Conditions: COPD
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 4
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled, single-center, chronic-dosing (7 days), two-period, two-treatment, cross-over study to evaluate the treatment effect of PT003 compared with that of Placebo MDI on Cardiovascular Hemodynamics following chronic-dosing (7 days) in subjects with moderate to severe COPD.

Detailed description:

Arms:
arm 1: Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; PT003, Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI) arm 2: Placebo Metered Dose Inhaler (MDI) for Glycopyrronium and Formoterol Fumarate Inhalation Aerosol

Interventions: intervention 1: GFF MDI (PT003) intervention 2: Placebo MDI
Intervention descriptions: intervention 1: Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; PT003, Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI) intervention 2: Placebo Metered Dose Inhaler (MDI) for Glycopyrronium and Formoterol Fumarate Inhalation Aerosol

Protocol document:
Prot_SAP_000.pdf: 
 
 
Revised Clinical Study Protocol 
Study Code 
PT003017 
NCT #  
NCT02643082 
Date 
26 September 2016 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Phase IIIb, Two-period, Double-blind, Two treatment, 
Chronic-dosing (7 Days), Single-center Crossover Study to Evaluate the Treatment Effect 
of PT003 on Cardiovascular Hemodynamics in Subjects With Moderate to Severe 
Chronic Obstructive Pulmonary Disease, Compared with Placebo 
 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
The following Amendment(s) are included in this revised protocol: 
  
Amendment No.        
Date of Amendment                
Version 1 
14 October 2015 
Version 2,  Amendment 1 
04 February 2016 
Version 3,  Amendment 2  
26 September 2016 
 
 
 


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Clinical Trial Protocol: PT003017-02
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Confidential and Proprietary
Page 1 of 121
Clinical Trial Protocol: PT003017-02 
Title:
A Randomized, Phase IIIb, Two-period, Double-blind, Two-
treatment, Chronic-dosing (7 Days), Single-center Crossover Study to 
Evaluate the Treatment Effect of PT003 on Cardiovascular 
Hemodynamics in Subjects With Moderate to Severe Chronic 
Obstructive Pulmonary Disease, Compared with Placebo
Study Number:
PT003017-02 
Study Phase:
IIIb
Product Name:
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol, PT003 
IND Number 
107739
Indication:
COPD
Investigators: 
Single-center
Sponsor:
Pearl Therapeutics, Inc.
 
 
 
Sponsor Contact 
  
Version Number
Date
Original Protocol: 
Version 1.0 
14 October 2015 
Amended Protocol
Version 2.0 
04 February 2016 
Amended Protocol
Version 3.0 
26 September 2016 
 
 
 
 
 
 
Confidentiality Statement
Property of Pearl Therapeutics
This document is confidential and may not be used, divulged, published or otherwise 
disclosed without consent of Pearl Therapeutics, Inc. 


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SUMMARY OF CHANGES TO AMENDED PROTOCOL VERSION 2.0, 
DATED 04 FEBRUARY 2016 FOR VERSION 3.0
The amended study protocol, PT003017-02 (Version 3.0), includes the following edits. When 
specifically mentioned, newly added or deleted text is indicated in quotation marks.
No.
Description of Change
Rationale
1
Synopsis; Former Section 3.4: Exploratory 
Endpoints (Evaluated on Treatment Day 
8); Previous Section 7.1.6: Biomarkers; 
Section 8.3: Visit 3 (Randomization/Day 
1); Section 8.4: Visit 4 (Day 8); Section 
8.6: Visit 6 (Day 8); Section 9.2.1: 
Efficacy Endpoints, Former Section 9.2.2: 
Exploratory Endpoints (Evaluated on 
Treatment Day 8)
Deleted biomarker endpoints, any 
reference to biomarker endpoints and 
exploratory endpoints
Current biomarker endpoints considered 
to not add value to the study as 
biomarkers are not expected to show a 
difference between GFF MDI and 
Placebo MDI.
2
Synopsis
Corrected that baseline for 
plethysmography endpoints will be defined 
as the pre-dose value at Visit 2 and not the 
-30 min value at Visit 2.
Corrected to align with Section 7.1.3: 
Plethysmography, which indicates that 
at Visit 2, pre-bronchodilator 
plethysmography assessments will be 
conducted. No -30 min assessment will 
be conducted at Visit 2.
3
Synopsis, Primary Efficacy Endpoint; 
Section 3.1: Primary Efficacy Endpoint; 
Section 9.2.1.1: Primary Efficacy Endpoint
Revised that RVEDVi endpoint will be 
measured 2-3 hours post-dose instead of 2 
hours post-dose
Changed to allow correct sequence in 
timing for the MRI 
4
Synopsis, Secondary Efficacy Endpoints 
(Measured using MRI at 2 hours post-dose 
on Day 8); Section 3.2: Secondary Efficacy 
Endpoints (Measured using MRI at 2 hours 
post-dose on Day 8); Section 9.2.1.2: 
Secondary Efficacy Endpoints (Measured 
using MRI at 2 hours post-dose on Day 8) 
Changed to allow site flexibility in 
timing for the MRI assessments
Added to clarify that the PVR 
measurement is measured at a different 
time point than the timeframe the title 
indicates secondary endpoints will be 
measured.


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Revised that the MRI endpoints will be 
measured 2-3 hours post-dose instead of 2 
hours post-dose on Day 8
Indicated that the PVR will be measured at 
30 minutes and 60 minutes post-dose
5
Synopsis, Other Efficacy Endpoints 
(Measured at 2 hours post-dose on Day 8 
unless otherwise noted); Section 3.3: Other 
Efficacy Endpoints (Measured at 2 hours 
post-dose on Day 8 unless otherwise 
noted); Section 9.2.1.3: Other Efficacy 
Endpoints (Measured at 2 hours post-dose 
on Day 8 unless otherwise noted)
Deleted “(Measured at 2 hours post-dose 
on Day 8 unless otherwise noted)” 
Revised that the plethysmography will be 
measured 1-2 hours post-dose instead of 2 
hours post-dose on Day 8 and the ICG 
assessments will occur 30 and 60 minutes 
post-dose instead of 2 hours on Day 8; 
Revised that MRI assessments will occur at 
2-3 hours post-dose on Day 8 instead of 2 
hours post-dose and that post-dose FEV1,
IC, and FVC will be measured at 1 hour 
post-dose on Day 8 instead of 2 hours post-
dose
Deleted under ICG assessments (Under 
second bullet) that the PVR will be 
measured at morning pre-dose trough and 
each post-dose time point (first sub-bullet);
Deleted PVR on Day 1 (second sub-bullet)
and Cardiac output on Day 1 (third sub-
bullet) as endpoints. This leaves only one 
endpoint under “other efficacy endpoints” 
for ICG endpoints.
Deleted timing as each set of 
assessments has been changed to a 
different time post-dose
Changed timings to allow site flexibility 
in timing for the plethysmography, ICG,   
MRI, and spirometry assessments
Deleted “Morning pre-dose trough for 
PVR” as an other efficacy endpoint and 
put as a secondary endpoint as post-dose 
PVR measurements are also secondary 
endpoints; Deleted “and each post-dose 
time point for PVR” as an other efficacy 
endpoint as this is already covered under 
the secondary endpoint of “ Pulmonary 
Vascular Resistance (PVR) by ICG”; 
Deleted PVR on Day 1 and Cardiac 
output on Day 1 as endpoints as there 
are no post-dose assessments on Day 1
6
Section 1: Introduction and Study 
Rationale
Updated the GOLD reference from 2014 to 
2016.
Updated as new GOLD strategy was 
published in 2016.


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7
Section 1: Introduction and Rationale
Updated section to include Utibron™ 
Neohaler® and Stiolto™ Respimat® to 
fixed-dose LAMA/LABA combination 
products 
For completeness, added all of the 
LAMA/LABA fixed-dose combination 
products commercially available.
8
Section 1: Introduction and Rationale
Updated section to indicate that Pearl has 
developed GFF MDI as a combination 
product instead of is developing this 
product. 
Updated as GFF MDI is now an 
approved product and no longer in 
development stage.
9
Section 4.1: Overall Study Design and Plan
Corrected wording under Screening Period 
to indicate that subjects must meet 
spirometry criteria of an FEV1/FVC ratio 
of <0.70 and FEV1 of <65% at Visit 1 to 
qualify for study enrollment. 
Corrected to reflect actual criterion for 
spirometry at Visit 1.
10
Section 4.1: Overall Study Design and 
Plan; Section 5.4.1: Prohibited COPD 
Medications and Required Washout Prior 
to Visit 2
Corrected to indicate that Ventolin HFA 
(albuterol sulfate Inhalation Aerosol) will 
be administered PRN instead of QID 
Corrected to indicate correct dosing 
regimen for Ventolin HFA.
11
Section 4.1: Overall Study Design and Plan 
(General Considerations for Treatment 
Visits 3 through Visit 6 (in-clinic): 
Deleted wording in bullet #7 that subjects 
must return to the clinic “but no later than 
10:00 AM” and changed that in-clinic 
dosing time is before “approximately 11:00 
AM”
To allow the subjects more flexibility 
with visit scheduling and to allow the 
site more flexibility with in-clinic dosing 
time to ensure all pre-dose assessments 
can be performed in a timely manner.
12
Section 4.1: Overall Study Design and 
Plan, Figure 1 Study Flow Diagram
Deleted Peak FEV1 at Visit 2 under 
Screening/Baseline Assessments
Deleted Day 1 IC pre- and post-dose and 
Deleted as these assessments are not 
being collected 


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deleted Biomarker assessments under 
Assessments During Treatment
13
Section 5.5.1: Illicit Drugs
Added text to reflect that the subject will 
be discontinued from the study if any illicit 
drugs or drugs of abuse are used by the 
subject during the study.
Clarification that subjects who use illicit 
drugs or drugs of abuse will be 
discontinued from the study.
14
Section 5.6: Smoking Status
Added text under the Note to clarify that 
electronic cigarettes will not be used for 
the calculation of pack-year history 
Clarification as only cigarettes can be 
used for calculation of pack-year 
history.
15
Section 5.7: Reasons for Discontinuation
Under last Note in this section, added 
Utibron™ Neohaler® to the list of recently 
marketed LABA/LAMA products
For completeness, to include the entire 
list of recently marketed LABA/LAMA 
products
16
Section 7: Study Procedures
Indicated that assessments should be 
performed at the same time for a given 
subject across each treatment period. 
Clarified order of pre-dose assessments at 
Visit 3 and Visit 5 and order of pre-and 
post-dose assessments at Visit 4 and Visit 
6.
To ensure assessments are performed at 
a consistent time pre-and post-dose to 
avoid variability in response    
Based on revised timing for some 
assessments, the order was changed to 
align with these timings.
17
Section 7.1.1: Pulmonary Function Tests 
(Spirometry) 
Under the Note, added that spirometry will 
be conducted at Visit 1.
Revised timing of post-dose spirometry 
assessment from 2 hours to 1 hour at Visit 
4 and Visit 6. 
For completeness, added Visit 1 to the 
list of visits at which spirometry 
assessments are obtained.
Revised timing to allow for site 
flexibility to allow all post-dose 
assessments to be conducted in a timely 
manner. 
18
Section 7.1.1.2: Characterization of 
Reversibility
Added that reversibility to Ventolin HFA 
Clarification to add Atrovent HFA since 
reversibility to be obtained after 
administration of both Ventolin HFA 


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and Atrovent HFA will be determined 
following administration of both Ventolin 
HFA “and Atrovent HFA”
and Atrovent HFA 
19
Section 7.1.2 Inspiratory Capacity (IC) 
Revised timing of IC assessment at Visit 4 
and Visit 6 from 2 hours to 1 hour.
Revised timing to allow for site 
flexibility to ensure assessments are 
conducted in a timely manner
20
Section 7.1.3: Plethysmography
Revised plethysmography assessment at 
Visit 4 and Visit 6 from 30 minutes prior to 
study drug administration to 60 minutes
prior to study drug administration. 
Revised timing of Visit 4 and Visit 6 post-
dose plethysmography assessment from 2 
hours to 1-2 hours.
Revised timing so that plethysmography 
assessment would not occur at the same 
time as the 30 minute pre-dose 
spirometry assessment to allow site 
flexibility to obtain all pre-dose 
assessments.
Revised timing to allow for site 
flexibility to ensure all post-dose 
assessments are conducted in a timely 
manner.
21
Section 7.1.4: Magnetic Resonance 
Imaging
Added that MRI at Visit 3 will be 
conducted on the same day and deleted the 
text indicating that the MRI will be 
conducted 30 minutes prior to study drug 
administration.  Text now says MRI will be 
conducted prior to study drug 
administration. 
Revised timing of post-dose MRI 
assessment at Visit 4 and Visit 6 from 2 
hours to 2-3 hours.
Clarified that the MRI must be 
performed on the same day as the visit 
and removed any timing requirement for 
MRI assessment so the MRI would not 
have to be performed at the same time as 
the 30 minute pre-dose spirometry 
assessment. 
To allow site flexibility to perform all 
post-dose assessments in a timely 
manner and to not perform the MRI 
assessment any longer than 3 hours post-
dose so as not to significantly interfere 
with peak bronchodilator effect of GFF 
when the MRI is conducted. 
22
Section 7.1.5: Impedence Cardiography 
(ICG)
Revised that ICG will not be conducted 60 
minutes prior to administration of Ventolin 
HFA and Atrovent HFA to just indicate 
timing as prior to administration of these 
agents. 
To allow site flexibility so that all Visit 
2 pre-dose assessments will be 
conducted in a timely manner
To allow site more flexibility to 


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Changed timing of Visit 3 and Visit 5 ICG 
assessment from 60 minutes prior to study 
drug administration to just prior to study 
drug administration.
Changed timing of Visit 4 and Visit 6 ICG 
assessment from 60 minutes prior to study 
drug administration to prior to study drug 
administration and removed 2 hour post-
dose ICG assessment.
complete all pre-dose assessments in a 
timely manner. 
To allow site more flexibility to 
complete all pre- and post-dose 
assessments in a timely manner.  
23
Section 7.2.2.: Vital Sign Measurements
Clarified that at all visits (Visit 1 through 
Visit 6) , not just Visit 2, that a single vital 
sign measurement will be obtained prior to 
study drug administration and following 
completion of the last assessment of the 
visit if clinically indicated. 
Removed language that at Visits 3 to 6 a 
single vital sign measurement will be 
obtained prior to study drug administration 
and following completion of the last 
assessment of the visit. 
To provide consistency across visits 
when vital signs will be obtained.
24
Section 7.2.3: 12-Lead Electrocardiogram
Added that ECG assessments should occur 
prior to spirometry assessments.
For Visit 3, removed the within 60 minutes 
timing prior to study drug administration 
for the ECG assessment.  
For Visit 5, removed the within 30 minutes 
timing prior to study drug administration 
for the ECG assessment.
To minimize any effect of spirometry 
may have on heart rate, indicated that 
ECG should occur prior to spirometry 
assessments. 
To allow the site flexibility to obtain all 
pre-dose assessments in a timely 
manner.
25
Section 7.3.12: Use of Steroids during the 
Trial
Deleted language indicating use of 
corticosteroids for the management of 
COPD is not a reason for early termination 
and language regarding management of 
subjects’ spirometry assessments if they 
have taken corticosteroids within 14 days 
Deleted as not applicable as per Section 
5.7.1: Reasons for Discontinuation, 
subjects who suffer a moderate or severe 
COPD exacerbation will be discontinued 
from the study.


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of a scheduled visit.
26
Section 8: Study Activities, Table 8.1 
Schedule of Events 
Deleted Biomarker Sample Collection
Not applicable as samples for 
biomarkers will no longer be collected 
in this study
27
Section 8: Study Activities, Table 8-2
Rearranged order of assessments, deleted 
spirometry assessment at -30 minutes pre-
dosing and 30 minutes post-dosing at Visit 
1, changed superscripts to indicate if an 
assessment was timed or not as applicable.  
Revised Note under Table 8-2
Changed order of assessments to reflect 
the order in which the assessments will 
be performed; deleted timings for 
spirometry at Visit 1 as there is no 
dosing at Visit 1, indicated the correct 
superscripts depending on whether an 
assessment was timed or not. 
Revised Note to reflect the correct order 
in which assessments should be 
performed. 
28
Section 8: Study Activities, Table 8-3
Rearranged order of assessments and 
changed timing of some assessments to be 
consistent with timings in Section 7.
Revised footnote “f” to indicate new MRI 
timing post-dose at Visit 4 and Visit 6. 
Revised footnote “g” to indicate new post-
dose plethysmography timing at Visit 4 
and Visit 6.  
Revised Note under Table 8-3
Changed order of assessments to reflect 
the order in which the assessments will 
be performed. Revised timings of some 
assessments to allow pre-dose 
assessments to be performed in a timely 
manner and to allow post-dose 
assessments at Visit 4 and Visit 6 to 
occur at a time as to not compromise the 
MRI assessment timing.
Revised footnotes for clarification of 
Visit 4 and Visit 6 MRI and 
plethysmography post-dose timings. 
Revised Note to reflect the correct order 
in which assessments should be 
performed.
29
Section 9.3.1.1: Primary Efficacy Analysis; 
Section 9.3.1.2:  Secondary Efficacy 
Analysis
Revised that the baseline value for 
RVEDVi and secondary MRI endpoints 
will use the value from Visit 3 instead of 
Visit 4
Correction as pre-dose MRI only 
performed at Visit 3


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30
Section 9.3.1.2: Secondary Efficacy 
Analysis
Added sentence “In addition, since there 
are two responses (30- and 60-min post-
dose) per period for PVR, an unstructured 
covariance matrix will be fit to the repeated 
measures within a subject-period for this 
endpoint.
To improve the clarity of the modeling
31
Section 9.3.1.3: Other Efficacy Analysis
Added sentence “For the ICG endpoint of 
change in right ventricular stroke volume, 
an additional unstructured covariance 
matrix will be fit to the repeated measures 
within a subject period.” 
Indicated that the baseline for the 
plethysmography endpoints will use the 
pre-bronchodilator value at Visit 2 instead 
of the -30 min value at Visit 2.
Added text :”For spirometry endpoints, the 
mean of the -60 and -30 minute values for 
each visit will be obtained prior to 
averaging across visits.” 
To improve the clarity of the modeling
Correction as plethysmography is not a 
timed assessment at Visit 2.
Clarification 
32
Former Section 9.3.2 Exploratory Analysis 
Deleted text regarding analysis of 
biomarker endpoints
Not applicable as biomarker endpoints 
have been removed 
33
Minor typographical errors were addressed 
but not captured as individual items in the 
summary of changes 
To improve readability


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SYNOPSIS 
Sponsor:
Pearl Therapeutics, Inc. (“Pearl”)
 
 
Names of Finished Products:
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol, PT003;  
Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI)
Placebo for GFF MDI
Name of Active Ingredients:
Glycopyrronium and Formoterol Fumarate
Study Title:
A Randomized, Phase IIIb, Two-period , Double-blind, Two-treatment, Chronic-dosing (7 
Days), Single-center Crossover Study to Evaluate the Treatment Effect of PT003 on 
Cardiovascular Hemodynamics in Subjects With Moderate to Severe Chronic Obstructive 
Pulmonary Disease, Compared with Placebo 
Study Number:  PT003017-02
Study Phase: IIIb
Primary Objective:
x
To assess the effect of GFF MDI on cardiovascular hemodynamics following chronic 
dosing (7 days) in subjects with moderate to severe COPD
Secondary Objectives:
x
To assess the effect of GFF MDI on pulmonary hemodynamics following  
chronic dosing (7 days) 
x
To assess the effect of GFF MDI on lung function following chronic dosing  
(7 days)
Safety Objective:
x
To assess the safety of GFF MDI based on adverse events (AEs), vital sign 
measurements, electrocardiograms (ECGs), and clinical laboratory evaluations


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Study Design:
This is a randomized, two-period, double-blind, two-treatment, chronic-dosing (7 days) 
single-center, crossover study to evaluate the treatment effect of GFF MDI (PT003) 
compared with Placebo MDI on cardiovascular hemodynamics following chronic dosing (7 
days) in subjects with moderate to severe chronic obstructive pulmonary disease (COPD). 
It is planned that approximately 40 subjects will be randomized to provide approximately 
32 study completers. 
Subjects will undergo a Screening Period of 7 to 28 days in duration. During the Screening 
Period, subjects that are receiving an inhaled corticosteroid (ICS)/long acting E2-agonist 
(LABA) will discontinue the ICS/LABA, but will continue the ICS component for the 
duration of the study.  Similarly, subjects treated with an ICS as part of their inhaled 
maintenance therapy will also be permitted to continue their ICS for the duration of the 
study.
All subjects will discontinue their previously prescribed inhaled bronchodilators and switch
to Sponsor-provided Atrovent® HFA MDI administered four times daily (QID) as COPD 
maintenance therapy during the Screening Period and during the Washout Period of the 
study. Sponsor-provided Ventolin® HFA (albuterol sulfate inhalation aerosol) administered 
as needed for control of symptoms will be provided throughout the study. At 
randomization subjects will discontinue Atrovent HFA, but will be permitted to use their 
ICS and sponsor- provided rescue inhaler (albuterol sulfate inhalation aerosol) throughout 
the study.
Subjects that meet all other entry criteria but are using certain prohibited COPD
medications must discontinue the use of prohibited medications at Visit 1 (Screening). 
Prohibited COPD medications include, but are not limited to oraOȕ2-agonists, LABAs,
long-acting muscarinic agonists(LAMA), LABA/LAMA, ICS/LABA combination 
products, cromoglycate or nedocromil inhalers, leukotriene antagonists [e.g., zafirlukast, 
montelukast, zileuton], or tiotropium [Spiriva], aclidinium [Tudorza™], and umeclidinium 
[Incruse® Ellipta®]. The use of these medications is prohibited throughout the screening 
period and the duration of the study. 
Subjects will be issued and trained on the use of the Subject Diary at Visit 1 (Screening) 
and will be instructed to collect practice data during the Screening Period (between Visit 1 
and Visit 3). Subject Diary compliance will be reviewed at Visit 3, and the subject will be 
retrained if necessary.
All subjects will be administered both GFF MDI and Placebo MDI in separate treatment 
periods. Enrollment into the active period of the study will be stratified by severity of 
disease such that half of the subjects will have moderate COPD and half will have severe 
COPD as categorized by post-bronchodilator FEV1 -<65% for moderate and 30% -
<50% for severe). The entire study period is scheduled to take approximately 12 weeks for 
each individual subject. The study is anticipated to run for approximately 6 months and 
duration should be approximately 12 months. 


