¹,^†

# participants affected / at risk

2/15 (13.33%)

3/13 (23.08%)

4/16 (25.00%)

4/15 (26.67%)

# events

Gastrointestinal disorders

Toothache¹,^†

# participants affected / at risk

1/15 (6.67%)

0/13 (0.00%)

0/16 (0.00%)

0/15 (0.00%)

# events

General disorders

Chest discomfort¹,^†

# participants affected / at risk

1/15 (6.67%)

0/13 (0.00%)

0/16 (0.00%)

0/15 (0.00%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

0/15 (0.00%)

1/13 (7.69%)

1/16 (6.25%)

1/15 (6.67%)

# events

Injury, poisoning and procedural complications

Contusion¹,^†

# participants affected / at risk

1/15 (6.67%)

0/13 (0.00%)

0/16 (0.00%)

0/15 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Muscle tightness¹,^†

# participants affected / at risk

1/15 (6.67%)

0/13 (0.00%)

0/16 (0.00%)

0/15 (0.00%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

1/15 (6.67%)

1/13 (7.69%)

1/16 (6.25%)

1/15 (6.67%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

2/15 (13.33%)

1/13 (7.69%)

1/16 (6.25%)

5/15 (33.33%)

# events

Nervous system disorders

Tremor¹,^†

# participants affected / at risk

0/15 (0.00%)

1/13 (7.69%)

2/16 (12.50%)

1/15 (6.67%)

# events

Reproductive system and breast disorders

Dysmenorrhea¹,^†

# participants affected / at risk

0/15 (0.00%)

0/13 (0.00%)

1/16 (6.25%)

0/15 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Rhinitis¹,^†

# participants affected / at risk

2/15 (13.33%)

0/13 (0.00%)

0/16 (0.00%)

1/15 (6.67%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.