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Study Population:
It is planned that approximately 40 subjects with moderate to severe COPD will be 
randomized to provide an estimated 32 subjects to complete the study.
Product, Dose, and Mode of Administration:
Investigational materials will be provided by Pearl Therapeutics (Pearl), as shown 
below:
Product Name and Dose
Product Strength
Dosage Form/
Fill Count
Administration
Study Medications
GFF MDI (PT003)
14.4/9.6 μg ex-actuator
7.2/4.8 μg per actuation
MDI/
120 inhalations
Taken as 
2 inhalations BID
Open-Label Products
Albuterol Sulfate inhalation 
aerosol 90 μga
ex-actuator
Ventolin® HFA
HFA inhalation aerosol. Albuterol 
sulfate inhalation aerosol.  Each 
inhalation contains 108 ȝJ
corresponding to 90 μg albuterol 
base from the mouthpiece.
MDI/
60 or 200 
actuations
Taken as directed
Supplies are open-
label 
Ipratropium bromide HFA 
inhalation aerosol 34 ȝJb
ex-actuator
Atrovent® HFA. 
Ipratropium bromide HFA. Each 
inhalation contains 17 ȝJSHU
actuation.
MDI/
200 actuations
Taken as 
2 inhalations QID 
Supplies are open-
label 
Placebo
Placebo MDIc
Formulation does not contain active 
ingredient
MDI
120 inhalations
Taken as two 
inhalations 
BID
Abbreviations: BID=twice daily; GFF MDI= Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; 
HFA=hydrofluoroalkane; MDI=Metered Dose Inhaler; QID=four times daily; US=United States
a. The Sponsor will provide Ventolin HFA for reversibility testing during Screening and as rescue medication throughout the 
study.
b. The Sponsor will provide Atrovent HFA for reversibility testing during Screening and as COPD maintenance medication during
the Screening Period and Washout Period.  
c. Placebo MDI will be used for training purposes and also administered as a randomized treatment. All placebos are created by
Pearl in the image of the active test product, with no active moieties.     


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Duration of Treatment:
It is planned that each subject will receive study treatment over 2 Treatment Periods for 1 
week duration each.  It is anticipated that the entire study will take approximately 12 weeks 
for each individual subject from the time of Screening.
All efficacy assessments will be compared to a change from baseline. Baseline for Magnetic 
Resonance Imaging (MRI) will be defined as the pre-dose value at Visit 3. Baseline for the 
plethysmography endpoints will be defined as the pre-bronchodilator value at Visit 2. 
Baseline for the Impedance Cardiography (ICG) and spirometry endpoints will be defined 
as the average of the subject values obtained pre-dose on Day 1 of each Treatment Period 
(average of Visit 3 and Visit 5 pre-dose).  The first day of treatment in each Treatment 
Period is Day 1. Each Treatment Period is planned to be 7 days in duration occurring 
between the first and last dose which will correspond to 8 calendar days. Therefore, 
assessments collected on Day 8 will occur following 7 days of treatment.
Primary Efficacy Endpoint: 
x
Right Ventricular End Diastolic Volume Index (RVEDVi) measured at 2-3 hours post-
dose on Day 8
Secondary Efficacy Endpoints (Measured using MRI at 2-3 hours post-dose on Day 8 
unless otherwise noted):
x
Aortic left ventricular stroke volume [LVSV] 
x
Right Ventricular Stroke Volume (RVSV), phase contrast from pulmonic valve 
x
Pulmonary Artery Velocity 
x
Left Ventricular End Diastolic Volume Index (LVEDVi) 
x
Cardiac Output 
x
Morning pre-dose trough and post-dose Pulmonary Vascular Resistance (PVR) by ICG 
(Measured at 30 minutes and 60 minutes post-dose)
x
Pulmonary artery/Aortic diameter ratio (PA:A) 
x
Left Atrial End Diastolic Volume (LAEDV) 
x
Left Atrial End Systolic Volume (LAESV) 
x
Left Atrial Ejection Fraction (LAEF) 
x
Left Ventricular End Systolic Volume Index (LVESVi) 
x
Right Ventricular End Systolic Volume Index (RVESVi)
x
Pulsatility Index Aorta (PIAo)
x
Pulmonary Artery Pulsatility Index (PAPi)


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Other Efficacy Endpoints 
x
Plethysmography (Measured 1-2 hours post-dose)
o
Total airway resistance (Raw)
o
Specific airway conductance (sGaw)
o
Total lung capacity (TLC)
o
Residual volume (RV)
o
Functional residual capacity (FRC)
o
RV/total lung capacity (RV/TLC)
o
Diffusing capacity for carbon monoxide (DLCO)
o
Inspiratory Capacity (IC)
x
Impedance Cardiography (Measured at 30 and 60 minutes post-dose) 
o
Change in right ventricular stroke volume
x
Magnetic Resonance Imaging (Measured 2-3 hours post-dose) 
o
Change in right ventricular ejection fraction (RVEF) 
o
Change in left ventricular ejection fraction (LVEF) 
o
Pulmonary arterial dispensability 
o
Pulmonary Vascular Volume
o
Right Atrial End Diastolic Volume (RAEDV)
o
Right Atrial End Systolic Volume (RAESV)
o
Right Atrial Ejection Fraction (RAEF)
x
Spirometry
o
Morning pre-dose trough FEV1  
o
Morning pre-dose trough IC
o
1-hour post-dose FEV1
o
1-hour post-dose IC  
o
Morning pre-dose trough and 1-hour post-dose FVC 
Safety Endpoints:
x
Adverse events (AEs)
x
12-lead electrocardiogram (ECG) 
x
Clinical laboratory testing
x
Vital sign measurements
Statistical Methods: 
Primary Efficacy Analysis: 
A mixed model will be used to evaluate the difference between treatments in the change 
from baseline in right ventricular end diastolic volume indexed to body surface area 
(RVEDVi). Baseline will use the value from Visit 3 obtained prior to the first dosing of 
Treatment Period 1. The model will include adjustment for baseline, period, and treatment. 
Sequence will only be included in the model if found to be significant (p<0.10). Subject 
will be treated as a random effect in order to model within subject correlation across the two 


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periods. Point estimates and 95% confidence intervals for the difference between GFF MDI 
and Placebo MDI will be produced.
Sample Size: 
Based on a two-period, two-treatment crossover study comparing Breo® Ellipta® versus 
placebo after cardiac MRI, the within-subject SD for the change from baseline in RVEDVi 
was estimated to be 7.11 mL/m2.  Assuming that 90% of the randomized subjects will 
complete the trial, the study has approximately 90% probability to demonstrate a difference 
of 5.59 mL/m2 in RVEDVi.
Safety Analyses:
Safety analyses will be based on the frequencies of adverse events (AEs).
Date of Protocol: 14 October 2015
Date of Protocol Amendment 01 (Version 2.0): 04 February 2016
Date of Protocol Amendment 02 (Version 3.0) 26 September 2016


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TABLE OF CONTENTS
SUMMARY OF CHANGES TO AMENDED PROTOCOL VERSION 2.0, DATED 04
FEBRUARY 2016 FOR VERSION 3.0............................................................................2 
SYNOPSIS...............................................................................................................................10 
TABLE OF CONTENTS.........................................................................................................16 
LIST OF IN-TEXT TABLES ..................................................................................................20 
LIST OF IN-TEXT FIGURES.................................................................................................20 
LIST OF APPENDICES..........................................................................................................20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................21 
TRADEMARK INFORMATION ...........................................................................................23 
1 
INTRODUCTION AND STUDY RATIONALE ...........................................................24 
1.1 
Study Rationale......................................................................................................26 
2 
STUDY OBJECTIVES....................................................................................................27 
2.1 
Primary Objective..................................................................................................27 
2.2 
Secondary Objectives.............................................................................................27 
2.3 
Safety Objective.....................................................................................................27 
3 
STUDY ENDPOINTS.....................................................................................................28 
3.1 
Primary Efficacy Endpoint ....................................................................................28 
3.2 
Secondary Efficacy Endpoints (Measured using MRI at 2-3 hours post-dose 
on Day 8 unless otherwise noted)..........................................................................28 
3.3 
Other Efficacy Endpoints.......................................................................................28 
3.4 
Safety Endpoints....................................................................................................29 
4 
INVESTIGATIONAL PLAN..........................................................................................30 
4.1 
Overall Study Design and Plan..............................................................................30 
4.2 
Rationale of Study Design .....................................................................................35 
4.3 
Rationale of Dose/Regimen, Duration of Treatment, and Placebo Arm ...............35 
5 
STUDY POPULATION SELECTION, PRIOR AND CONCOMITANT 
MEDICATIONS AND WITHDRAWAL CRITERIA....................................................36 
5.1 
Inclusion Criteria....................................................................................................36 
5.2 
Exclusion Criteria ..................................................................................................37 
5.3 
Subject Identification.............................................................................................41 
5.4 
Prior, Concomitant, and Prohibited Medications...................................................41 
5.4.1 
Prohibited COPD Medications and Required Washout Prior to Visit 2......41 
5.4.2 
Other Prohibited Medications......................................................................43 
5.5 
Other Restrictions, Illicit Drugs or Drugs of Abuse ..............................................46 
5.5.1 
Illicit Drugs ..................................................................................................46 
5.5.2 
Dietary Restrictions .....................................................................................46 
5.6 
Smoking Status ......................................................................................................46 


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5.7 
Reasons and Procedures for Early Termination from the Study............................46 
5.7.1 
Reasons for Discontinuation........................................................................46 
6 
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES....................................................................................................49 
6.1 
Subject Information ...............................................................................................49 
6.2 
Product Descriptions and Primary Packaging and Labeling Information .............49 
6.3 
Primary Packaging and Labeling Information.......................................................50 
6.4 
Secondary Packaging and Labeling Information...................................................51 
6.5 
Emergency Unblinding of Treatment Assignment ................................................51 
6.6 
Storage Requirements ............................................................................................52 
6.7 
Instructions for Preparation of Treatments for Administration and Dispensing....52 
6.7.1 
GFF MDI and Placebo MDI ........................................................................52 
6.7.2 
Atrovent® HFA (Ipratropium Bromide) ......................................................52 
6.7.3 
Ventolin HFA® (Albuterol Sulfate) .............................................................52 
6.8 
Drug Accountability/Return of Clinical Supplies..................................................53 
7 
STUDY PROCEDURES .................................................................................................54 
7.1 
Efficacy Assessments.............................................................................................54 
7.1.1 
Pulmonary Function Tests (Spirometry)......................................................54 
7.1.1.1 
FEV1 Baseline Stability Criteria........................................................55 
7.1.1.2 
Characterization of Reversibility.......................................................55 
7.1.2 
Inspiratory Capacity (IC).............................................................................56 
7.1.3 
Plethysmography..........................................................................................56 
7.1.4 
Magnetic Resonance Imaging (MRI)...........................................................57 
7.1.5 
Impedance Cardiography (ICG) ..................................................................58 
7.1.6 
Subject Diary Data Collection .....................................................................58 
7.1.7 
Rescue Ventolin HFA Use...........................................................................59 
7.1.8 
Medication Compliance...............................................................................59 
7.1.9 
Chronic Obstructive Pulmonary Disease Assessment Test (CAT)..............59 
7.2 
Safety Assessments................................................................................................61 
7.2.1 
Medical/Surgical History and Physical Examination ..................................61 
7.2.2 
Vital Sign Measurements.............................................................................61 
7.2.3 
12-Lead Electrocardiogram .........................................................................61 
7.2.4 
Clinical Laboratory Tests.............................................................................62 
7.2.4.1 
Pregnancy Test...................................................................................63 
7.3 
Adverse Events ......................................................................................................64 
7.3.1 
Performing Adverse Events Assessments....................................................64 
7.3.2 
Adverse Event Definitions...........................................................................64 
7.3.3 
Pre-Randomization Adverse Events ............................................................65 
7.3.4 
Severity ........................................................................................................65 


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7.3.5 
Relationship .................................................................................................65 
7.3.6 
Chronic Obstructive Pulmonary Disease Exacerbations .............................66 
7.3.7 
Adverse Events of Special Interest ..............................................................66 
7.3.8 
Clinical Laboratory Adverse Events............................................................66 
7.3.9 
Serious Adverse Events ...............................................................................67 
7.3.9.1 
Reporting Serious Adverse Events ....................................................67 
7.3.9.2 
Supplemental Investigations of SAEs................................................68 
7.3.9.3 
Post-Study Follow-Up of Adverse Events.........................................68 
7.3.9.4 
Notification of Post-Study Serious Adverse Events..........................68 
7.3.9.5 
Investigational Research Board/Independent Ethics Committee 
Notification of Serious Adverse Events.............................................68 
7.3.9.6 
Health Authority Safety Reports........................................................68 
7.3.10 
Overdose ......................................................................................................69 
7.3.11 
Pregnancy.....................................................................................................69 
7.3.12 
Use of Steroids during the Trial...................................................................69 
7.4 
Termination of the Study .......................................................................................69 
8 
STUDY ACTIVITIES .....................................................................................................70 
8.1 
Visit 1 (Screening).................................................................................................75 
8.2 
Visit 2 (Screening).................................................................................................75 
8.3 
Visit 3 (Randomization/Day 1)..............................................................................76 
8.4 
Visit 4 (Day 8) .......................................................................................................77 
8.5 
Visit 5 (Day 1) .......................................................................................................78 
8.6 
Visit 6 (Day 8) .......................................................................................................79 
8.7 
Unscheduled Visit/Premature Discontinuation Visit.............................................80 
8.8 
Follow-Up Telephone Call ....................................................................................81 
8.9 
Completion of the Study........................................................................................81 
9 
PLANNED STATISTICAL METHODS ........................................................................82 
9.1 
Introduction............................................................................................................82 
9.2 
Protocol Variables..................................................................................................82 
9.2.1 
Efficacy Endpoints.......................................................................................82 
9.2.1.1 
Primary Efficacy Endpoint ................................................................82 
9.2.1.2 
Secondary Efficacy Endpoints (Measured using MRI at 2-3 hours 
post-dose on Day 8 unless otherwise noted)......................................82 
9.2.1.3 
Other Efficacy Endpoints...................................................................83 
9.2.2 
Safety Endpoints..........................................................................................84 
9.3 
Analysis..................................................................................................................84 
9.3.1 
Efficacy Analysis.........................................................................................84 
9.3.1.1 
Primary Efficacy Analysis.................................................................84 
9.3.1.2 
Secondary Efficacy Analysis .............................................................84 
9.3.1.3 
Other Efficacy Analysis.....................................................................85 
9.3.2 
Safety Analysis ............................................................................................85 


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9.3.2.1 
Adverse Events ..................................................................................85 
9.4 
Randomization.......................................................................................................85 
9.5 
Experimental Design..............................................................................................85 
9.6 
Sample Size Consideration ....................................................................................86 
9.7 
Data Validation and Transformation .....................................................................86 
9.8 
Analysis Plan .........................................................................................................86 
9.9 
Study Populations ..................................................................................................86 
9.10 
Handling of Missing Data......................................................................................87 
9.11 
Statistical Software ................................................................................................87 
10 ADMINISTRATIVE CONSIDERATIONS....................................................................88 
10.1 
Regulatory Authority Approval .............................................................................88 
10.2 
Ethical Conduct of the Study and Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) Approval....................................................88 
10.3 
Subject Information and Consent...........................................................................88 
10.4 
Laboratory Accreditation.......................................................................................89 
10.5 
Confidentiality .......................................................................................................89 
10.5.1 
Confidentiality of Data ................................................................................89 
10.5.2 
Confidentiality of Subject/Patient Records..................................................89 
10.6 
Quality Control and Assurance..............................................................................89 
10.7 
Data Management ..................................................................................................89 
10.8 
Study Monitoring...................................................................................................90 
10.9 
Retention of Data...................................................................................................91 
10.10 Financial Disclosure...............................................................................................91 
10.11 Investigator's Final Report.....................................................................................91 
10.12 Publication Policy..................................................................................................91 
11 REFERENCE LIST .........................................................................................................92 
12 
APPENDICES ................................................................................................................97 


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LIST OF IN-TEXT TABLES
Table 5-1. 
Prohibited COPD Medications and Required Washout Periods, Prior to 
Visit 2.........................................................................................................42 
Table 5-2. 
Other Respiratory/Nasal Medications: Required Washout Periods...........43 
Table 5-3. 
Non-COPD Medications Allowed Under Certain Condition ....................44 
Table 5-4. 
Prohibited Medications..............................................................................45 
Table 6-1. 
Product Descriptions..................................................................................50 
Table 6-2. 
Description of Boxes..................................................................................51 
Table 7-1 
Clinical Laboratory Tests...........................................................................63 
Table 8.1 
Schedule of Events.....................................................................................71 
Table 8.2 
Timed Assessments at Screening Visit 1 and Visit 2 ................................73 
Table 8.3 
Timed Assessments at Treatment Visits 3 and 5 (Day 1) and Visits 4 
and 6 (Day 8) .............................................................................................74 
LIST OF IN-TEXT FIGURES
Figure 1. 
Study Flow Diagram..................................................................................34 
Figure 2. 
Indicator at Top of Canister.....................................................................106 
Figure 3. 
Wash Actuator through Top of Actuator .................................................107 
Figure 4. 
Wash Actuator through Mouthpiece........................................................108 
Figure 5. 
Metered Dose Inhaler Parts......................................................................109 
LIST OF APPENDICES
Appendix 1 
Spirometry Performance Recommendations ............................................98 
Appendix 2 
Spirometry Assessment Criteria .............................................................104 
Appendix 3 
Subject Instructions for Use of GFF and Placebo MDI..........................106 
Appendix 4 
Instructions for Use of Atrovent HFA Inhalation Aerosol Device..........110 
Appendix 5 
Instructions for Use of Ventolin HFA Inhaler........................................113 
Appendix 6 
COPD Assessment Test..........................................................................118 
Appendix 7 
Dose Indicator Display Reading Instructions .........................................119 
Appendix 8 
Sponsor Signatory...................................................................................120 
Appendix 9 
Investigator’s Agreement and Signature Page.........................................121 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
Adverse event
BID
bis in die, Twice Daily
BP
Blood Pressure
BPM
Beats Per Minute
CAT
COPD Assessment Test
CFR
Code of Federal Regulations
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
ECG
Electrocardiogram
eg
Exempli gratia, for example
FDA
Food and Drug Administration
FF MDI
Formoterol Fumarate Metered Dose Inhaler
FRC
Functional Residual Capacity 
GCP
Good Clinical Practice
GFF MDI
Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler 
GP MDI
Glycopyrronium Metered Dose Inhaler 
HFA
Hydrofluoroalkane
HR
Heart Rate
IB
Investigator’s Brochure
IC
Inspiratory Capacity
ICF
Informed Consent Form
ICG
Impedance Cardiography   
ICS
Inhaled Corticosteroid
ie
Id est, that is
IRB
Institutional Review Board
ITT
Intention-to-treat
LABA
Long-acting Beta Agonist
LAEDV
Left Atrial End Diastolic Volume


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LAEF
Left Atrial Ejection Fraction
LAESV
Left Atrial End Systolic Volume
LAMA
Long-acting Muscarinic Antagonist
LVEDV
Left Ventricular End Diastolic Volume
LVEF
Left Ventricular Ejection Volume
LVSV
Left Ventricular Stroke Volume
LVESVi
Left Ventricular End Systolic Volume Index
MDI
Metered Dose Inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
MRI
Magnetic Resonance Imaging 
Msec (ms)
Millisecond
NT-proBNP
N-terminal pro-B-type natriuretic peptide 
PFT
Pulmonary Function Test
PA:A
Pulmonary Artery/Aortic diameter ratio 
PAPi
Pulmonary Artery Pulsatility Index
PIAo
Pulsatility Index Aorta
PVR
Pulmonary Vascular Resistance
PP
Per Protocol
PRN
pro re nata, As Needed
QD
quaque die, Once Daily
QTcF
QT corrected using Fridericia’s formula (QT/(RR 1/3)
RAEDV
Right Atrial End Diastolic Volume
RAEF
Right Atrial Ejection Fraction
RAESV
Right Atrial End Systolic Volume
RV
Residual Volume 
RVEDVi
Right Ventricular End Diastolic Volume Index
RVEF
Right Ventricular Ejection Fraction 
RVESVi
Right Ventricular End Systolic Volume Index
SABA
Short-acting Beta Agonist
SAE
Serious Adverse Event


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SAP
Statistical Analysis Plan
SSRI
Selective Serotonin Reuptake Inhibitors
TLC
Total Lung Capacity 
US
United States
TRADEMARK INFORMATION
Trademarks Not Owned By Pearl
Anoro
Atrovent
Combivent
Ellipta
Neohaler
Respimat
Spiriva
Stiolto
Tudorza
Utibron
Ventolin


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1
INTRODUCTION AND STUDY RATIONALE
Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable 
disease characterized by persistent airflow limitation that is usually progressive and
associated with an enhanced chronic inflammatory response in the airways and the lung to 
noxious particles or gases. Exacerbations and co-morbidities contribute to the overall severity
in individual patients. Chronic obstructive pulmonary disease is a leading cause of morbidity
and mortality worldwide and results in significant economic and social burden that is both 
substantial and increasing. Pharmacologic therapy in COPD is used to reduce symptoms, 
reduce the frequency and severity of exacerbations, and improve health status and exercise
tolerance [Global Initiative for Chronic Obstructive Lung Disease [GOLD, 2016)].
Bronchodilator medications are central to the symptomatic management of COPD.  The 
SULQFLSDOEURQFKRGLODWRUWUHDWPHQWVDUHȕ2-agonists, anticholinergics, and methylxanthines 
used as monotherapy or in combination.  Treatment with long-acting bronchodilators is more 
convenient and more effective at producing maintained symptom relief than treatment with 
short-acting bronchodilators.
Chronic obstructive pulmonary disease (COPD) is associated with resting hyperinflation as 
a result of expiratory flow obstruction.  Although hyperinflation independently predicts 
exercise tolerance and mortality in COPD, pathophysiologic mechanisms to explain these 
findings are incompletely understood [Budweiser, 2013]. Cardiac phenotyping in COPD 
implicate a potential cardiac etiology for poor outcomes associated with hyperinflation.  
Severe emphysema is known to be associated with both decreased intrathoracic blood 
volume as well as reduced right ventricular (RV) size, suggesting hyperinflation and the 
associated increase in intrathoracic pressure may reduce RV volume through decreased RV 
preload [Jörgensen, 2007]. Gold-standard assessment of RV volume is performed using 
cardiac magnetic resonance imaging using RV end diastolic volume (RVEDV) 
[Lorenz, 1999].  In order to account for expected variances of RVEDV with body habitus, 
RVEDV is normalized to body surface area, referred to as RVEDV index (RVEDVi) 
[Chalal, 2012]. 
Treatment with combined long acting muscarinic antagonists (LAMA) and long-acting 
bronchodilators (LABA) can improve inspiratory capacity and reduce hyperinflation, 
potentially increasing pulmonary blood volume and therefore RVEDVi.  Due to the Frank-
Starling mechanism, decreasing RVEDVi will result in reduced RV stroke volume (SV) and 
cardiac output (CO), thereby resulting in multiple negative hemodynamic sequelae 
including decreased pulmonary perfusion, left ventricular (LV) filling, coronary perfusion, 
and ultimately LV forward flow.  
The direct cardiac effects of LAMA and LABA therapy suggest the potential to reverse 
these negative hemodynamic phenomena in COPD. Preclinical data from healthy canines 
indicate that acute treatment with the muscarinic antagonist glycopyrrolate increases cardiac 
index [Jacobson, 1994]. In addition, administration of the long-DFWLQJȕ2 agonist formoterol 
to explanted rat hearts increases left ventricular contractility [Watson, 2013]. Therefore, the 
improved outcomes in COPD associated with chronic LAMA/LABA therapy may be in part 
attributable to improved cardiac hemodynamics. Because improved LV forward flow should 


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parallel increases in LV preload and therefore RVEDVi, we propose to investigate the effect 
acute administration of combined Glycopyrronium and Formoterol Fumarate Inhalation 
Aerosol (GFF MDI) on RVEDVi in patients with moderate to severe COPD with evidence 
of resting hyperinflation. 
Pharmacologic therapy for COPD is used to reduce symptoms, reduce the frequency and 
severity of exacerbations, and improve health status and exercise tolerance.  Bronchodilators 
are the mainstay of pharmacologic treatment of COPD.  The principal bronchodilator
treatments are short-acting beta agonists (SABAs), long-acting beta agonists (LABAs), short
acting muscarinic antagonists, long-acting muscarinic antagonists (LAMAs) and
methylxanthines used as monotherapy or in combination.  In subjects with significant 
symptoms but low risk of exacerbations regular treatment with LABAs is more effective in 
the management of COPD than SABAs.  In subjects with a high risk of exacerbations 
regardless of the number of symptoms, a fixed combination of an inhaled 
corticosteroid/LABA or a LAMA is recommended [GOLD, 2016].
Fifteen different doses of GFF MDI have been evaluated in sixteen studies conducted by 
Pearl. The GFF MDI doses that have been studied include the following dosing 
FRPELQDWLRQVȝJȝJȝJȝJȝJȝJ
ȝJȝJȝJȝJȝJȝJȝJȝJ
DQGȝJ7KURXJKRXWWKLV3KDVH,,ESURJUDPRYHUVXEMHFWVZLWK&23'KDYH
been exposed to one or more doses of GFF MDI. GFF MDI has been evaluated in 3 Phase III 
clinical studies in patients with COPD, during the Phase III program over 1,000 subjects with 
&23'KDYHEHHQH[SRVHGWR*))0',ȝJ*))0',ȝJZDVGHPRQVWUDWHGWR
be safe and efficacious in the Phase III studies.
Currently, three fixed-dose combinations of a LABA and a LAMA are  commercially 
available Anoro ™Ellipta® [umeclidinium and vilanterol] from GlaxoSmithKline, Utibron™ 
Neohaler® from Novartis, and Stiolto™ Respimat® from Boehringer Ingelheim.  Combivent® 
[salbutamol sulfate and ipratropium bromide] from Boehringer Ingelheim is a short-acting 
fixed dose combination of a SABA and short acting muscarinic antagonist indicated for the 
treatment of COPD and is administered as two inhalations four times daily.  Published 
studies [van Noord, 2005; van Noord, 2006; Vogelmeier, 2006] have shown that the 
complementary mechanisms of action of a LABA (formoterol fumarate) and a LAMA
(tiotropium bromide) significantly improved bronchodilation in COPD subjects compared to 
the individual agents.
Pearl Therapeutics, Inc. (hereafter referred to as Pearl) has developed a combination product, 
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol (PT003, Glycopyrronium and 
Formoterol Fumarate Metered Dose Inhaler [MDI]; hereafter referred to as GFF MDI), as a 
maintenance bronchodilator treatment in subjects with COPD. Phase IIb studies were 
conducted which supported the dose selection of GFF MDI 14.4/9.6 μg BID for Phase III 
clinical studies, including this study.
Glycopyrronium is a LAMA, which exerts its bronchodilatory effect via muscarinic receptors 
located on smooth muscle cells within the trachea and bronchi. Glycopyrronium is approved 
in many countries in multiple formulations for different indications, including COPD. GP 


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MDI has been evaluated in eight studies conducted by Pearl, including a single dose, single 
center, healthy volunteer study in Australia and seven multi-center studies in subjects with 
COPD conducted in the US, Australia, and New Zealand. This program has assessed the 
VDIHW\DQGHIILFDF\RI*30',DFURVVDZLGHUDQJHRIGRVHVIURPȝJGRZQWRȝJ
Across these eight studies, approximately 350 subjects with mild to severe COPD were 
exposed to one or more doses of GP MDI. The lower end of the dose response curve has 
been adequately characterized in two chronic dose, dose-ranging studies (Studies PT001002 
and PT001003), and the findings from these two studies and the previous Phase II studies 
VXSSRUW*30',ȝJ%,'DVWKHPRVWDSSURSULDWHGRVHWREHHYDOXDWHGLQ3KDVH,,,
clinical studies. 
Formoterol fumarate is a potent and selective LABA approved in many countries worldwide
for use in asthma and COPD. When inhaled, formoterol fumarate acts locally in the lung as a 
EURQFKRGLODWRU)RUPRWHUROIXPDUDWHVWLPXODWHVȕ-adrenoreceptors in the airways, inducing 
airway smooth muscle relaxation and reducing or preventing bronchoconstriction. Although 
formoterol fumarate is classified as a LABA, it has a rapid onset of action similar to SABAs. 
Formoterol fumarate is highly potent, displays high intrinsic activity, and can result in greater 
than 80% relaxation even under induced tone [Anderson, 1993]. Studies in patients with 
COPD have demonstrated that the onset of action with formoterol fumarate is faster than 
with anticholinergic agents or salmeterol and similar to that of SABAs, such as albuterol, and 
that WKHGXUDWLRQRIDFWLRQLVKRXUV>Berger, 2008]. Five large, placebo-controlled clinical 
studies of up to 12 months in duration in nearly 2500 patients demonstrated that formoterol 
fumarate is effective and well tolerated in patients with COPD [Dahl, 2001; Rossi, 2002;
Albers, 2002; Campbell, 2005; Campbell, 2007]. 
Pearl conducted three studies to confirm dose selection and safety for FF MDI. These include 
studies: PT0050801, PT0031002, and PT003005. Results demonstrated dose proportionality 
RI))0',ȝJDQGELRHTXLYDOHQFHWR)RUDGLO,QWHUPVRIVDIHW\UHVXOWVVKRZHGQR
substantial differences between the FF MDI treatment groups to placebo or to Foradil 12 ȝJ
and there were no important trends noted for FF MDI at any dose. 
1.1
Study Rationale
The purpose of this study is to evaluate the effect of GFF MDI on Cardiovascular 
Hemodynamics following chronic dosing (7 days) in subjects with moderate to severe 
COPD.  


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2
STUDY OBJECTIVES
2.1
Primary Objective
x
To assess the effect of GFF MDI on cardiovascular hemodynamics following chronic 
dosing (7 days) in subjects with moderate to severe COPD
2.2
Secondary Objectives
x
To assess the effect of GFF MDI on pulmonary hemodynamics following 
chronic dosing (7 days) 
x
To assess the effect of GFF MDI on lung function following chronic dosing (7 days) 
2.3
Safety Objective
x
To assess the safety of GFF MDI based on adverse events (AEs), and any clinically 
relevant findings from vital sign measurements, electrocardiograms (ECGs), and clinical 
laboratory evaluations


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3
STUDY ENDPOINTS
All efficacy assessments are relative to pre-dose baseline obtained at or prior to Day 1. The 
first day of treatment in each Treatment Period is Day 1. Each Treatment Period is planned 
to be 7 days in duration occurring between the first and last dose which will correspond to 
8 calendar days. Therefore, assessments collected on Day 8 will occur following 7 days of 
treatment. 
3.1
Primary Efficacy Endpoint
x
Right Ventricular End Diastolic Volume Index (RVEDVi) measured at 2-3 hours post-
dose on Day 8
3.2
Secondary Efficacy Endpoints (Measured using MRI at 2-3 hours 
post-dose on Day 8 unless otherwise noted)
x
Aortic left ventricular stroke volume [LVSV] 
x
Right Ventricular Stroke Volume (RVSV), phase contrast from pulmonic valve 
x
Pulmonary Artery Velocity 
x
Left Ventricular End Diastolic Volume Index (LVEDVi)
x
Cardiac Output 
x
Morning pre-dose trough and post-dose Pulmonary Vascular Resistance (PVR) by ICG 
(Measured at 30 minutes and 60 minutes post-dose)
x
Pulmonary artery/Aortic diameter ratio (PA:A) 
x
Left Atrial End Diastolic Volume (LAEDV)
x
Left Atrial End Systolic Volume (LAESV)
x
Left Atrial Ejection Fraction (LAEF)
x
Left Ventricular End Systolic Volume Index (LVESVi)
x
Right Ventricular End Systolic Volume Index (RVESVi)
x
Pulsatility Index Aorta (PIAo)
x
Pulmonary Artery Pulsatility Index (PAPi)
3.3
Other Efficacy Endpoints 
x
Plethysmography (Measured 1-2 hours post-dose)
o
Total airway resistance (Raw)
o
Specific airway conductance (sGaw)
o
Total lung capacity (TLC)
o
Residual volume (RV)


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o
Functional residual capacity (FRC)
o
RV/total lung capacity (RV/TLC)
o
Diffusing capacity for carbon monoxide (DLCO)
o
Inspiratory Capacity (IC)
x
Impedance Cardiography (Measured 30 and 60 minutes post-dose) 
o
Change in right ventricular stroke volume  
x
Magnetic Resonance Imaging (Measured 2-3 hours post-dose) 
o
Change in right ventricular ejection fraction (RVEF) 
o
Change in left ventricular ejection fraction (LVEF) 
o
Pulmonary arterial dispensability 
o
Pulmonary Vascular Volume
o
Right Atrial End Diastolic Volume (RAEDV)
o
Right Atrial End Systolic Volume (RAESV)
o
Right Atrial Ejection Fraction (RAEF)
x
Spirometry
o
Morning pre-dose trough FEV1
o
Morning pre-dose trough IC
o
1-hour post-dose FEV1
o
1-hour post-dose IC  
o
Morning pre-dose trough and 1-hour post-dose FVC 
3.4
Safety Endpoints
x
Adverse events (AEs)
x
12-lead electrocardiograms (ECGs) 
x
Clinical laboratory testing
x
Vital sign measurements


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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is a randomized, double-blind, placebo-controlled, single-center, chronic-dosing 
(7 days), two-period,  two-treatment, crossover study to evaluate the treatment effect of GFF 
MDI compared to Placebo MDI on cardiovascular hemodynamics following chronic dosing 
(7 days) in subjects with moderate to severe COPD. 
It is planned to randomize approximately 40 subjects to provide approximately 32 study 
completers. 
All subjects will be administered GFF MDI and Placebo MDI in randomized order
(see Figure 1). Enrollment into the active period of the study will be stratified by severity of 
disease such that half of the subjects will have moderate COPD and half will have severe 
COPD as categorized by post-bronchodilator FEV1 -<65% for moderate and 30% -
<50% for severe).The entire study period is scheduled to take approximately 12 weeks for 
each individual subject. The study is anticipated to run for approximately 6 months and 
should not exceed 12 months. 
Screening Period:
The Screening Period will be comprised of 2 study visits. 
At Visit 1 (Screening), all subjects are to sign an informed consent form prior to the conduct
of any screening assessments.  The Investigator will obtain a medical history including 
specific cardiovascular history, COPD exacerbations within the last year, clinical laboratory 
tests, physical examination, pregnancy test and any required documentation in order to 
determine eligibility for participation (i.e., inclusion/exclusion criteria). Subjects must meet
spirometry criteria of an FEV1/FVC ratio of <0.70 and FEV1 of <65% predicted normal value 
at Visit 1 to qualify for study enrollment.  Re-screening is not allowed for subjects who do 
not meet the spirometry criteria at Visit 1.  Providing the subject meets the eligibility criteria, 
the Investigator or designee will review current COPD medications and, if necessary, will 
make arrangements to adjust the prohibited COPD therapy to protocol-allowable COPD 
therapy as described below. An ECG will also be conducted.
Subjects will undergo a Screening Period of 7 to 28 days in duration. During the Screening 
Period, subjects that are receiving an ICS/LABA will discontinue the ICS/LABA, but will 
continue an equivalent dose of the ICS component for the duration of the study. 
Similarly, subjects treated with an ICS as part of their inhaled maintenance therapy will also 
be permitted to continue their ICS for the duration of the study.
All subjects will discontinue their previously prescribed inhaled bronchodilators and switch 
to Sponsor-provided Atrovent HFA administered four times daily (QID) as COPD 
maintenance therapy during the Screening Period and during the Washout Period of the 
study. All subjects will be provided with sponsor-provided Ventolin HFA (albuterol sulfate 


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Inhalation Aerosol) administered PRN as needed for control of symptoms throughout the 
study. At randomization subjects will discontinue Atrovent HFA, but will be permitted to use 
their ICS and sponsor- provided rescue albuterol. 
At Visit 1 (Screening), subjects will be trained on and issued a Diary. Subjects will be 
instructed to collect practice data during the screening period (between Visit 1 and Visit 3). 
They are required to maintain a daily record of their study drug dosing, rescue medication 
use, and collection of COPD symptoms. Subjects that fail to demonstrate proper Diary 
compliance prior to Randomization (Visit 3) may not be enrolled to the study.
To allow for an adequate washout of previous maintenance medications Visit 2 will be 
scheduled a minimum of 7 days (at least 14 days if taking tiotropium) from Visit 1
(see Table 5-1 for washout period guidelines). 
At Visit 2, reversibility to Ventolin (albuterol sulfate) HFA and Atrovent (ipratropium 
bromide) HFA will be evaluated (Refer to Section 7.1.1.2). The spirometry data obtained at 
Visit 2 will be used as an inclusion criterion (Refer to Section 5.1) and to characterize the 
population. Correspondingly, at Visit 2 a series of plethysmography maneuvers will be 
performed to assess total capacity and residual volume. In addition, impedance cardiography 
(ICG) will be performed to assess cardiac output. Subject Diary compliance will be 
reviewed, and the subject will be retrained, if appropriate (Refer to Section 7.1.6).  
At Visit 2, subject’s burden of disease will be assessed using the COPD Assessment Test 
(CAT).  
Treatment Period:
After Visit 3 (Randomization), subjects that meet study inclusion criteria will be examined at 
Visit 4, Visit 5, and Visit 6. In total, each completed subject will attend 6 scheduled visits 
in this study for a maximum of 12 weeks. For the assessments scheduled at each of these 
visits, refer to the Schedule of Events (Table 8-1).
At Visit 3, all sponsor-provided Atrovent HFA provided during the screening period will be 
discontinued and collected by site personnel for accountability.
The Investigator will reevaluate the subject’s study eligibility criteria as described at Visit 1. If
a subject is assigned to GFF MDI or Placebo MDI, it will not be possible to differentiate
between these treatments since they will appear to be identical in all aspects. Randomization 
will be stratified by COPD disease severity (moderate vs. severe) to ensure even distribution 
of treatment arms within each stratum. 
Subjects will be required to take their blinded study medication twice a day.  Subjects will 
inhale 2 puffs from their MDI in the morning between 06:00 and 10:00 AM (Breakfast time) 
and in the evening between 06:00 and 10:00 PM (Dinner time).  
Pre-dose PFTs will be obtained at -60 and -30 minutes prior to dosing on Day 1 of each 
Treatment Period (Visits 3 and 5) (Refer to Section 7.1.1).  


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General Considerations for Treatment Visits 3 through Visit 6(in-clinic):
x
At the start of each treatment visit, prior to the administration of study drug and 
performance of any study procedures, site personnel must confirm that the subject 
withheld all COPD medications (including randomized study medication, ICS and rescue 
medication, e.g., Ventolin HFA) for at least 6 hours by confirming the last time of dosing 
for all COPD medication(s).  

Note: For subjects who inadvertently took COPD medication within 6 hours of the 
start of study procedures, the visit date must be rescheduled within the specified visit 
window as soon as it is practical.

Note: Before the in-clinic dose is administered, the site must confirm that the subject 
meets all protocol-specified requirements (e.g., FEV1 baseline criteria; see 
Section 7.1.1.1).
x
Protocol-adjusted ICS therapy as defined at Visit 1 (Screening) if any, should be 
continued and remain stable for the duration of the Study (refer to Section 5.4). 
x
Subjects must not ingest xanthine (caffeine)-containing foods and beverages for at 
least 6 hours prior to each study visit and for the duration of each study visit.
x
Subjects will be required to refrain from smoking (nicotine gums or patches are 
allowed) for at least 4 hours prior to each study visit and throughout the duration of 
each study visit.
x
In order to minimize diurnal variance, sites should make every effort to assess 
subjects at the same time throughout the study and to discuss the importance of 
dosing in a timely manner, every 12 hours.
x
Subjects will be required to return to the clinic at approximately the same time as 
Visit 2 for all treatment visits (± 2 hours) and will be required to remain at the clinic
until completion of all protocol-defined assessments.
x
Sites should make every effort to ensure that the in-clinic dosing time is before 
approximately 11:00 AM and within 12±2 hours of the prior at home evening dosing 
time.
x
The in-clinic dosing time for study drug (GFF MDI or Placebo MDI) will be recorded 
as the time of administration of the second puff.
x
To ensure standardization of dosing times, it is recommended that sites encourage 
subjects to maintain a dosing schedule consistent with their in-clinic dosing time and 
that sites call the subject on the day before a scheduled visit to remind the subject of 
the following:

Subjects should take their last dose the evening before the scheduled visit;

To bring their study medications and Subject Diary with them to the clinic and to 
withhold all COPD medications (including ICS and phosphodiesterase inhibitors) 
or for at least 6 hours prior to PFTs;

Refrain from ingesting xanthine (caffeine)-containing foods and beverages for at 
least 6 hours prior to each study visit and for the duration of each study visit;


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
Refrain from smoking for at least 4 hours prior to the study visit and throughout 
the duration of each study visit.
x
Site personnel will instruct subjects not to take any COPD medications, without site 
personnel permission, during a visit until all study procedures have been completed, 
and the subject is discharged.  Site personnel should take every precaution to prevent 
subject use of COPD medications during test day.  Site personnel may request the 
subject to surrender all COPD medications prior to the start of the visit before 
performing any study procedures and return the COPD medications to the subject at 
the end of the visit when all study procedures are completed.  Subjects will be asked 
to abstain wherever possible from using rescue Ventolin HFA during study visits.  If 
a subject is experiencing severe symptoms and requires Ventolin HFA for relief of 
COPD symptoms at any time during a test day, site personnel must note the time and 
justification of use in the subject’s chart and all subsequent spirometry assessments 
should be stopped.  However, safety assessments should be continued at the 
discretion of the Investigator.
Note: If, during a Day 8 visit, a subject requires rescue Ventolin HFA and the MRI 
has not been obtained, the visit needs to be rescheduled.
x
Subjects will complete all Visit 6 (Final Study Visit) assessments and will be 
scheduled for a post-study follow-up telephone call at least 14 days from Visit 6.
A Study Flow Diagram is displayed in Figure 1 below.


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Figure 1. Study Flow Diagram


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4.2
Rationale of Study Design
This study will assess the effect of GFF MDI 14.4/9.6 μg on cardiovascular hemodynamics 
following chronic dosing (7 days) in subjects with moderate to severe COPD compared to 
Placebo MDI.
4.3
Rationale of Dose/Regimen, Duration of Treatment, and Placebo 
Arm
Summaries of studies from the clinical development program supporting the dose selection 
and duration of treatment can be found in the introduction (Section 1) of this protocol.


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5
STUDY POPULATION SELECTION, PRIOR AND CONCOMITANT 
MEDICATIONS AND WITHDRAWAL CRITERIA 
5.1
Inclusion Criteria
Subjects eligible for enrollment in the study must meet all of the following criteria:
1.
Give their signed written informed consent to participate.
2.
Are at least 40 years of age and no older than 80 at Visit 1.
3.
A female is eligible to enter and participate in the study if she is of:
-
Non-child bearing potential (i.e., physiologically incapable of becoming pregnant, 
including any female who is 2 years post-menopausal); or
-
Child bearing potential, has a negative serum pregnancy test at Visit 1, and agrees
to one of the following acceptable contraceptive methods used consistently and
correctly as outlined below (i.e., in accordance with the approved product label
and the instructions of the physician for the duration of the study – from Visit 1
(Screening) until 14 days after Visit 6; or
-
Complete abstinence from intercourse; or
-
Implants of levonorgestrel inserted for at least 1 month prior to the study drug 
administration but not beyond the third successive year following insertion; or
-
Injectable progestogen administered for at least 1 month prior to study drug
administration; or
-
Oral contraceptive (combined or progestogen only) administered for at least one 
monthly cycle prior to study drug administration; or
-
Double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps)
plus spermicidal agent (foam/gel/film/cream/suppository); or
-
An intrauterine device (IUD), inserted by a qualified physician, with published data
showing that the highest expected failure rate is less than 1% per year; or
-
Estrogenic vaginal ring; or
-
Percutaneous contraceptive patches.
4. Evidence of lung hyperinflation; residual volume > 120% predicted normal value pre-
bronchodilator at Visit 2.
5. COPD Diagnosis: Subjects with an established clinical history of COPD as defined by
the American Thoracic Society (ATS)/European Respiratory Society (ERS) (Celli, 2004) 
characterized by:
-
Airflow limitation that is not fully reversible. Progressive airflow limitation 
associated with an abnormal inflammatory response of the lungs to noxious particles
or gases, primarily caused by cigarette smoking.
6. Tobacco Use: Current or former smokers with a history of at least 10 pack-years of 
cigarette smoking.  [Number of pack-years = (number of cigarettes per day / 20) x 
number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day 
for 20 years represent 10 pack-years)].
7. COPD Severity: Subjects with an established clinical history of COPD and severity
defined as:


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
At Visit 1, FEV1/FVC ratio must be <0.70 and FEV1 must be <65% predicted
normal value calculated using NHANES III reference equations.

At Visit 2, post-bronchodilator FEV1/FVC ratio of <0.70 and post-bronchodilator 
FEV1 must be WR% predicted normal value, calculated using NHANES III
reference equations.

At Visit 3, the average of the -60 min and -30 min pre-dose FEV1 assessments must 
be <65% predicted normal value, calculated using NHANES III reference equations.
 6\PSWRPDWLF&$7DW6FUHHQLQJ9LVLW
8. Subject is willing and, in the opinion of the Investigator, able to adjust current COPD
therapy as required by the protocol
9. Screening clinical laboratory tests must be acceptable to the Investigator.
10. Screening ECG must be acceptable to the Investigator.
11. Chest X-ray or computed tomography (CT) scan of the chest/lungs within 6 months prior
to Visit 1 must be acceptable to the Investigator. Subjects who have a chest X-ray
(or CT scan) that reveals clinically significant abnormalities not believed to be due to the
presence of COPD should not be included. A chest X-ray must be conducted if the most 
recent chest X-ray or CT scan are more than 6 months old at the time of Visit 1.
12. Compliance: Subjects must be willing to remain at the study center as required per
protocol to complete all visit assessments.
5.2
Exclusion Criteria
Subjects meeting any of the following criteria are to be excluded:
1. Significant diseases or conditions other than COPD which, in the opinion of the 
Investigator, may put the patient at risk because of participation in the study or may 
influence either the results of the study or the subject’s ability to participate in the study
2. Women who are pregnant or lactating, or are planning to become pregnant during the 
course of the study, or women of childbearing potential who are not using an acceptable 
method of contraception.
3. Respiratory
a) Asthma: Subjects, who in the opinion of the Investigator, have a current diagnosis of
asthma. (Note: Subjects with a prior history of asthma are eligible if COPD is 
currently their primary diagnosis).
b) Alpha-1 Antitrypsin Deficiency: Subjects who have alpha-1 antitrypsin deficiency as
the cause of COPD.
c) Other Respiratory Disorders: Subjects who have other active pulmonary disease such
as active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary
pulmonary hypertension, interstitial lung disease, and uncontrolled sleep apnea (i.e., 
in the opinion of the Investigator severity of the disorder would impact the conduct of
the study). Note: Allergic rhinitis is not exclusionary.
d) Lung Volume Reduction: Subjects who have undergone lung volume reduction 
surgery, lobectomy or bronchoscopic lung volume reduction (endobronchial blockers, 
airway bypass, endobronchial valves, thermal vapor ablation, biological sealants, and 
airway implants) within 1 year of Visit 1.


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e) Hospitalization: Subjects who have been hospitalized due to poorly controlled COPD
within 3 months prior to Visit 1 (Screening) or during the Screening Period (Visit 1 to 
Visit 3).
f)
Poorly Controlled COPD: Subjects who have poorly controlled COPD, defined
as acute worsening of COPD that requires treatment with oral corticosteroids or
antibiotics within 6 weeks prior to Visit 1 (Screening) or during the Screening Period 
(Visit 1 to Visit 3).
Note: Subjects who are steroid dependent and maintained on an equivalent of 5 mg 
prednisone per day or 10 mg every other day for at least 3 months prior to Visit 1a are 
eligible for enrollment providing the dose of oral steroids remains stable during the 
Screening Period (Visit 1 through Visit 3).
g) Lower Respiratory Tract Infection: Subjects who had lower respiratory tract
infections that required antibiotics within 6 weeks prior to Visit 1 (Screening)
or during the Screening Period (Visit 1to Visit 3).
h) Other Respiratory tract infections that have not resolved at least 7 days prior to 
Screening.
i)
Spirometry Performance:
-
Acceptability: Subjects who cannot perform acceptable spirometry (i.e., meet 
ATS/ERS acceptability criteria)
-
Repeatability: Subjects who cannot perform technically acceptable spirometry 
with at least 3 acceptable flow-volume curves with 2 or more meeting ATS
repeatability criteria for FEV1 during at least 1 of the pre-bronchodilator
assessments at Visit 2 (-30 minute) and at the post-bronchodilator assessment 
at Visit 2.
j)
Oxygen: Subjects receiving long term treatment with oxygen >4.0 liters/minute 
(L/min) at rest. While breathing supplemental oxygen, at rest, subjects should 
GHPRQVWUDWHDQR[\KHPRJORELQVDWXUDWLRQ,QRUGHUWREHDGPLWWHGWRWKHWULDO
subjects on LTOT have to be ambulatory and be able to attend clinic visits.
k) Subject use of any non-invasive positive pressure ventilation device (NIPPV). 
Note: Subjects using continuous positive airway pressure (CPAP) or bi-level positive 
airway pressure (BiPAP) for Sleep Apnea Syndrome are allowed in the study.
l)
Change in smoking status (i.e., start or stop smoking,) or initiation of a smoking 
cessation program within 6 weeks of Visit 1 and throughout the Screening Period 
(Visit 1 to Visit 3).
m) Pulmonary Rehabilitation: Subjects who have participated in the acute phase
of a pulmonary rehabilitation program within 4 weeks prior to Visit 1 (Screening)
or who will enter the acute phase of a pulmonary rehabilitation program during the
study. Subjects who are in the maintenance phase of a pulmonary rehabilitation 
program are not to be excluded.
n) Subjects who have initiated or altered the dose regimen of intranasal corticosteroids, 
intranasal antihistamines, or a combination thereof within 7 days prior to Visit 1 or 
during the Screening Period (Visit 1 to Visit 3)
4. Cardiac disease
a) Subjects who have unstable ischemic heart disease, left ventricular failure, 
or documented myocardial infarction within 6 months of enrollment.  


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Subjects with a recent history of acute coronary syndrome, or who have 
undergone percutaneous coronary intervention or coronary artery bypass 
graft within the past 3 months are to be excluded. 
b) Subjects with congestive heart failure (CHF NYHA Class III/IV).
c) Clinically significant abnormal ECG:  A clinically significant abnormal ECG is 
defined as (but not limited to) any of the following: 
-
Clinically significant conduction abnormalities [e.g., left bundle branch block, 
Wolff-Parkinson-White syndrome or evidence of second degree (Mobitz Type 
II) or third degree atrioventricular block (unless pacemaker or defibrillator has 
been inserted)].
-
Clinically significant arrhythmias (e.g., atrial fibrillation with irregular 
ventricular response, atrial flutter, ventricular tachycardia). Note: atrial 
fibrillation that has been clinically stable for at least 6 months and that has 
been appropriately treated with anticoagulation and controlled with a rate 
control strategy (i.e., selective beta blocker, calcium channel blocker, digoxin 
or ablation therapy) for at least 6 months is allowed for inclusion. In such 
subjects, atrial fibrillation must be present at pre-randomization visits, with a 
resting ventricular rate <100 beats per minute (bpm). At screening, the atrial 
fibrillation must be confirmed by central reading.
QT interval corrected for heart rate (using Fridericia’s formula; QTcF) 
 milliseconds (msec) in patients wiWK456PVHFDQG47F)
PVHFLQSDWLHQWVZLWK456PVHF
-
Ventricular rate <45 bpm.
-
ST-T wave abnormalities deemed to be clinically significant by the 
Investigator.  Note: Subjects with non-specific ST-T wave abnormalities that 
are not deemed clinically significant (per Investigator) are allowed.
-
Any other ECG abnormalities not listed above that in the opinion of the 
Investigator are clinically significant.
d) Clinically Uncontrolled Hypertension: Subjects who have clinically significant 
uncontrolled hypertension. 
5. Neurological 
a) Subjects with seizures requiring anticonvulsants within 12 months prior to 
Visit 1 (Screening).  Note:  Subjects treated with anticonvulsant medication for 
12 months or more with no seizure events are eligible. 
b) Subjects taking selective serotonin reuptake inhibitors (SSRIs) or serotonin–
norepinephrine reuptake inhibitors (SNRIs) whose dose has not been stable for 
at least 4 weeks prior to Visit 1 or is altered at any point during the Screening 
Period (Visit 1 to Visit 3), or exceeds the maximum recommended dose.
c) Subjects who have experienced a cerebrovascular accident within the 6 months 
prior to Visit 1
6. Renal 
a) Subjects with symptomatic prostatic hypertrophy that is clinically significant 
and not adequately controlled with appropriate therapy, in the opinion of the 
Investigator.  Subjects with a trans-urethral resection of prostate or full resection 
of the prostate within 6 months prior to Visit 1 are excluded from the study. 


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b) Subjects with bladder neck obstruction or urinary retention that is clinically 
significant in the opinion of the Investigator. 
c) 6XEMHFWVZLWKDFDOFXODWHGFUHDWLQLQHFOHDUDQFH mL/minute using Chronic 
Kidney Disease Epidemiology Collaboration. 
(CKD-EPI) formula (Levey, 2009) at Visit 1 and on repeat testing prior to 
Visit 2.
Note:  Subjects with overactive bladder syndrome treated with oral 
anticholinergics that have been on treatment for at least one month are allowed in 
the Study.
7. Endocrine 
a) Subjects, who in the opinion of the Investigator, have uncontrolled hypo-or 
hyperthyroidism, hypokalemia or hyperadrenergic state
b) Subjects, who in the opinion of the Investigator, have uncontrolled Type I or II 
diabetes
8. Liver: Subjects with abnormal liver function tests defined as AST, ALT, or total bilirubin 
 1.5 times upper limit of normal at Visit 1 and on repeat testing prior to Visit 2 (only in 
subjects clinically assessed by PI to be repeated). Note:  Chronic stable hepatitis B and C 
is acceptable if the subject otherwise meets study entry criteria.
9. Cancer: Subjects who have cancer that has not been in complete remission for at least 
five years.  Note: Subjects with squamous cell carcinoma of the skin, basal cell
carcinoma of the skin, or localized prostate cancer are eligible, if in the opinion of the
Investigator, the condition has been adequately worked up, is clinically controlled and the
subject’s participation in the study would not represent a safety concern.
10. Glaucoma: Subjects with a diagnosis of glaucoma, who in the opinion of the Investigator, 
have not been adequately treated.  All medications approved for control of intraocular 
pressures are allowed, including topical ophthalmic non-selective beta-blockers such as 
betaxolol, carteolol, levobunolol, metipranolol, and timolol).
11. Drug Allergy: Subjects who have a history of hypersensitivity to ȕ2-agonists, 
glycopyrronium or other muscarinic anticholinergics, lactose/milk protein or any
component of the MDI.
12. Substance Abuse: Subjects, who in the opinion of the Investigator, significantly abuse 
alcohol or drugs (Refer to Exclusion Criterion 1).
13. Medication prior to spirometry: Subjects who are medically unable to withhold their 
short-acting bronchodilators for the 6-hour period required prior to spirometry testing at
each study visit will be excluded.
14. Prohibited Medications:  Subjects who, in the opinion of the Investigator, would be 
unable to abstain from protocol-defined prohibited medications during the screening 
period and treatment phases of this study (Refer to Tables 5-1 to 5-4 in Section 5.4).
15. Subjects using any herbal inhalation and nebulizer products within 2 weeks prior to 
Visit 1 (Screening) and do not agree to stop using them during the study drug treatment.
16. Vaccinations:  Subjects who received a live attenuated vaccination within 7 days prior to 
Visit 1 (Screening).
17. Non-compliance:  Subjects unable to comply with study procedures, including 
meeting the compliance requirement of >70% subject completion of Diary 


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assessments in the last 7 days preceding the Randomization Visit (Visit 3) to be 
randomized in the study.  Subjects who fail to demonstrate proper Diary compliance 
prior to randomization must be screen failed.
18. Affiliations with Investigator site: Study Investigators, sub-Investigators, study
coordinators, employees of a participating Investigator or immediate family members of
the aforementioned are excluded from participation in this study. 
19. Questionable Validity of Consent: Subjects with a history of psychiatric disease,
intellectual deficiency, poor motivation, substance abuse (including drug and alcohol), or 
other conditions that will limit the validity of informed consent to participate in the study.
20. Subjects using prohibited medications (refer to Table 5-1)
21. Investigational Drugs or Devices: Treatment with investigational study drug or device in 
another clinical trial within the last 30 days or five half-lives prior to Visit 1 (Screening), 
whichever is longer.  Note: Subject participation in observational studies (i.e., studies that 
do not require change to medication or an additional intervention) is not exclusionary.
22. Hand-to-Breath Coordination:  Subjects who requires the use of a spacer device to
compensate for poor hand-to-breath coordination with a MDI.  Note:  Use of a nebulizer 
to deliver COPD medications is prohibited throughout the trial.
23. Previous Participation:  Subjects who were previously enrolled in any previous PT001, 
PT003 or PT005 study conducted or sponsored by Pearl.  
5.3
Subject Identification 
All subjects who undergo screening will be assigned a unique screening identification
number at the Screening visit (Visit 1). Only subjects continuing to meet entry
inclusion/exclusion criteria at Visit 3 will be assigned a unique subject randomization
number.
5.4
Prior, Concomitant, and Prohibited Medications 
All prescription and over-the-counter (OTC) medications taken by the subject within 30 days 
before Visit 1 (Screening) will be recorded on the prior/concomitant medications Case 
Report Form (CRF) page.  Any additions, deletions, or changes in the dose of these 
medications while in the study should be entered on the CRF.  Any current ongoing 
medications, including OTC drugs and herbal supplements, will be allowed provided they are 
not prohibited by the protocol (refer to Section 5.4.1) and are approved by the Investigator.  
Subjects should also be instructed to contact the Investigator if they develop any illnesses. 
All concomitant medications taken during the study will be recorded on the Concomitant 
Medications CRF with indication, dose, dose regimen, and dates of drug administration.
5.4.1 Prohibited COPD Medications and Required Washout Prior to Visit 2
Subjects that meet the screening criteria at Visit 1 that are being treated with any of the 
medications listed in Table 5-1 need to discontinue these medication and observe the 
minimum washout requirement before returning for Visit 2.  These medications are 
prohibited throughout the course of the study, and should a subject require use of any of the 
listed medications, they should be discontinued.


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Table 5-1.
Prohibited COPD Medications and Required Washout Periods, 
Prior to Visit 2
Class of medication
Minimum Washout Period prior to Visit 2
LAMAs
Tiotropium: 14 days
Aclidinium: 7 days
Glycopyrronium: 7 days
Umeclidinium: 7 days 
Short-acting muscarinic antagonists (SAMA) a
6 hours
LABAs (inhaled)
7 days (indacaterol and olodaterol: 15 days)
Fixed-combinations of LABA/LAMA
7 days or the duration of the individual agents if 
longer
Fixed-combinations of LABA/ICS
7 days 
Fixed-combinations of SABAs and SAMAs 
6 hours
SABAs b
6 hours
ICS
7 days 
2UDOȕ-agonists
2 days 
Theophylline (total daily dose >400 mg/day)c
7 days
Abbreviations:  COPD=chronic obstructive pulmonary disease; HFA=hydrofluoroalkane; ICS=inhaled 
corticosteroid; LABA=long-DFWLQJȕ2-agonist; LAMA=long-acting muscarinic antagonist; 
SABA=short-DFWLQJȕ2-agonist; SAMA=short-acting muscarinic antagonist
Note: Subjects taking roflumilast are allowed provided they have been on stable dose of therapy for at least 
2 months prior to Randomization.
a.
Discontinue and use only sponsor provided  Atrovent HFA during screening
b.
Discontinue and use only sponsor provided  rescue Ventolin HFA throughout the study
c.
Theophylline (<400 mg/day) is permitted provided the subject has been on a stable dose of therapy for at 
least 4 weeks prior to Randomization.
Subjects who have received depot corticosteroids including intra-articular or intraocular
corticosteroids require a 3-month washout prior to Screening (Visit 1).  Subjects that have 
received oral, intravenous or intramuscular corticosteroids for any reason require a 6-week 
washout prior to Screening (Visit 1).  Any subject that requires systemic corticosteroids 
during the Screening Period from Visit 1 up to but not including Visit 3 will be screen failed.
Note: 6XEMHFWVZKRDUHVWHURLGGHSHQGHQWDQGPDLQWDLQHGRQDQHTXLYDOHQWRI mg oral 
SUHGQLVRQHSHUGD\RUPJRUDOSUHGQLVRQHHYHU\other day for at least 3 months prior to 
Visit 1 are eligible providing the dose of oral steroids remains stable during the screening 
period from Visit 1 up to but not including Visit 3.
During the Treatment Period (Visit 3 to Visit 6), subjects may be treated with corticosteroids 
if required.


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Subjects who meet all entry criteria but are using one or more of the prohibited COPD 
medications (previously listed) will have their maintenance therapy for COPD adjusted as 
follows: 
Subjects taking COPD medications (listed previously) at Visit 1 (Screening) will discontinue 
these medications for the duration of the trial and be switched to sponsor-provided Atrovent 
HFA administered QID and sponsor-provided Ventolin HFA to be administered PRN for 
control of symptoms during the Screening Period.
Subjects receiving a maintenance dose of an ICS as part of a fixed dose combination therapy
containing fluticasone and salmeterol, mometasone and formoterol, budesonide and 
formoterol or fluticasone and formoterol must have been on the ICS component for at least 4 
weeks prior to Visit 1 (Screening) and maintained on a stable dose for at least 4 weeks prior to 
Visit 1 (Screening).  These subjects will be switched to the corresponding dose of fluticasone,
mometasone or budesonide administered as a single agent BID, with sponsor provided 
Atrovent HFA administered QID, and sponsor provided Ventolin HFA to be administered 
PRN for control of symptoms during the Screening Period.
Subjects receiving a maintenance dose of an ICS that is not administered as a fixed-dose 
combination together with a LABA will be permitted to continue the ICS provided they have
been maintained on a stable dose for at least 4 weeks prior to Visit 1 (Screening).
All subjects treated with either a LABA (salmeterol, formoterol, indacaterol, olodaterol) or
currently marketed long- acting anti-muscarinic agent (LAMA) (tiotropium and aclidinium) 
administered alone or as a loose combination will have these medications discontinued and
replaced with sponsor provided Atrovent HFA MDI administered four times per day (QID), 
and sponsor provided Ventolin HFA to be administered PRN for control of symptoms during 
the Screening Period.
The following respiratory medications are not permitted during this study (Table 5-2).
Table 5-2. Other Respiratory/Nasal Medications: Required Washout Periods
Required Washout Periods Prior to Visit 2
Class of medication
Minimum cessation period prior to Visit 2
Leukotriene antagonists (e.g., zafirlukast, 
montelukast, and zilueton) 
7 days
Cromoglycate
7 days
Nedocromil
7 days
Ketotifen a
7 days
a Ketotifen eye drops are allowed
5.4.2 Other Prohibited Medications
The following medications should be used under the stated conditions during this study 
(Table 5-3).  Each concomitant drug must be individually assessed against all exclusion 


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criteria.  If in doubt, the Investigator should contact the Pearl Medical Monitor before 
randomizing a subject or allowing a new medication to be started:
Table 5-3.
Non-COPD Medications Allowed Under Certain Condition
Medications allowed under certain 
conditions 
Condition
SSRIs or SNRIs
Intranasal corticosteroids, intranasal 
antihistamines or combination thereof
Treatment regimen has been stable for at 
least 4 weeks prior to Visit 1 and not altered 
during the Screening Period, and does not 
exceed the maximum recommended dose
Administered at constant dose and dosing 
regimen for at least 7 days prior to Visit 1
(Screening) and prior to Visit 2
Abbreviations:  COPD=chronic obstructive pulmonary disease; SNRI=serotonin–norepinephrine reuptake 
inhibitors; SSRI=selective serotonin reuptake inhibitors
Subjects requiring the medications presented in Table 5-4 are prohibited from participating in 
this study. Subjects who recently discontinued use of these medications may be considered 
for study enrollment providing they have met the minimum washout period prior to Visit 1
(Screening).  These medications are prohibited throughout the course of the study, and, 
should a subject require use of any of the listed medications, the subject should be 
discontinued from the study.


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Table 5-4.
Prohibited Medications
Prohibited Medications
Minimum cessation period prior to Visit 1 
(Screening)
Any drug with potential to significantly prolong the 
QT interval
14 days or 5 half-lives, whichever is longer
Other investigational drugs
30 days or 5 half-lives, whichever is longer 
Non-selective beta-blocking agents 
7 days
Cardiac antiarrhythmics Class Ia, III
7 days; amiodarone, 3 months
Anticonvulsants for seizure disorder
Allowed if stable dose for 12 months and free of 
seizures for 1 year 
Anticonvulsants for other indications
Allowed if stable dose for at least 3 months and the 
Investigator confirms there have been no seizures 
within the past 12 months. 
Tricyclic antidepressants
14 days
Monoamine oxidase inhibitors
14 days 
Anti-WXPRUQHFURVLVIDFWRUĮ71)Įantibodies (e.g., 
infliximab and any other members of this class of 
drugs)
30 days or 5 half-lives, whichever is longer
Monoclonal antibodies
30 days or 5 half-lives, whichever is longer
Antipsychotic drugs a
30 days
Systemic calcineurin inhibitors, systemic antifungal 
agents, protease inhibitors and cimetidine
30 days
Systemic anticholinergics b
7 days
a. Antipsychotic agents used for other indications may be allowed after consultation with the Medical Monitor 
of the trial.
b. If systemic anticholinergics are used for treatment of Overactive Bladder and the treatment has been constant 
for at least 1 month, they are allowed.
Note: Benzodiazepines are not exclusionary.


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5.5
Other Restrictions, Illicit Drugs or Drugs of Abuse
5.5.1 Illicit Drugs
Illicit drugs or drugs of abuse will not be allowed from the start of Screening (Visit 1) to the 
end of Visit 6 or to whenever the subject discontinues the study.  If any illicit drugs or drugs 
of abuse are used by the subject during the study, the dates of use and the amount will be 
documented, and the subject will be discontinued from the study.  Medical marijuana is not 
an exclusionary drug if used for medical purposes, and there is no change in the dose or 
frequency of consumption.  
5.5.2 Dietary Restrictions
Subjects must not ingest xanthine (caffeine)-containing foods and beverages for at least 
6 hours prior to each study visit and for the duration of each study visit.  Examples of such 
products include coffee, tea, chocolate, and cola.  Decaffeinated beverages are acceptable.
5.6
Smoking Status
Changes in a subject’s smoking status (i.e., stopping or re-starting smoking) may have an 
impact on the efficacy outcome measures.  At all visits the subject will be asked about any 
recent change in their smoking status (i.e., whether a subject’s status has changed from 
smoker to non-smoker or vice versa).  Any change in smoking status during the Screening 
Period (Visit 1 to Visit 3) will result in a screen failure.  Smoking status changes during the 
Treatment Period will be captured in the CRF, but the subject will be permitted to continue in 
the study.  Subjects will be required to refrain from smoking (including medical marijuana 
and electronic cigarettes) for at least 4 hours prior to each study visit and throughout the
duration of each study visit.  Study participants may utilize various nicotine replacement 
treatments such as chewing gum and patches (PRN), in accordance with recommendations 
from the Investigator during the entire study visit.
Note:  For this study, the use of electronic cigarettes will be treated in the same manner as 
cigarette smoking except for the calculation of pack-year history.
5.7
Reasons and Procedures for Early Termination from the Study
5.7.1 Reasons for Discontinuation
Subjects may be withdrawn from the study at any time at their own request, upon request of 
the Investigator, or by Pearl at any time or for any reason.  If a subject is lost to follow up 
(i.e., fails to return for study visits), reasonable efforts must be made to contact the subject 
and complete study termination procedures.  All subjects who discontinue the study because 
of AEs will be followed up at suitable intervals in order to evaluate the course of the AE and 
to ensure the reversibility or stabilization of the abnormality.  All subjects who prematurely 
discontinue the study after Randomization, regardless of the cause, should undergo only the 
assessments outlined in Section 8.7 on the date of discontinuation.
If a subject experiences any of the changes of concern listed below, a repeat assessment 
should be obtained, and, if confirmed, the Investigator or designee needs to make a 


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determination as to the suitability of continuing the subject in the study. The changes of 
concern include:
x
Following dosing, a heart rate increase of greater than 40 bpm from the pre-dose 
value obtained on that specific test day and the measured value is also >120 bpm.
x
Following dosing, a systolic BP (SBP) increase of more than 40 mmHg from the pre-
dose value obtained on that specific test day and the measured value is also >160 
mmHg.
x
Decrease in creatinine clearance to a value below 30 mL/minute using CKD-EPI 
formula clinically relevant change from baseline as determined by the Investigator.
x
Calculated QTcF intervals >500 msec, and have increased by 60 msec or more over 
baseline value obtained at Randomization (Visit 3).
x
Hepatic impairment defined as abnormal liver function test of AST, ALT or total 
ELOLUXELQWLPHVXSSHUOLPLWRIQRUPDORQUHSHDWWHVWLQJ
Subjects who suffer a moderate or severe COPD exacerbation will be discontinued from the 
study.
A COPD exacerbation will be defined as a change in the subject’s baseline dyspnea, cough, 
and/or spXWXPLQFUHDVHLQYROXPHRUFKDQJHLQFRORUWRZDUGVSXUXOHQFHWKDWODVWV days, 
is beyond normal day-to-day variations, is acute in onset, and may warrant a change in 
regular medication.  The severity of COPD exacerbations will be classified as follows:
-
Mild:  Exacerbations that do not require systemic steroids or antibiotics and do not 
result in hospitalization or death
-
Moderate:  Exacerbations that require treatment with systemic steroids and/or 
antibiotics, and do not result in hospitalization or death
-
Severe:  Exacerbations that result in hospitalization or death
x
Subjects who failed to meet FEV1 baseline stability criteria may be discontinued at 
the investigators discretion (see Section 7.1.1.1)
x
An Investigator may choose to discontinue a subject from study participation at any 
time or for any reason, with sufficient notice by the Investigator, as per the terms of 
the contract with Pearl. The reason for discontinuation will be documented in the 
source documents.
x
Pearl reserves the right to discontinue the study at any time for clinical or 
administrative reasons. Such a termination must be implemented by the Investigator, 
if instructed to do so by Pearl, in a timeframe that is compatible with the subjects’ 
well-being.
If a subject requires the following prohibited medications, they should be discontinued from
the study:
x
Initiation of maintenance therapy with any prohibited medications (see 
Section 5.4). 


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x
Initiation of maintenance therapy with a marketed LABA (e.g., salmeterol, 
formoterol, indacaterol, vilanterol, olodaterol) administered alone or in 
combination with an ICS or a marketed LAMA (e.g., tiotropium, aclidinium, 
umeclidinium, or glycopyrronium bromide [Seebri]).
x
Note: Includes recently marketed LABA/LAMA (tiotropium/olodaterol [StioltoTM
Respimat®],umeclidinium/vilanterol [Anoro® Ellipta®], and 
indacaterol/glycopyrrolate [Utibron™ Neohaler®])
If a female subject becomes pregnant during the course of the study, the subject will be 
discontinued and the pregnancy will be followed full-term through delivery or final outcome. 
(Refer to Section 7.3.11).


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6
LABELING, PACKAGING, STORAGE, DISPENSING, AND 
RETURN OF CLINICAL SUPPLIES
6.1
Subject Information
Clinical supplies will be packaged to support enrollment of the study.  Treatments will be
blinded in terms of dose administered.  The characteristics of the single GFF MDI dose that
will be administered during the study are provided in Table 6-1.
An envelope-based randomization system will be used to assign blinded study medication to 
subjects. The site will receive two large portfolio envelopes aligned to the two subject 
stratification criteria, with one envelope containing subject randomization envelopes for 
subjects with Moderate COPD, and the other containing subject randomization envelopes 
for subjects with Severe COPD. Each large portfolio envelope contains a series of subject 
randomization envelopes, identified by a unique randomization number and organized in 
sequential order. Only subjects eligible for randomization will be assigned the next-in-
sequence randomization envelope, drawn from the large portfolio envelope specific to the 
subject’s stratification (Moderate or Severe COPD).
The subject randomization envelope contains two smaller envelopes, one marked Treatment 
Period 1 and the other marked Treatment Period 2. The Treatment Period 1 envelope 
contains a form which provides the blinded component IDs to be assigned to the subject for 
Visit 3 and Visit 4 (specific to blinded treatment assigned for Treatment Period 1). The form 
will also indicate a “Reserve” replacement component ID which will be kept at the site and 
will not be dispensed to the subject unless the subject requests the replacement component 
ID in the case of an emergency, and will return to the site to obtain the replacement 
medication. After the washout period from Treatment Period 1, the site would open the 
Treatment Period 2 envelope and follow the same process as for Treatment Period 1 and 
dispense component IDs aligned to the second treatment (blinded) independently at Visit 5 
and Visit 6. A replacement component ID for Treatment Period 2 will also be provided, but 
will only be dispensed at the request of the subject in case of emergency.
Twenty of the
planned 40 subjects will be included in each treatment sequence. Should all subjects
complete the study, the design is balanced for period and first-order carryover effects.
For each subject, single dose administration of study drug during each of the two Treatment
Periods should occur at approximately the same time of day.
6.2
Product Descriptions and Primary Packaging and Labeling 
Information
Investigational materials will be packaged by Pearl as summarized in Table 6-1. Atrovent 
(ipratropium bromide) HFA and Ventolin HFA supplies will be supplied as open-label MDIs.




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Lot # (Packaging Lot Trace ID)
Space for entry of screening #
Component ID #
Space for entry of randomization #
Fill Count & Dosage Form
Visit # (Space for Entry of Interval ID)
Storage Conditions
Protocol #
Country regulatory requirements
Sponsor address Translation Key
ID = identification; # = number
6.4
Secondary Packaging and Labeling Information 
Blinded investigational drug and open-label (Atrovent HFA, Ventolin HFA) supplies will be
packaged in individual boxes as outlined in Table 6-2.  Box configuration is subject to 
change as a result of packaging constraints.
Table 6-2.
Description of Boxes
Drug Supplies
Individual Box Contents
Blinded
Atrovent HFA
Ventolin HFA 
1 MDI
1 MDI
1 MDI
Abbreviations:  HFA=hydrofluoroalkane; MDI=metered dose inhaler
Each box will be labeled with a 2-part label printed with black ink and may include the 
following text:
Packaging Lot ID #
Space for entry of screening #
Component ID #
Space for entry of randomization #
Kit Contents (1 MDI)
Space for entry of Interval ID
Re-evaluation/Expiration date (if applicable)
Dosing Instructions (if applicable)
Storage Conditions
Compound ID - Protocol #
Country regulatory requirements
Sponsor address (if applicable)
Translation Key (if applicable)
ID = identification; # = number
6.5
Emergency Unblinding of Treatment Assignment
Pearl will provide disclosure envelopes with the clinical supplies for the purpose of
unblinding.  Emergency unblinding envelopes (bright red in color) which contain the 
unblinded treatment sequence associated with each randomization number, are also 
provided and to be stored in a separate, secure location accessible by the Site Investigator. 
The Investigator or treating physician may unblind a subject’s treatment assignment only in
the case of an emergency, when knowledge of the study treatment is essential for the


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appropriate clinical management or welfare of the subject. Whenever possible, the
Investigator must first discuss options with the Medical Monitor or appropriate study
personnel before unblinding the subject’s treatment assignment. If this is impractical, the
Investigator must notify Pearl as soon as possible, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the safety of
subjects currently in the study.  The date and reason for the unblinding must be recorded in
the appropriate data collection tool.
6.6
Storage Requirements
Blinded Supplies should be stored below 25° C (77° F) in a dry place.  Excursions permitted 
up to 30° C (86° F).
Ventolin® HFA supplies: Store between 15°C and 25°C (59°F and 77°F).  Store the inhaler 
with the mouthpiece down.  For best results, the inhaler should be at room temperature 
before use.  Do not use or store near heat or open flame.  Exposure to temperatures above 
120°F (49°C) may cause bursting. Never throw into a fire or incinerator.
Atrovent® HFA supplies: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F 
to 86°F) [Refer to Unites States Pharmacopoeia Controlled Room Temperature].  For optimal 
results, the canister should be at room temperature before use.  Do not puncture.  Do not use 
or store near heat or open flame.  Exposure to temperatures above 120°F (49°C) may cause 
bursting.  Never throw the inhaler into a fire or incinerator.
The clinical supplies storage area at the site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range specified in 
accordance with the product label.  Documentation of temperature monitoring should be 
maintained.
6.7
Instructions for Preparation of Treatments for Administration and 
Dispensing
6.7.1 GFF MDI and Placebo MDI
Refer to Appendix 3 for instructions on the administration and cleaning of GFF MDI and 
Placebo MDI. 
6.7.2
Atrovent® HFA (Ipratropium Bromide)
Refer to Appendix 4 for the manufacturer’s instructions on the administration of Atrovent® 
HFA.
6.7.3
Ventolin HFA® (Albuterol Sulfate)
Refer to Appendix 5 for the manufacturer’s instructions on the administration of Ventolin 
HFA.


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6.8
Drug Accountability/Return of Clinical Supplies
Under no circumstances will the Investigator(s) allow the study drug to be used other than as 
directed by this protocol.
Investigational clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secure location to which only the 
Investigator and designated assistants have access.  Storage conditions for the clinical 
supplies should be observed, monitored and documented.  Clinical supplies are to be 
dispensed only in accordance with the protocol.  The Investigator is responsible for keeping 
accurate records of the clinical supplies received from Pearl, the amount dispensed to and 
returned by the subject, and the amount remaining at the conclusion of the study. Study 
medication should be handled in accordance with Good Pharmacy Practices (i.e., gloves 
should always be worn by study personnel if directly handling tablets or capsules that are 
returned).  The Clinical Monitor should be contacted with any questions concerning 
investigational products where special or protective handling is indicated.  At the end of the 
study, all clinical supplies including partial and empty containers must be returned as 
directed by Pearl.
Sites should check with the Pearl representative for appropriate documentation that needs to 
be completed for drug accountability.
The Investigator or designated assistant should not open individual clinical supply containers 
until all pre-dose assessments have been completed and the subject is eligible to be 
randomized/continue with the study.  Any deviation from this must be discussed with the 
Clinical Monitor.
For each subject, all used study drug materials will be collected.  Used subject supplies will 
be kept at room temperature in a secure and locked cabinet until returned to Pearl or 
designee.  
Note: Used study drug will be stored separately from unused study drug.
All product complaints (including device malfunctions) must be reported to Pearl using the 
Product Complaints Form provided in the site’s regulatory binder. Pearl will contact the site 
to evaluate the nature of the complaint and determine what further action is needed


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7
STUDY PROCEDURES
A time and events schedule is provided in Table 8-1. Detailed schedules for pre- and
post-dose procedures to be performed at Screening and at each treatment visit are provided in 
Table 8-2 and Table 8-3, respectively.
Every effort should be made to conduct study assessments at approximately the same time 
for a given subject across each treatment period.  
All pre-dose assessments for Visit 3 and Visit 5 are recommended to be conducted in the 
following order: vital signs, clinical laboratory assessments, ICG, ECG, MRI (Visit 3 only) 
and spirometry (IC, when conducted should be obtained prior to all other spirometry
assessments).
All pre-dose assessments for Visit 4 and Visit 6 are recommended to be conducted in the 
following order: vital signs, clinical laboratory assessments, ICG, plethysmography, and 
spirometry (IC, when conducted should be obtained prior to all other spirometry
assessments).
All post-dose assessments for Visit 4 and Visit 6 are recommended to be conducted in the 
following order: ICG, ECG, spirometry (IC, when conducted should be obtained prior to all 
other spirometry assessments), plethysmography, and MRI.
7.1
Efficacy Assessments
7.1.1 Pulmonary Function Tests (Spirometry)
Forced expiratory spirometry for derivation of FEV1 and FVC, will be assessed using a 
spirometer that meets or exceeds minimum performance recommendations of the ATS (Refer 
to Appendix 1).
The volume accuracy of the spirometer is to be checked daily using a 3 L syringe across 3 
flow ranges e.g., at <2 L/sec, 4-6 L/sec and >8 L/sec with temperature and barometric 
pressure correction. The calibration syringe must meet ATS specifications and must not be 
used beyond the expiry date. Required accuracy is ± 3%, i.e., 3.09 L to 2.91 L (ATS/ERS). 
The results will be printed and maintained in a calibration log, which will be monitored for 
compliance during the monitoring visits (Refer to Appendix 2, Spirometry Assessment 
Criteria).
All PFTs including FEV1 and FVC as defined in ATS/ERS guidelines will be performed in 
accordance with ATS criteria (Miller, 2005).
To standardize spirometry, the site will use the identical spirometry systems across all 
subjects and study visits. Site will document in their site study file and provide the sponsor a 
listing the manufacture, make and model of spirometry equipment used for this study. Site 
will be responsible for maintaining calibration and maintenance records of all spirometry 
equipment used for this study and provide these records to the sponsor upon request. 


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Note: Spirometry must meet both acceptability and repeatability criteria (Refer to exclusion 
criterion 3i).
Spirometry assessments will be obtained at:
x
Visit 1
x
At Visit 2, pre-bronchodilator spirometry assessments will be conducted 30 minutes prior 
to Ventolin HFA and Atrovent HFA administration and at 30 minutes post Ventolin HFA 
and Atrovent HFA administration. At Visits 3 and 5 (Day 1 of each Treatment Period), 
spirometry will be conducted 60 minutes and 30 minutes prior to study drug 
administration.
Note: The mean of the -60 minutes and -30 minutes pre-dose spirometry assessments 
conducted at Visit 3 and Visit 5 will be used to establish baseline FEV1 and FVC.
x
At Visits 4 and 6 (Day 8 of each Treatment Period), spirometry will be conducted 30 
minutes prior to study drug administration and at 1 hour post study drug administration.
7.1.1.1
FEV1 Baseline Stability Criteria
It is important to ensure that the baseline FEV1 is stable and reflective of the subject’s COPD 
severity prior to continuation in the second treatment period. As such, the baseline FEV1 at 
Visit 5 must be within ±20% or 200 mL of the pre-dose FEV1 obtained at the Randomization 
Visit (Visit 3). 
At Visit 5, if the pre-dose FEV1 average is outside of the ±20% or 200 mL range, but the 
30-minute pre-dose assessment is within ±22% or 220 mL, then another assessment may be 
conducted 30 minutes later. If the last two assessments meet the reproducibility requirements 
(i.e., within ±20% or 200 mL), the initial 60-minute pre-dose assessment will not be used and 
the last two assessments will be used to establish the eligibility criteria. 
If the baseline FEV1 is not within ±20% or 200 mL, the visit may be rescheduled (for a 
maximum of three attempts) at the Investigator’s discretion (e.g., within 1 week), or the 
subject may be discontinued.
7.1.1.2
Characterization of Reversibility
5HYHUVLELOLW\LVGHILQHGDVDQGP/LPSURYHPHQWLQEDVHOLQH)(91 following 
administration of four puffs of Ventolin HFA followed by four puffs of Atrovent HFA. 
Reversibility to Ventolin HFA and Atrovent HFA will be evaluated at Screening (Visit 2) to 
characterize the subject population.  The procedure is as follows:
x
Reversibility testing to Ventolin HFA and Atrovent HFA (Visit 2 Only):
-
Perform pre-bronchodilator PFTs -30 minutes prior to administration of Ventolin 
HFA and Atrovent HFA
-
Administer 4 puffs of Ventolin HFA followed by four puffs of Atrovent HFA 


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-
Perform post-bronchodilator PFT 30 minutes after the administration of Ventolin 
HFA and Atrovent HFA
Reversibility will be a comparison of the average best FEV1 effort obtained -30 min pre-
bronchodilator to the best FEV1 effort obtained at 30 minutes post- bronchodilator.  A subject 
is determined to be reversible to Ventolin HFA and Atrovent HFA, if the improvement in 
FEV1 approximately 30 minutes following administration of 4 puffs of Ventolin HFA and 
$WURYHQW+)$LVDQGP/
7.1.2 Inspiratory Capacity (IC)
On all test days throughout the conduct of the study, IC assessments will be conducted at the 
same time points, and just prior to all other spirometry assessments.  The average of the two 
assessments on Day 1 of each Treatment Period will be used to establish the baseline IC.  
Specifically, IC data will be analyzed for secondary and other assessments.
x
On Day 1 of each Treatment Period (Visits 3 and 5): IC assessments will only be 
conducted 30 minutes prior to study drug administration. 
x
On Day 8 of each Treatment Period (Visits 4 and 6): IC assessments will be conducted 30 
minutes prior to study drug administration and at 1 hour post study drug administration.  
All subjects will be instructed on the performance of the IC maneuver. Subjects must be 
tested in the seated position wearing a nose clip with no air leaks between the mouth and 
mouthpiece.  Subjects should be relaxed with shoulders down and asked to breathe regularly 
for several breaths until the end-expiratory lung volume is stable (this usually requires at 
least five tidal maneuvers). They are then urged to take a deep breath to total lung capacity 
with no hesitation. From at least three acceptable trials, the two largest IC measurements 
should agree within 5% or 200 mL, both of these IC values will be captured and analyzed.
7.1.3 Plethysmography 
Plethysmography is the measurement of changes in the volume of organs or other body parts, 
particularly those changes resulting from blood flow. It has been demonstrated be a reliable 
lung tests that assess lung diseases, which are often associated with a decrease in total lung 
capacity (TLC). Plethysmographic measurements are based on defining the relationship 
between the pressure and volume of a gas. The test also follows the course of a disease and 
its response to treatment, measures your resistance to airflow and measures your response to 
bronchodilator medications.
Assessments will be performed using a Plethysmograph. To standardize plethysmographic 
measurements, the site will use the identical plethysmography systems across all subjects and 
study visits. Site will document in their site study file and provide the sponsor a listing the 
manufacture, make and model of plethysmography equipment used for this study. Site will 
be responsible for maintaining calibration and maintenance records of all plethysmography 
equipment used for this study and provide these records to the sponsor upon request.
Measurements will be classified performed as follows:


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•
Total airway resistance (Raw)
•
Specific airway conductance (sGaw)
•
Total lung capacity (TLC)
•
Residual volume (RV)
•
Functional residual capacity (FRC)
•
RV/total lung capacity (RV/TLC)
•
Diffusing capacity for carbon monoxide (DLCO)
x
At Visit 2, pre-bronchodilator plethysmography assessments will be conducted. 
Thereafter, four puffs of Ventolin HFA will be administered followed immediately by 
administration of four puffs of Atrovent HFA. Post-bronchodilator plethysmography 
assessments will be obtained 30 to 60 minutes after administration of both Ventolin HFA 
and Atrovent HFA.
x
On Day 8 of each Treatment Period (Visits 4 and 6): plethysmography assessments will 
be conducted 60 minutes prior to study drug administration and at 1-2 hours post study 
drug administration. 
7.1.4
Magnetic Resonance Imaging (MRI)
Assessments will be performed using standard MRI equipment. To standardize MRI, the site 
will use the identical MRI systems across all subjects and study visits. Site will document in 
their site study file and provide the sponsor a listing the manufacture, make and model of 
spirometry equipment used for this study. Site will be responsible for maintaining calibration 
and maintenance records of all MRI equipment used for this study and provide these records 
to the sponsor upon request.  Subjects using oxygen should continue use of oxygen at the 
same flow (L/min) they normally use while the MRI is being performed. 
Assessments will be as follows:
• Right Ventricular Stroke Volume (RVSV), phase contrast from pulmonic valve 
• Pulmonary artery velocity 
• Pulmonary vascular volume 
• Right Ventricular End Diastolic Volume (RVEDV)
• Left Ventricular End Diastolic Volume (LVEDV) 
• Cardiac output 
• Pulmonary vascular resistance (PVR) by ICG
• Pulmonary artery/Aortic diameter ratio (PA:A) 
x
At Visit 3 only (Randomization), MRI assessments will be conducted on the same day 
prior to study drug administration
x
On Day 8 of each Treatment Period (Visits 4 and 6): MRI assessments will be conducted 
2-3 hours post study drug administration


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7.1.5 Impedance Cardiography (ICG)
Assessments will be performed using standard ICG equipment. To standardize ICG, the site 
will use the identical ICG systems across all subjects and study visits. Site will document in 
their site study file and provide the sponsor a listing the manufacture, make and model of 
ICG equipment used for this study. Site will be responsible for maintaining calibration and 
maintenance records of all ICG equipment used for this study and provide these records to 
the sponsor upon request.
Assessments will be as follows:
ƕ Morning pre-dose trough and each post-dose time point for PVC 
ƕ PVR 
ƕ Change to right ventricular stroke volume
x
At Visit 2, ICG assessments will be conducted prior to administration of Ventolin HFA 
and Atrovent HFA 
x
On Day 1 of each Treatment Period (Visits 3 and 5), ICG assessments will be conducted 
prior to study drug administration
x
On Day 8 of each Treatment Period (Visits 4 and 6) ICG assessment will be conducted
prior to study drug administration, 30 minutes and 1 hour post study drug administration 
7.1.6
Subject Diary Data Collection
Subjects will be provided with a Diary to be completed BID to record their study drug dosing, 
and rescue medication use. 
x
Starting at Screening (Visit 1) and for the duration of the study, subjects will be issued 
and trained on diary collection. They will be asked to maintain a daily record of their 
study drug dosing, and rescue medication use 
Site personnel will review the Diary entries during the Screening Period to assess the 
subject’s compliance and understanding of how to use the Diary to maintain a daily record of 
their study drug dosing, and rescue medication use 
x
At the Randomization Visit (Visit 3), subjects should meet the compliance requirement of 
70% subject completion of Diary assessments in the last 7 days preceding the 
Randomization Visit to be randomized in the study. Subjects who fail to demonstrate 
proper Diary compliance prior to Randomization must be screen failed. 
Note: In-clinic dosing times will be documented in the source by the site staff and will not 
be entered by subjects into their Diary.


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x
At all treatment visits (Visits 3 to 5) site personnel must review the Diary prior to dosing 
study drug in the clinic Table 8-1)
The patient is to return the completed diary at each scheduled visit. The study coordinator 
will be responsible for reviewing the diary for completeness and accuracy with the patient. 
All fields should be completed by the patient. The patient will sign (initial) and date each 
page of the diary on the day it was completed and the study coordinator will initial and date 
each diary page at the site visit when the diary is returned to validate the authenticity of the 
entries. If discrepancies or omissions of data are observed at this review, the patient, not the 
study coordinator, should make the corrections. The patient should draw a single line through 
the error and initial and date all corrections. The patient should make all entries in the diary 
in blue or black ink.
Furthermore, in conjunction with review of the diary, the patient will be prompted by the 
study coordinator about missed doses of study medication and additional COPD medication. 
The patient should be instructed to record this information in the diary. Missing data from 
>24 hours prior to the site visit should be left blank. Subjects should be instructed to record 
the time and doses of study medication and rescue medication in hours and minutes a.m. or 
p.m., not in 24-hour clock time. Study sites will enter the Diary information into the eCRF.
7.1.7 Rescue Ventolin HFA Use
The subject will record the total number of puffs of rescue Ventolin HFA used in the Diary 
on a PRN basis.  The number of puffs of rescue Ventolin HFA to be recorded is the number of 
actuations of the canister.  For example, when rescue Ventolin HFA is required and 
two actuations are inhaled, this should be recorded as two puffs.  In the event the subject 
requires four actuations, this should be recorded as four puffs.  Subjects requiring more than 
eight puffs per day on three or more consecutive days with worsening symptoms should 
contact the site.
7.1.8 Medication Compliance 
Time of dosing with study medication will be recorded in the subject’s Diary for each day of 
treatment (except the in-clinic dosing time).  Study medication compliance will be checked at 
all visits, and any issues identified will be documented in the appropriate study files.
7.1.9 Chronic Obstructive Pulmonary Disease Assessment Test (CAT)
The CAT is a self-administered questionnaire designed to assess the condition of subjects 
and overall impact of COPD [Jones, 2009].  It has been proven that the CAT has good 
repeatability and discriminative properties, which suggest that it is sensitive to treatment 
effects at a group level.  Since the CAT is designed to assess the impact of COPD on the 
subject by measuring overall impairment, it has moderate correlations with other instruments, 
such as the Modified Medical Research Council Dyspnea Scale, SGRQ, and the 6-minute 
walk test.  


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Subjects will complete the CAT (Refer to Appendix 6) at Visit 2.  The CAT score will 
describe the burden and symptomatic impact of COPD in subjects enrolled in the Study and 
will be used to determine subject eligibility to participate in the study at Visit 2.


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7.2
Safety Assessments
The safety assessments include AEs, vital sign measurements, ECGs, and clinical laboratory 
testing. 
7.2.1 Medical/Surgical History and Physical Examination
Medical history, including specific cardiovascular history details, will be collected at Visit 1 
(Screening) and updated during the Screening Period (Visit 1 to Visit 3)  
x
The number of COPD exacerbations requiring oral steroids and/or oral antibiotics, or 
hospitalization within 12 months of Visit 1 (Screening) will be collected 
x
A complete physical examination will be performed at Visit 1 (Screening) and at Visit 6 
(Final Visit) or Treatment Discontinuation/Withdrawal Visit
x
A complete physical examination will include evaluation of the following: general 
appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, 
chest, heart, abdomen, extremities, and nervous system  
x
Height assessed in ordinary indoor clothing with shoes removed will be recorded at Visit 
1 (Screening) only
x
Weight assessed in ordinary indoor clothing with shoes removed will be recorded at Visit 
1, Visit 3, Visit 4, Visit 5, and Visit 6
7.2.2 Vital Sign Measurements
Heart rate and systolic and diastolic blood pressure, and oral and/or tympanic temperature 
(‘vital signs’) will be assessed as outlined below; assessments may be obtained in a supine 
position at all times.
x
At Visit 1 and the Treatment Discontinuation/Withdrawal Visit, if applicable, a single 
vital sign assessment will be obtained
x
At all visits (Visit 1 through Visit 6) a single vital sign assessment will be obtained prior 
to study drug administration and following the completion of the last assessment of the 
visit if clinically indicated. 
x
Temperature will be obtained at Screening (Visit 1), and at pre-dose at all visits and will 
not be repeated post-dose at subsequent time points unless clinically indicated
7.2.3 12-Lead Electrocardiogram 
Assessments will be performed using standard ECG equipment. The Principal Investigator 
(PI) and study staff responsible for performing ECGs will receive standardized training at the 
site initiation visit.  Study personnel are required to demonstrate proficiency in performance 
abilities and the use of the equipment. 


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Each test should be labeled with the study number, patient initials, subject number, date, and 
kept in the source documents at the study site. 
QT intervals and calculated QTcF intervals will be reviewed and checked for gross 
inaccuracies by the Investigator or designated ECG reviewer.  If the calculated QTcF 
intervals are > 500 msec, and have increased by 60 msec or more over test day baseline 
value, the Investigator will make a determination on the suitability of continuing the subject 
in the study.  If QTcF interval prolongation exceeding these limits is verified during 
treatment, the subject’s medical history should be examined closely for risk factors that may 
have contributed to the event, including evidence of prior genotyping for hereditary long QT 
syndromes, if appropriate.
Any sign of arrhythmia should be noted.  During treatment, any indication of Torsade de 
Pointes, a polymorphic ventricular tachyarrhythmia that appears on the ECG as continuous 
twisting of the vector of the QRS complex around the isoelectric baseline, must be recorded 
as an AE and reported to the Pearl Medical Monitor. 
All such subjects, including subjects with cardiac arrhythmias, should be monitored closely.  
If appropriate, ECG monitoring should be performed until the QT and QTcF interval and 
waveform morphology have returned to normal. If the prolongation or abnormal rhythm 
persists, the Pearl Medical Monitor must be contacted immediately. 
All ECG assessments should occur prior to spirometry assessments.
x
A single 12-Lead ECG will be obtained at Visit 1 (Screening) and the Treatment 
Discontinuation/Withdrawal Visit, if applicable
x
Visit 3 only (Randomization), 12-Lead ECGs will be obtained twice at least five minutes 
apart prior to study drug administration
x
At Visit 5, a 12-Lead ECG will be obtained once prior to study drug administration
x
At Visit 4 and Visit 6, a 12-Lead ECG will be obtained at 1 hour after study drug 
administration 
The ECG parameters that will be assessed include heart rate, PR interval, QRS axis, QRS 
interval, and QT/QTcF interval.
7.2.4 Clinical Laboratory Tests
Clinical safety laboratory tests, hematology (hemoglobin, hematocrit, red blood cell count, 
white blood cell count with differential, and platelet count), and clinical chemistry 
(comprehensive metabolic panel) will be analyzed by the site’s local laboratory according to 
standardized, validated assays.  The laboratory will supply detailed instructions and all
containers for blood and urine investigations.  Blood sample volumes will meet the
laboratory’s specification. All clinical laboratory tests will be obtained at:
x
Visit 1 (Screening) and the Treatment Discontinuation/Withdrawal Visit, if applicable


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x
At Visit 3 (Randomization), Visit 4, Visit 5, and Visit 6 prior to study drug administration
The site’s local laboratory will supply procedures for the preparation and collections of these 
samples refer to Table 7-1 below.
Table 7-1 Clinical Laboratory Tests
Hematology
Hemoglobin 
Mean corpuscular hemoglobin 
Hematocrit 
Mean corpuscular hemoglobin concentration 
White blood cell count with differential 
Mean corpuscular volume 
Red blood cell count 
Eosinophils
Platelet count 
Clinical Blood Chemistry
Liver Enzyme and Other Liver Function Tests
Other Clinical Blood Chemistry
Alanine aminotransferasea
Albumina
Aspartate aminotransferasea
Blood Urea Nitrogen (BUN) a
Alkaline phosphatasea
Calciuma
Bilirubin, totala
Chloridea
Gamma-glutamyl transferasea
Cholesterola
Bicarbonate
Creatininea
Glucosea
Magnesiuma
Potassiuma
Phosphatea
Protein, totala
Sodiuma
Triglyceridesa
Other Tests
Pregnancy test (women of childbearing potential only): Serum hCG at Visits 1 and 6, and the Treatment 
Discontinuation/Withdrawal Visit, if applicable and urine hCG at Visits 3, and 5.
Creatinine clearance will be estimated by the CKD-EPI published formula.
Abbreviations:  CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration Equation (according to National Kidney 
Disease Education Program); hCG=human chorionic gonadotropin
a Parameters included in the Comprehensive Metabolic Panel.
7.2.4.1
Pregnancy Test
The pregnancy test should be performed prior to ECG, spirometry, or blood collection for 
laboratory assessments.
A serum pregnancy test will be performed at the Central Laboratory in pre-menopausal 
women who are not surgically sterile:


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x
At Visit 1 (Screening) and prior to dosing at Visit 6 and the Treatment 
Discontinuation/Withdrawal Visit, if applicable
x
A urine pregnancy test will be performed at Visits 3 and Visit 5
If any of these tests are positive, the subject must be discontinued from the study.
7.3
Adverse Events
7.3.1 Performing Adverse Events Assessments
The Investigator is responsible for promptly documenting and reporting all AEs observed 
during the study in the subject’s CRF and on the AE Reporting Form. If the AE is 
“alarming,” the Investigator must report the AE immediately to Pearl. In addition, certain 
AEs (as described in Section 7.3.9) are classified as "serious" and must be reported no later 
than 24 hours after the Investigator recognizes/classifies the event as an SAE to Pearl or its 
designee.
In the case of SAEs, after discussing the details of the event, the Investigator and the Medical 
Monitor may discontinue the subject prematurely.
7.3.2 Adverse Event Definitions
The following definitions of terms are guided by the International Conference on 
Harmonization, the U.S. Code of Federal Regulations [21 CFR 312.32] and European Union 
Directive 2001/83/EC and are included herein.
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  An AE (also referred to as an adverse experience) 
can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a drug, without any judgment about 
causality.  An adverse event can arise from any use of the drug (eg, off-label use, use in 
combination with another drug) and from any route of administration, formulation, or dose, 
including an overdose.
Adverse events include, but are not limited to:
x
Any symptom or condition not previously reported by the subject (medical history).
x
An exacerbation of a pre-existing symptom or condition.
x
A significant increase in frequency or intensity of a pre-existing episodic event or 
condition.
x
A drug interaction
x
A condition first detected or diagnosed after study drug administration even though it 
may have been present prior to the start of the study.


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An AE does not include:
x
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, blood 
transfusion); the condition that leads to the procedure are an AE (e.g., bleeding 
esophageal varices, dental caries).
x
Overdose of either study drug or concurrent medication without any clinical signs or 
symptoms.
x
Non-clinically significant abnormal laboratory values.  (If accompanied by 
signs/symptoms, the signs or symptoms are considered an AE).
7.3.3 Pre-Randomization Adverse Events
Adverse events that occur between the time subject signs the informed consent form for the 
study and the time when that subject is randomized will be summarized as medical history 
and not as a treatment emergent adverse event unless the event meets the definition of an 
SAE as defined below.
7.3.4 Severity
The Investigator must categorize the severity of each AE according to the following 
guidelines:
Mild: Associated with no limitation of usual activities or only slight discomfort; generally 
not requiring alteration or cessation of study drug administration; and/or not needing 
therapeutic intervention.
Moderate: Associated with limitation of usual activities or significant discomfort; generally 
requiring alteration or cessation of study drug administration; and/or requiring therapeutic 
intervention.
Severe: Associated with inability of subject to carry out usual activities or very
marked discomfort; considered to be life-threatening; resulting in significant disability or 
incapacity; and requiring therapeutic intervention.
7.3.5 Relationship
The relationship of each adverse event to the study drug administration will be assessed by 
the Investigator after careful consideration, and according to the following guidelines:
Definitely: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; it disappears 
or decreases on cessation or reduction in study drug dose; and/or it reappears or worsens 
when the study drug is administered.
Probably: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; and/or that 
could not be reasonably explained by other factors such as underlying disease, complications, 
concomitant drugs, or concurrent treatments.


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Possibly: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug, but that 
could reasonably have been produced by a number of other factors including underlying 
disease, complications, concomitant drugs, or concurrent treatments.
Not Related: A reaction for which sufficient data exist to indicate that the etiology is 
unrelated to the study drug.
7.3.6 Chronic Obstructive Pulmonary Disease Exacerbations
All COPD exacerbations must be captured using the COPD Exacerbation eCRF. COPD 
exacerbations of any severity will be considered expected study endpoints and will not be 
reported as adverse events (AEs) unless considered a serious AE (SAE). 
Exacerbation(s) of COPD is expected to occur as a progression of disease despite 
standardized drug treatment, or treatment(s) with combination therapies. As a result, the 
Sponsor has classified this event as a protocol specified criteria expected event. Any 
individual case safety reports received related to exacerbation of COPD will not be submitted 
on an expedited basis as a Suspected Unexpected Serious Adverse Reaction (SUSAR) unless 
otherwise required as per the Sponsor’s medical assessment.
7.3.7
Adverse Events of Special Interest
Paradoxical bronchospasm may occur following inhalation from an MDI. 
Monitoring for paradoxical bronchospasm will occur at each visit during the Treatment 
Period (Visits 4 through 6).  In this study, paradoxical bronchospasm is defined as a 
reduction in FEV1 of >20% from test day baseline (i.e., the mean FEV1 values obtained 60 
and 30 minutes prior to study drug administration) with associated symptoms of wheezing, 
shortness of breath, or cough.  All AEs and SAEs will be recorded, as appropriate.
7.3.8 Clinical Laboratory Adverse Events
Many laboratory abnormalities observed during the course of a study will be included under 
a reported AE describing a clinical syndrome (e.g., elevated blood urea nitrogen and 
creatinine in the setting of an AE of renal failure, or decreased hemoglobin in a case of 
bleeding esophageal varices). However, when an isolated laboratory abnormality is 
considered clinically significant by the Investigator, it must be reported as an AE.
Criteria for a “clinically significant” laboratory abnormality are:
x
A laboratory abnormality that leads to dose-limiting toxicity (e.g., an abnormality that 
results in study drug dose reduction, suspension, or discontinuation)
x
A laboratory abnormality that results in any therapeutic intervention (i.e., concomitant 
medication or therapy)
x
Any other laboratory abnormality judged by the Investigator to be of any particular 
clinical concern (e.g., significant fall in hemoglobin not requiring transfusion)


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For laboratory abnormalities that do not meet the above criteria but are outside of the normal 
range (e.g., < or > normal reference range), the Investigator should indicate whether the 
value is clinically significant or not clinically significant for the subject.
7.3.9 Serious Adverse Events
An AE is considered “serious” if, in the view of the Investigator or Sponsor, it results in any 
of the following outcomes:
x
Death
x
A life-threatening AE 
x
In-patient hospitalization or prolongation of existing hospitalization 
x
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
x
A congenital anomaly/birth defect
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate judgment, they may 
jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of 
drug dependency or drug abuse.
Hospitalization for a pre-existing condition, including elective procedures, which has not 
worsened, does not constitute an SAE.
An adverse event or suspected adverse reaction is considered “life-threatening’ if, in the view 
of the Investigator or Sponsor, its occurrence places the subject or subjects at immediate risk 
of death. It does not include an adverse reaction or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.
An AE or suspected adverse reaction is considered unexpected if it is not listed in the current 
Investigator Brochure (IB) or is not listed at the specificity or severity that has been 
observed.
7.3.9.1
Reporting Serious Adverse Events
In agreeing to the provisions of this protocol, the Investigator accepts all legal responsibilities 
for AE identification, documentation, grading, assignment of causality, and prompt 
notification of SAEs to Pearl Pharmacovigilance or designee. All SAEs must be reported to 
Pearl no later than 24 hours after the Investigator recognizes/classifies the event as a serious 
adverse event. At a minimum, a description of the event and the Investigator’s judgment of 
causality must be provided at the time of the initial report using the appropriate form (e.g., 
SAE Report Form). After the initial report, as necessary, the Investigator must provide any 
additional information on the SAE to Pearl Pharmacovigilance or designee within two 


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working days after he/she receives that information. This follow-up information may include 
copies of hospital records, case reports, and autopsy reports, and other pertinent documents.
Post-study SAEs occurring up to 14 days following the last dose of study drug must be 
reported to Pearl Pharmacovigilance as described in Section 7.3.9.3.
The Investigator is responsible for continuing to report to Pearl or designee any new or 
relevant follow-up information that he/she learns about the SAE.
7.3.9.2
Supplemental Investigations of SAEs
The Investigator and supporting personnel responsible for subject care should discuss with 
the Pearl Medical Monitor or designee any need for supplemental investigations of SAEs. 
The results of these additional assessments conducted must be reported to Pearl. If a subject 
dies during participation in the study and a post-mortem examination is performed, a copy of 
the autopsy report must be submitted to Pearl.
7.3.9.3
Post-Study Follow-Up of Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
eCRF. Pearl retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
7.3.9.4
Notification of Post-Study Serious Adverse Events
Investigators are not obligated to actively follow subjects after the completion of the study.  
However, if the Investigator becomes aware of a post-study SAEs occurring up to 14 days 
following the last dose of study drug, the SAE must be reported to Pearl, whether or not the 
event is attributable to study drug.  All SAEs must be reported to Pearl no later than 24 hours 
after the Investigator recognizes/classifies the event as an SAE.
7.3.9.5
Investigational Research Board/Independent Ethics Committee Notification of 
Serious Adverse Events
The Investigator is responsible for promptly notifying her/his Institutional Review Board/
Independent Ethics Committee (IRB/IEC) of all SAEs, including any follow-up information, 
occurring at her/his site and any SAE regulatory report, including any follow-up reports that 
he/she receives from Pearl.  Documentation of the submission to the IRB/IEC must be 
retained for each safety report.  The Investigator is also responsible for notifying Pearl if their 
IRB/IEC requires revisions to the informed consent form or other measures based on its 
review of an SAE report.
7.3.9.6
Health Authority Safety Reports
Pearl or its representatives will submit a safety report to the Food and Drug Administration 
(FDA) and/or any other appropriate regulatory agencies, for any suspected adverse reaction 
that is both serious and unexpected within the appropriate time frame.


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Pearl or its representatives will send copies of each safety report submitted to the FDA and/or 
other regulatory agencies to the Investigators who are actively participating in Pearl-
sponsored clinical studies.  Safety reports must be submitted to the appropriate IRB/IEC as 
soon as possible.  Documentation of the submission to the IRB/IEC must be retained for each 
safety report.
7.3.10 Overdose
An overdose is defined as a dose greater than the high dose level evaluated in this study as 
described in Section 6.2 (Product Descriptions and Primary Packaging and Labeling 
Information) that results in clinical signs and symptoms.  In the event of an overdose of study 
medication, the Investigator should use clinical judgment in treating the overdose and contact 
the study Medical Monitor or designee. The Investigator should refer to the relevant 
document(s) for detailed information regarding warnings, precautions, contraindications, 
adverse events, and other significant data pertaining to the study drug(s) being used in this 
study. Such document may include, but not be limited to, the Investigator’s brochure for GFF 
MDI.
7.3.11 Pregnancy
To ensure subject safety, each pregnancy in a female subject from Visit 1 (Screening) until 
study completion must be reported to Pearl within 24 hours of learning of its occurrence. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. Pregnancy should be recorded on a 
Paper Pregnancy Form and reported by the Investigator to Pearl Pharmacovigilance or 
designee. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the Pearl study drug of any pregnancy outcome. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form.
7.3.12 Use of Steroids during the Trial
At each visit, subjects will be asked whether they have been administered oral, intramuscular 
or intravenous corticosteroids since last visit.  Use of corticosteroids should be documented.  
Subjects treated with oral, intramuscular, or intravenous corticosteroids for other indications 
will follow their visit schedule.  If a subject requires intraocular corticosteroids this should be 
fully documented and the Investigator should make a determination as to the suitability of the 
subject continuing in the study.
7.4
Termination of the Study
An Investigator may choose to discontinue study participation at any time with sufficient 
notice by the Investigator for any reason as per the terms of the contract with Pearl.  
Pearl reserves the right to discontinue the study at any time for clinical or administrative 
reasons.  Such a termination must be implemented by the Investigator, if instructed to do so 
by Pearl, in a time frame that is compatible with the subjects’ well-being.


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8
STUDY ACTIVITIES
A time and events schedule for the study is presented in Table 8-1. Tables 8-2 and 8-3
present details about timed activities conducted pre and post-dose at Visits 1 through 6.


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Table 8.1 Schedule of Events
Procedures
Screeninga
Treatment Period 
Follow-Up/
Final
Visit 1
Visit 2
Visit 3
(Day 1)
Visit 4
( Day 8)
Visit 5
( Day 1)
Visit 6
(Day 8)
Follow-up
Phone call 
Study Daya
-28 to -1a
1a
8±2a
1a
8±2a
14±2a
Informed Consent
X
Review Inclusion/Exclusion Criteria
X
X
Verify Continued Eligibility
X
X
X
X
Reversibility to Ventolin and Atrovent HFA 
(including FEV1 and FVC)b
X
Demographics & Medical/Surgical History
X
X
COPD Assessment Test (CAT)
X
Prior/Concomitant Medicationsc
X
X
X
X
X
X
X
Spirometry (including FEV1, and FVC)b
X
X
X
X
X
X
Inspiratory Capacity (IC)b
X
X
X
X
Plethysmographyb
X
X
X
Magnetic Resonance Imaging (MRI)b
X
X
X
Impedance Cardiography (ICG)b
X
X
X
X
X
Physical Examinationb
X
X
Vital Signsb
X
X
X
X
X
X
12-Lead ECGb
X
X
X
X
X
Serum Pregnancy Testb
X
X
Urine Pregnancy Testb
X
X
Clinical Laboratory Testingb
X
X
X
X
X
Adjust COPD Medicationsd
X
X
X
COPD Exacerbations and Adverse Events
X
X
X
X
X
X
X
Inhalation Device Training
X
X
X
X
X
Study Drug Administratione
X
X
X
X
Dispense Subject Diary
X
X
X
Collect/Review Subject Diary
X
X
X
X
Study Drug Dispensing
X
X
X
X
Study Drug Collection
X
X
X
X


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a
Screening period of at least 14 days and up to 28 days.  Subjects are to return to the clinic within 7 days following initiation of each treatment arm. There must also be at least 
7 days (not to exceed 21 days) between Visits 4 and 5 to allow for appropriate washout of study drug. The indicated Study Days are estimates calculated based on a 7-day
treatment period and a 7-day washout period.
b
Refer to Section 7for specific assessments and specific time points to be performed at each treatment visit.
c
At all visits beyond Screening, note time of last dose of short-acting bronchodilator and other COPD medications (if <6 hours, visit should be rescheduled).
d
At Screening, stop prohibited COPD medications and change COPD medications as specified in protocol Section 7 (i.e., Sponsor-provided Atrovent HFA with or without 
ICS). At the end of the Visit 6, return subject to pre-study or other appropriate inhaled maintenance COPD medications. 
e
At the start of each treatment visit, subject must withhold all COPD medications, including study medication, rescue medications (Albuterol) and ICS for at least 6 hours
prior to start of test day procedures


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Table 8.2 Timed Assessments at Screening Visit 1 and Visit 2
Visit 1 (Screening)
Visit 2 (Screening)
Clinical Variablea
Pre-dosing
Post-dosing
Pre-dosing
Post-dosing
-60
min
-30
min
30
min
1 hr
2hr
-60
min
-30
min
30
min
1 hr
2 hr
Review Diary Data
Xb
Vital Signsc
Xb
Xb
COPD Assessment Test (CAT)b
Xb
Clinical Laboratory Testingc
Xb
12- Lead ECGc
Xb
Impedance Cardiography (ICG)c
Xb
Spirometry (FEV1, FVC)c
Xb
X
X
Plethysmographyc
Xb
X
X
Run-in Medication  Dispensingd
Xd
a.
In-clinic dosing time is recorded as time of the second puff. Safety assessments (vital signs and ECG) should be started approximately 5 to 
10 minutes ahead of the specified time point to ensure that spirometry for FEV1 and FVC assessments will be conducted as close to the 
specified time points as possible (i.e., FEV1 and FVC assessments need to be conducted within ±15 minutes of specified time points prior 
to study drug administration and ±5 minutes of specified time points for the first 60 minutes post study drug administration..)
b.
This is not a timed assessment.  Sites should plan to perform these activities so as not to interfere with collection of timed assessments 
such as spirometry.
c.
Refer to Section 7for specific assessments and specific time points to be performed at each treatment visit.
d.
Sponsor provided screening medication will be provided only after a subject is determined to be eligible to proceed to Visit 2 (i.e. only if a 
subject meets COPD definition following spirometry assessments at Screening), and will be collected prior to Randomization at Visit 3.
Note: Sites should plan to perform these activities so as not to interfere with collection of timed assessments such as spirometry. Assessments
should be conducted in the following order: Vital signs, CAT (Visit 2 only), Clinical laboratory testing (Visit 1 only), ECG (Visit 1 only), ICG
(Visit 2 only), Spirometry and Plethysmography (Plethysmography at Visit 2 only).


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Table 8.3 Timed Assessments at Treatment Visits 3 and 5 (Day 1) and Visits 4 and 6 (Day 8)
Visits 3 and 5 (Day 1)
Visits 4 and 6 (Day 8)
Clinical Variablea
Pre-dosing
Post-Dosing
Pre-dosing
Post-Dosing
-60 min
-30
min
30 min
2 hr
-60
min
-30
min
30
min
1 hr
2hr
Study Drug Collectionb
Xb
Xb
Review Diary Data
Xc
Xc
Vital Signsd
Xc
Xc
Clinical Laboratory Testing d
Xc
Xc
Impedence Cardiography (ICG)d
Xc
Xc
X
X
12- Lead ECGd
Xc
X
Magnetic Resonance Imaging (MRI)d
Xc,e
Xf
Plethysmographyd
X
Xg
Inspiratory Capacity (IC)d
X
X
X
Spirometry(FEV1, FVC)d
X
X
X
X
Study Drug Dispensingh
Xh
a.
In-clinic dosing time is recorded as time of the second puff.  Safety assessments (vital signs and ECG) should be started approximately 5 to 10 minutes 
ahead of the specified time point to ensure that spirometry for FEV1 and  FVC assessments will be conducted as close to the specified time points as 
possible (i.e., FEV1 and FVC assessments need to be conducted within ±15 minutes of specified time points prior to study drug administration and ±5 
minutes of specified time points for the first 60 minutes post study drug administration
b.
At the start of each treatment visit, subject must withhold all COPD medications, including study drug, rescue medication, and ICS for at least 6 hours 
prior to start of test day procedures. In-clinic dosing time is recorded as time of the second puff/inhalation. The in-clinic dosing time should be timed to 
be within 12±2 hours of the prior evening dosing time.
c.
This is not a timed assessment.  Sites should plan to perform these activities so as not to interfere with collection of timed assessments such as 
spirometry.
d.
Refer to Section 7 for specific assessments and specific time points to be performed at each treatment visit.
e.
At Visit 3 only
f.
MRI to be performed 2-3 hours post-dose at Visit 4 and Visit 6.
g.
Plethysmography to be  performed 1-2 hours post-dose at Visit 4 and Visit 6.
h.
Sponsor provided screening medication will be collected prior to Randomization at Visit 3 and dispensing of study drug.
Note: Sites should plan to perform these activities so as not to interfere with collection of timed assessments such as spirometry. Assessments should be conducted in the following order: 
Visit 3 and Visit 5 pre-dose: Vital signs, Clinical Laboratory Assessments, ICG, ,ECG, MRI (Visit 3 only), and Spirometry. For pre-dose assessments at Visit 4 and Visit 6, assessments 
should be collected in the following order:  Vital signs, Clinical laboratory testing, ICG, Plethysmography, and Spirometry.  For post-dose assessments at Visit 4 and Visit 6, assessments 
should be collected in the following order:  ICG, ECG, Spirometry, Plethysmography, and MRI. 


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8.1
Visit 1 (Screening)
x
Obtain informed consent
x
Review inclusion/exclusion criteria
x
Site will assign subject screening number 
x
Obtain demographic data, including age, race, smoking history, medical/surgical history 
(including cardiovascular risk factors and history), and age of onset of COPD
x
Obtain medication history, including COPD medications
x
Conduct spirometry assessments
x
Conduct a complete physical examination. Refer to Section 7.2.1 for additional details
x
Obtain vital signs. Refer to Section 7.2.2 for additional details
x
Obtain a 12-lead ECG. Refer to Section 7.2.3for additional details
x
Conduct a serum pregnancy test for all female subjects unless it is documented in the 
medical history that the subject has been irreversibly surgically sterilized (hysterectomy, 
oophorectomy, or bilateral tubal ligation) or they are at least 2 years post-menopausal
x
Obtain laboratory samples (hematology and chemistry). Refer to Section 7.2.4 for 
additional details
x
Record COPD Exacerbations and AEs (if any)
Note: Adverse events that occur between the time when the subject signs the informed 
consent form for the study and the time when that subject is dosed with study drug will 
be summarized as medical history and not as a study adverse event unless the event meets 
the definition of an SAE.
x
Confirm subject’s ability to use MDI correctly (provide coaching as needed)
x
Assign Atrovent (ipratropium bromide) HFA and Ventolin (albuterol sulfate) HFA 
x
Dispense subject Diary and provide instruction to record needed information on Diary 
completion
x
Schedule Visit 2
o
In order to allow for an adequate washout of previous maintenance medications, 
subjects will undergo a washout period of at least 1 week (at least 2 weeks if taking 
Spiriva), but not greater than 26 days in duration prior to returning to the clinic for 
Visit 2
x
Subjects will be instructed to bring their Diary, sponsor provided Ventolin  HFA and 
Atrovent HFA to the next scheduled clinic visit
x
Adverse events must be recorded during the Screening Period, that is, from the time of 
consent to the start of study treatment.
8.2
Visit 2 (Screening)
x
Review inclusion/exclusion criteria and confirm subject eligibility to continue
x
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, Visit 2 must be rescheduled)


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x
Perform reversibility test to Ventolin HFA and Atrovent HFA respectively, and confirm 
subject continues to meet entry criteria based on pre- and post-dose spirometry quality 
(Refer to exclusion criterion 3i), and post-dose spirometry values. Conduct 
plethysmography measures. Refer to Section 7.1 for additional details on measurements
x
Conduct Impedance Cardiography (ICG) measures. Refer to Section 7.1.5 for additional 
details on measurements
x
If not previously reviewed, review of clinical laboratory results from Visit 1.  Please note 
whether the results are clinically significant and include comments where applicable
x
Obtain Vital Signs. Refer to Section 7.2.2 for additional details
x
Review all prior medications, if any, and ensure adherence to COPD regimen
x
Complete COPD Assessment Test (CAT)
x
Record COPD exacerbations and adverse events (if any)
Note: Adverse events that occur during the Screening Period (Visit 1 to Visit 3, pre study 
drug dosing) will be summarized as medical history and not as a study adverse event 
unless the event meets the definition of an SAE
x
Schedule Visit 3 (Randomization Visit, Day 1)
Note: Visit 3 (Randomization Visit, Day 1) can be scheduled at minimum 1 day after 
Visit 2 and no later than 28 days after Visit 1 (Screening)
x
Ensure subject has adequate supply of sponsor-provided Atrovent HFA and sponsor-
provided rescue Ventolin HFA
x
Subjects will be instructed to bring their Diary, Atrovent HFA, and sponsor-provided 
Ventolin HFA to the next scheduled clinic visit
8.3
Visit 3 (Randomization/Day 1)
x
Review inclusion/exclusion criteria and confirm subject eligibility for randomization
x
Review all concomitant medications, if any, and ensure adherence to COPD regimen
x
Review subject diary entries and screen fail subject if subject has not met diary 
compliance requirement of >70% subject completion of diary assessments in the last 
7 days preceding Visit 3
x
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, Visit 3 must be rescheduled)
x
Record COPD exacerbations and adverse events (if any)
x
Collect sponsor-provided Atrovent HFA and sponsor-provided Ventolin HFA dispensed 
during the Screening Period
x
Perform all pre-dose assessments. (Refer to Table 8.3
)
x
Conduct Pregnancy test (Urine HCG) for women of child- bearing potential only
x
Conduct inspiratory capacity measures
x
Conduct spirometry measures
x
Obtain vital signs Refer to Section 7.2.2 for additional details.


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x
Obtain a 12-lead ECG 
x
Conduct MRI assessments. Refer to Section 7.1.4 for additional details on measurements 
x
Conduct ICG measures.
x
Obtain laboratory samples (hematology and chemistry)
x
To allow for proper preparation of study drug, it is recommended that the seal around the 
study day treatment box is opened 15-30 minutes prior to dosing and the instructions for
administration of study drug followed:
o
Refer to Section 6.7.1 for detailed instructions for preparation of treatments for 
administration.  These instructions are to be adhered to and are relevant to all study 
treatment visits
x
Subject will administer first dose of newly assigned study drug at the clinic
x
Return Diary to subjects and provide retraining if appropriate
x
Subjects will be instructed to bring their Diary and all study medication (including used 
study drug and rescue Ventolin HFA) to the next scheduled clinic visit
x
Schedule next visit and ensure subject has adequate supply of study drug and rescue 
Ventolin HFA
8.4
Visit 4 (Day 8)
x
Confirm subject eligibility to continue
x
Collect study drug including sponsor-provided Ventolin HFA and ICS
x
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, Visit 4 must be rescheduled)
x
Confirm the subject took their last dose of randomized study medication as scheduled the 
prior evening  
x
Review all concomitant medications, if any, and ensure adherence to COPD regimen
x
Review subject diary for data collection compliance
x
Record COPD exacerbations and adverse events (if any)
x
Perform all pre-dose assessments. (Refer to Table 8.3
)
x
Conduct spirometry measures
x
Conduct plethysmography measures
x
Conduct ICG measures
x
Obtain Vital Signs
x
Obtain laboratory samples (hematology and chemistry)
x
Conduct IC measures
x
To allow for proper preparation of study drug, it is recommended that the seal around the 
study day treatment box is opened 15-30 minutes prior to dosing and the instructions for
administration of study drug followed:


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o
Refer to Section 6.7.1 for detailed instructions for preparation of treatments for 
administration.  These instructions are to be adhered to and are relevant to all study 
treatment visits
x
Record/document the dose indicator readings of the used MDI and the replacement MDI
x
Perform all post-dose assessments (Refer to Table 8.3
)
x
Conduct ICG measures
x
Conduct MRI measures. 
x
Conduct spirometry measures
x
Conduct plethysmography measures
x
Conduct IC measures
x
Obtain vital signs Refer to Section 7.2.2 for additional details.
x
Obtain a 12-lead ECG
x
Subject will administer one dose of newly assigned study drug at the clinic
x
Return Diary to subjects and provide retraining if appropriate
x
Subjects will be instructed to bring their Diary and all study medication (including used 
study drug and rescue Ventolin HFA and Atrovent HFA) to the next scheduled clinic visit
x
Schedule next visit and ensure subject has adequate supply of rescue Ventolin HFA and 
Atrovent HFA
8.5
Visit 5 (Day 1)
x
Confirm subject eligibility to continue
Note: To be randomized, all subjects must meet the FEV1 Baseline Stability criteria 
(Refer to Section 7.1.1.1) for additional details.  If the FEV1 Baseline Stability entry 
criteria are not met at Visit 3 (Randomization) the subject will not be eligible to be 
randomized and will be screen failed
x
Collect study drug including sponsor-provided Ventolin HFA and ICS
x
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, Visit 5 must be rescheduled)
x
Confirm the subject took their last dose of randomized study medication as scheduled the 
prior evening 
x
Review all concomitant medications, if any, and ensure adherence to COPD regimen
x
Review subject diary for data collection compliance
x
Record COPD exacerbations and adverse events (if any)
x
Perform all pre-dose assessments. (Refer to Table 8.3
)
x
Conduct Pregnancy test (Urine HCG) for women of child- bearing potential only
x
Conduct spirometry measures
x
Obtain vital signs Refer to Section 7.2.2 for additional details.


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x
Obtain a 12-lead ECG
x
Conduct ICG measures
x
Conduct inspiratory capacity measures
x
Obtain laboratory samples (hematology and chemistry) 
x
To allow for proper preparation of study drug, it is recommended that the seal around the 
study day treatment box is opened 15-30 minutes prior to dosing and the instructions for
administration of study drug followed:
o
Refer to Section 6.7.1 for detailed instructions for preparation of treatments for 
administration.  These instructions are to be adhered to and are relevant to all study 
treatment visits
x
Record/document the dose indicator readings of the used MDI and the replacement MDI
x
Subject will administer first dose of newly assigned study drug at the clinic
x
Return Diary to subjects and provide retraining if appropriate
x
Subjects will be instructed to bring their Diary and all study medication (including used 
study drug and rescue Ventolin HFA) to the next scheduled clinic visit
x
Schedule next visit and ensure subject has adequate supply of study drug and rescue 
Ventolin HFA
8.6
Visit 6 (Day 8)
x
Confirm subject eligibility to continue
x
Collect study drug including sponsor-provided Ventolin HFA and ICS
x
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, Visit 6 must be rescheduled)
x
Confirm the subject took their last dose of randomized study medication as scheduled the 
prior evening  
x
Review all concomitant medications, if any, and ensure adherence to COPD regimen
x
Review subject diary for data collection compliance
x
Record COPD exacerbations and adverse events (if any)
x
Perform all pre-dose assessments. (Refer to Table 8.3
)
x
Conduct a complete physical examination
x
Conduct a serum pregnancy test
x
Conduct spirometry measures
x
Conduct plethysmography measures
x
Conduct ICG measures
x
Obtain vital signs Refer to Section 7.2.2 for additional details.
x
Obtain laboratory samples (hematology and chemistry)
x
Conduct IC measures 


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x
To allow for proper preparation of study drug, it is recommended that the seal around the 
study day treatment box is opened 15-30 minutes prior to dosing and the instructions for
administration of study drug followed:
o
Refer to Section 6.7.1 for detailed instructions for preparation of treatments for 
administration.  These instructions are to be adhered to and are relevant to all study 
treatment visits
x
Subject will administer first dose of newly assigned study drug at the clinic
x
Record/document the dose indicator readings of the used MDI and the replacement MDI
x
Perform all post-dose assessments (Refer to Table 8.3
)
x
Conduct ICG measures
x
Conduct MRI measures
x
Conduct spirometry measures
x
Conduct plethysmography measures
x
Conduct IC measures
x
Obtain vital signs
x
Obtain a 12-lead ECG
x
Return subject to pre-study or appropriate maintenance COPD medications
x
Collect Subject Diary
x
Schedule the follow-up telephone call at least 14 days from Visit 6
8.7
Unscheduled Visit/Premature Discontinuation Visit
x
Repeat assessments, if needed, will be captured in unscheduled visits
x
Premature discontinuations visits will be captured as unscheduled visits. 
The following minimum procedures should be completed at the premature 
discontinuation visit:
x
Collect all study drugs, including rescue medications
x
Record COPD exacerbations and adverse events (if any)
x
Review concomitant medications, if any
x
Conduct a physical examination, including vital signs
x
Perform ECG and collect blood samples for hematology and chemistry
x
Conduct a serum pregnancy test for women of child- bearing potential only
x
Collect subject Diary
x
Inform subject about reporting all SAEs up to 14 days following the last dose of study 
drug
x
Return subject to pre-study or appropriate maintenance COPD medications
x
Capture the subject discontinuation reason


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x
Schedule a follow-up telephone call (TC) 14 days post last study drug dosing.  If the 
discontinuation visit is performed > 14 days post last study drug dosing a follow-up TC
will not be required
8.8
Follow-Up Telephone Call
Subjects will be followed-up through a TC 14 days post last study drug dosing.  The 
following information will be requested:
x
Review previously on-going COPD exacerbations and adverse events and record AEs (if
any)
x
Review concomitant medications, if any
8.9
Completion of the Study
The Investigator will document the completion or the reason for early withdrawal by a 
randomized subject in the CRF.  The following categories should be used to describe these 
events in the CRF:
Subject discretion (document reason)
Investigator or designee considers it to be in the best interest of the subject
AEs
Administrative reasons (e.g., early termination of the study)
Subject lost-to-follow-up
Lack of efficacy
Major protocol deviation 
Death
Completion of the study
Protocol-specific discontinuation criteria (see Section 5.7.1)


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9
PLANNED STATISTICAL METHODS
9.1
Introduction
This study will be conducted as a randomized, double-blind, single-center, chronic-dosing (7 
days), two-period, two-treatment, crossover study evaluating the effect of the following 
treatments on cardiovascular hemodynamics in approximately 32 subjects:
•
*))0',ȝJ%,'
•
Placebo MDI BID
The primary objective of this study is to evaluate the effect of GFF MDI on cardiovascular 
hemodynamics following chronic dosing (7 days) in subjects with moderate to severe COPD. 
9.2
Protocol Variables
9.2.1
Efficacy Endpoints
All efficacy assessments will be compared to baseline values. Baseline for the MRI endpoint 
will be defined as the pre-dose value at Visit 3. Baseline for the plethysmography endpoints 
will be defined as the pre-bronchodilator value at Visit 2. Baseline for the ICG and 
spirometry endpoints will be defined as the average of the subject values obtained pre-dose 
on Day 1 of each Treatment Period (average of Visit 3 and Visit 5 pre-dose). For spirometry 
endpoints, the mean of the -60 and -30 minute values for each visit will be obtained prior to 
averaging across visits. The first day of treatment in each Treatment Period is Day 1.  Each 
Treatment Period is planned to contain 7 days between the first and last dose corresponding 
to a span of 8 calendar days.  Therefore, assessments collected on Day 8 will occur following 
7 days of treatment. 
The MRI endpoints RVEDV, LVEDV, LVESV, and RVESV will be normalized to body 
surface area (BSA) to provide the indexed counterpart, e.g.: 
RVEDVi = RVEDV / BSA 
Prior to calculating the change from baseline, the baseline and post-dose RVEDV values will 
each be normalized separately using the respective BSA values. 
9.2.1.1
Primary Efficacy Endpoint
x
Right Ventricular End Diastolic Volume Index (RVEDVi) measured at 2-3 hours post-
dose on Day 8
9.2.1.2
Secondary Efficacy Endpoints (Measured using MRI at 2-3 hours post-dose on Day 
8 unless otherwise noted)
x
Aortic left ventricular stroke volume [LVSV] 
x
Right Ventricular Stroke Volume (RVSV), phase contrast from pulmonic valve 


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x
Pulmonary Artery Velocity 
x
Left ventricular End Diastolic Volume Index (LVEDVi) 
x
Cardiac Output 
x
Morning pre-dose trough and post-dose Pulmonary Vascular Resistance (PVR) by ICG 
(Measured at 30 minutes and 60 minutes post-dose)
x
Pulmonary artery/Aortic diameter ratio (PA:A) 
x
Left Atrial End Diastolic Volume (LAEDV)  
x
Left Atrial End Systolic Volume (LAESV) 
x
Left Atrial Ejection Fraction (LAEF) 
x
Left Ventricular End Systolic Volume Index (LVESVi)
x
Right Ventricular End Systolic Volume Index (RVESVi)
x
Pulsatility Index Aorta (PIAo)
x
Pulmonary Artery Pulsatility Index (PAPi)
9.2.1.3
Other Efficacy Endpoints 
x
Plethysmography (Measured 1-2 hours post-dose)
o
Total airway resistance (Raw)
o
Specific airway conductance (sGaw)
o
Total lung capacity (TLC)
o
Residual volume (RV)
o
Functional residual capacity (FRC)
o
RV/total lung capacity (RV/TLC)
o
Diffusing capacity for carbon monoxide (DLCO)
o
Inspiratory Capacity (IC)
x
Impedance Cardiography (Measured at 30 and 60 minutes post-dose) 
o
Change in right ventricular stroke volume 
x
Magnetic Resonance Imaging (Measured 2-3 hours post-dose) 
o
Change in right ventricular ejection fraction (RVEF) 
o
Change in left ventricular ejection fraction (LVEF) 
o
Pulmonary arterial distensibility 
o
Pulmonary Vascular Volume
o
Right Atrial End Diastolic Volume (RAEDV)
o
Right Atrial End Systolic Volume (RAESV)
o
Right Atrial Ejection Fraction (RAEF)
x
Spirometry 
o
Morning pre-dose trough FEV1
o
Morning pre-dose trough IC


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o
1-hour post-dose FEV1
o
1-hour post-dose IC  
o
Morning pre-dose trough and 1-hour post-dose FVC 
9.2.2
Safety Endpoints
x
AEs
x
12-Lead ECG 
x
Clinical Laboratory Testing
x
Vital Sign Measurements
9.3
Analysis
9.3.1
Efficacy Analysis
9.3.1.1
Primary Efficacy Analysis
A mixed model will be used to evaluate the difference between treatments in the change from 
baseline in RVEDVi. Baseline will use the value from Visit 3 obtained prior to the first 
dosing of Period 1. The model will include adjustment for baseline, period, and treatment. 
Sequence will only be included in the model if found to be significant (p<0.10). Subject will 
be treated as a random effect in order to model within subject correlation across the two 
periods. Point estimates and 95% confidence intervals for the difference between GFF MDI 
and Placebo MDI will be produced. P-values will thus be reported as two-sided. The primary 
null (H0) and alternative (H1) hypotheses with μ representing the mean are:
H0: μGFF = μplacebo
H1: μGFF  μplacebo
The primary analysis will use the modified Intent-to-Treat (mITT) Population.  Analyses 
using the Intent-to-Treat (ITT) Population will be considered supportive.
9.3.1.2
Secondary Efficacy Analysis
Change from baseline in each of the secondary efficacy endpoints will be analyzed using a 
similar mixed model as for the primary endpoint, change in RVEDVi. In addition, since there 
are two responses (30- and 60-min post dose) per period for PVR, an unstructured covariance 
matrix will be fit to the repeated measures within a subject-period for this endpoint. If 
sequence is found to be significant (p<0.10) in the primary analysis model, a term for 
sequence will also be included in each of the models for the secondary endpoints. Baseline 
for the MRI endpoints will use the value from Visit 3 obtained prior to the first dosing of 
Period 1. Baseline for the ICG endpoint, pulmonary vascular resistance, will be defined as 
the average of the subject values obtained pre-dose on Day 1 of each Treatment Period 
(average of Visit 3 and Visit 5 pre-dose). Point estimates, 95% confidence intervals and two-
sided p-values will be reported for the difference between GFF MDI and Placebo MDI.


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The secondary analyses will use the modified Intent-to-Treat (mITT) Population.  Analyses 
using the Intent-to-Treat (ITT) Population will be considered supportive.
9.3.1.3
Other Efficacy Analysis
Change from baseline in each of the other efficacy endpoints will be analyzed using a similar 
mixed model as for the primary endpoint, change in RVEDVi. For the ICG endpoint of 
change in right ventricular stroke volume, an additional unstructured covariance matrix will 
be fit to the repeated measures within a subject period. If sequence is found to be significant 
(p<0.10) in the primary analysis model, a term for sequence will also be included in each of 
the models for the other efficacy endpoints. Baseline for the plethysmography endpoints will 
use the pre-bronchodilator value at Visit 2. Baseline for the ICG and spirometry endpoints 
will be defined as the average of the subject values obtained pre-dose on Day 1 of each 
Treatment Period (average of Visit 3 and Visit 5 pre-dose). For spirometry endpoints, the 
mean of the -60 and -30 minute pre-dose values for each visit will be obtained prior to 
averaging across visits. Point estimates, 95% confidence intervals and two-sided p-values 
will be reported for the difference between GFF MDI and Placebo MDI.
The other efficacy analyses will use the Intent-to-Treat (ITT).
9.3.2
Safety Analysis
9.3.2.1
Adverse Events
Adverse events during each Treatment Period will be summarized by the number of subjects 
experiencing an event.  They will be tabulated at the level of the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term, and the MedDRA system organ class.  The 
version of MedDRA current at the time of database lock will be used for the final analysis of 
data.  Tabulations will be broken down by severity, seriousness, AEs leading to 
discontinuation, and by relationship to study drug. No hypothesis tests will be performed.  
Tables will show the overall incidence of AEs, and the incidence for each treatment.
9.4
Randomization
Subjects will be randomly assigned using the treatment sequence AB or BA in a 1:1 ratio 
where A= GFF MDI 14.4/9.6 μg BID and B= Placebo MDI BID, respectively. All subjects 
who complete the study will receive both treatments. Randomization will be stratified by 
severity of disease such that half of the subjects will have moderate COPD and half will have 
severe COPD as categorized by post-bronchodilator FEV1-<65% for moderate and 
30% -<50% for severe).
9.5
Experimental Design
The experimental design was chosen to be balanced with respect to period and first-order 
carryover effects.


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9.6
Sample Size Consideration
Based on a two-treatment, two-period crossover study comparing Breo® Ellipta® versus 
placebo after cardiac MRI (Stone, 2015), the within-subject SD for the change from baseline 
in RVEDVi was estimate to be 7.11 mL/m2.  Assuming that 90% of the randomized subjects 
will complete the trial, the study has approximately 90% probability to demonstrate a 
difference of 5.59 mL/m2 in RVEDVi.
9.7
Data Validation and Transformation
In general, the data captured within this study are expected to follow a normal distribution.  
However, under certain circumstances, (e.g., during a COPD exacerbation unrelated to 
treatment) extreme and atypical values can arise.  Such values may disproportionately affect 
model-based estimates of the fixed effect and variance parameters.  Prior to database lock 
and unblinding, the change from baseline values for efficacy endpoints will be examined as 
part of data quality management.  This will include production of normal probability plots, 
kernel density estimates, and normal order outlier statistics.  Based on this blinded 
evaluation, if a single or small number of extreme values are identified, nonparametric 
methods or data transformations (e.g. logarithmic or normal rank transformation) will be 
considered.  
If erroneous values are detected, every effort will be made to correct them prior to database lock; 
however if these values cannot be corrected, they will be considered for removal from analysis.
9.8
Analysis Plan 
All analyses will be specified in a detailed Statistical Analysis Plan (SAP) that will include 
table and data listing shells with mock graphical representations.  The SAP will be signed 
before database lock and unblinding.  
9.9
Study Populations
The following analysis populations are defined in this study:
x
The ITT Population is defined as all subjects who are randomized to treatment.  
Subjects will be analyzed according to the treatment assigned per the sequence 
randomization regardless of the treatment actually received.  
x
The mITT Population is a subset of the ITT Population including subjects who received 
treatment and have post-treatment efficacy data from both Treatment Periods.  Data 
judged to be impacted by major protocol deviations will be determined prior to 
unblinding and excluded.  Statistical tabulations and analyses will be by randomized 
treatment, but data obtained after subjects receive an incorrect treatment will be excluded 
from the affected periods.
x
The Safety Population is defined as all subjects who are randomized to treatment and 
receive at least one dose of the study treatment.  Statistical tabulations will be by the 
treatment actually received.


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x
The Not Randomized Population is defined as subjects who did not receive a 
randomization number and therefore did not receive a dose of study treatment 
(e.g., subjects who were screen failures or stopped participation prior to having been 
randomized). 
Analyses will be performed as follows:
Demographics will be summarized for the ITT, mITT, Safety, and the Not Randomized 
Populations.  Extent of exposure will be summarized for the Safety Population.  The Safety 
Population will be used to summarize safety.
Analyses for the primary and secondary efficacy endpoints will be performed for the mITT 
and ITT Populations, with the mITT Population being considered the primary population for 
these analyses. Analyses for the other efficacy endpoints and the exploratory endpoints will 
be conducted with the ITT Population.
9.10 Handling of Missing Data
All observed values will be included in the ITT Population for the efficacy and exploratory 
analyses. All observed values meeting specified criteria will be included in the mITT 
Population.
Missing data will be maintained as missing in the analysis datasets, unless specified 
otherwise. For variables where missing data is imputed, the analysis dataset will contain a 
new variable with the imputed value and the original variable value will be maintained as 
missing.
9.11
Statistical Software
Data processing, statistical screening, descriptive reporting and analysis of the efficacy and 
safety data will be performed using SAS (Version 9.2 or higher).  Graphs may also be 
produced using R (R Development, 2003)


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10 ADMINISTRATIVE CONSIDERATIONS
10.1 Regulatory Authority Approval
Pearl will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements prior to a site 
initiating the study in that country.
10.2 Ethical Conduct of the Study and Institutional Review Board (IRB) 
or Independent Ethics Committee (IEC) Approval
The study will be conducted in accordance with Good Clinical Practice (GCP).  These 
standards respect the following guidelines:
Guideline for Good Clinical Practice E6(R1):  Consolidated Guideline (International 
Conference on Harmonization of Technical Requirements for the Registration of 
Pharmaceuticals for Human Use, May 1996).
US Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR parts 50, 54, 
56, and 312).
Declaration of Helsinki, concerning medical research in humans (Ethical Principles for 
Medical Research Involving Human Subjects) [http://www.wma.net/en/10home/index.html].
Any additional regulatory requirements.
The Investigator (or Pearl, where applicable) is responsible for ensuring that this protocol, 
the site’s informed consent form (ICF), and any other information that will be presented to 
potential subjects (e.g., advertisements or information that supports or supplements the ICF) 
are reviewed and approved by the appropriate IRB/IEC.  The Investigator agrees to allow the 
IRB/IEC direct access to all relevant documents.  The IRB/IEC must be constituted in 
accordance with all applicable regulatory requirements.  
Pearl will provide the Investigator with relevant document(s)/data that are needed for 
IRB/IEC review and approval of the study.  If the protocol, the ICF, or any other information 
that the IRB/IEC has approved for presentation to potential subjects is amended during the 
study, the Investigator is responsible for ensuring the IRB/IEC reviews and approves, where 
applicable, these amended documents.  The Investigator must follow all applicable regulatory 
requirements pertaining to the use of an amended ICF including obtaining IRB/IEC approval 
of the amended form before new subjects consent to take part in the study using this version 
of the form.  The IRB/IEC approval of the amended ICF/other information and the approved 
amended ICF/other information must be forwarded to Pearl promptly.
10.3 Subject Information and Consent
The study will be conducted in accordance with applicable subject privacy requirements.  
The proposed ICF, which must be in compliance with applicable regulations, must be 
reviewed and approved by the IRB/IEC and Pearl prior to initiation of the study.  


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The Investigator will be responsible for obtaining written informed consent from potential 
subjects prior to any study-specific screening and entry into the study.  A copy of the signed 
ICF will be provided to the subject.  The original will be retained by the Investigator.
10.4 Laboratory Accreditation
Any laboratory facility intended to be used for analysis of clinical laboratory samples 
required by this protocol must provide evidence of adequate licensure or accreditation 
according to the prevailing regulations in that state and/or country.  Reference values and/or 
normal ranges for the test results must be provided to Pearl.  Pearl must be notified promptly 
in writing of any changes occurring in reference values during the course of the study.
10.5 Confidentiality
10.5.1 Confidentiality of Data
By signing this protocol, the Investigator affirms to Pearl that information furnished to the 
Investigator by Pearl will be maintained in confidence and such information will be divulged 
to the IRB/IEC, or similar or expert committee; affiliated institution; and employees only 
under an appropriate understanding of confidentiality with such board or committee, 
affiliated institution and employees. Data generated by this study will be considered 
confidential by the Investigator, except to the extent that it is included in a publication.
10.5.2 Confidentiality of Subject/Patient Records
By signing this protocol, the Investigator agrees that Pearl (or representative), IRB/IEC, or 
Regulatory Agency representatives may consult and/or copy study documents in order to 
verify worksheet/case report form data.  By signing the consent form, the subject/patient 
agrees to this process.  If study documents will be photocopied during the process of 
verifying worksheet/case report form information, the subject/patient will be identified by 
unique code only; full names/initials will be masked prior to transmission to Pearl.  In 
addition, the Investigator agrees to treat all subject data used and disclosed in connection 
with this study in accordance with all applicable laws (ie, Health Insurance Portability and 
Accountability Act), rules and regulations.
10.6 Quality Control and Assurance
Pearl is responsible for implementing and maintaining quality control and quality assurance 
systems with written standard operating procedures (SOPs) to ensure that trials are conducted 
and data are generated, documented, and reported in compliance with the protocol, accepted 
standards of GCP, and all applicable federal, state, and local laws, rules and regulations 
relating to the conduct of the clinical study.
10.7 Data Management
Data management procedures and information for this protocol will be provided by Pearl or 
their designee.


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10.8 Study Monitoring
In accordance with applicable regulations, GCP, and Pearl procedures, clinical monitors will 
contact the site prior to subject enrollment to review the protocol and data collection 
procedures with site staff.  In addition, the monitor will periodically contact the site, 
including conducting on-site visits.  The extent, nature, and frequency of on-site visits will be 
based on such considerations as the study objective and/or endpoints, the purpose of the 
study, study design complexity, and enrollment rate.
During these contacts, the monitor will:
Check the progress of the study.
Review study data collected.
Conduct source document verification.
Identify any issues and address their resolution.
This will be done in order to verify that the:
Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements.
The Investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues.
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the Investigator or site staff, as appropriate:
Return of all study data to Pearl.
Data queries. 
Accountability, reconciliation, and arrangements for unused investigational
product(s).
Review of site study records for completeness.
After the final review of the study files, the files should be secured for the appropriate time 
period as specified in Section 10.9. The Investigator will also permit inspection of the study 
files by Pearl’s Quality Assurance auditors, and authorized representatives of the FDA or 
other applicable regulatory agencies.


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10.9 Retention of Data
Documents that individually and collectively permit evaluation of the conduct of the study 
and the quality of the data produced must be maintained for review by Pearl' quality 
assurance auditors and by all applicable regulatory authorities.  The period of time these 
documents must be maintained is governed by applicable regulations.  Pearl or its designee 
will inform the Investigator when these documents may be destroyed.  Pearl or its designee 
must be notified in writing at least 6 months prior to the intended date of disposal of any 
study record related to this protocol to allow Pearl to make alternate storage arrangements.
10.10 Financial Disclosure
The principal Investigator or sub-Investigators named on the Form FDA 1572 will need to 
complete a financial disclosure form prior to study initiation, at any time during the study 
execution if new information needs to be disclosed, and for 1 year after study completion.  
Investigators should make the IRB/IEC aware of any financial interests that the Investigator 
has in the investigational product.
10.11 Investigator's Final Report
Shortly after completion of the Investigator's participation in the study, the Investigator will 
submit a written report to Pearl.
10.12 Publication Policy
A study site may not publish results of a study until after a coordinated multicenter 
publication has been submitted for publication or until one year after the study has ended, 
whichever occurs first. Therefore, the study site will have the opportunity to publish the 
results of the study, provided that “THE SPONSOR” has had the opportunity to review and 
comment on the study site’s proposed publication prior to its being submitted for publication 
with the prior advice of “LEGAL” (intellectual property council) and with proper regard to 
the protection of subjects’ identities.


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11 REFERENCE LIST
Albers R, Ayres J, Backer V, et al. Formoterol in patients with chronic obstructive 
pulmonary disease: a randomized, controlled, 3-month trial. European Respiratory Journal 
2002; 19:936–943.
Anderson GP. Formoterol: pharmacology, molecular basis of agonism, and mechanism of 
long duration of a highly potent and selective beta 2-adrenoceptor agonist bronchodilator. 
Life Science. 1993;52(26):2145-2160.
Atrovent Prescribing Information (US), Boehringer Ingelheim, 2012.
Berger WE, Nadel JA.  Efficacy and safety of formoterol for the treatment of chronic 
obstructive pulmonary disease.  Respir Med.  2008;102:173 88.
Budweiser S, Harlacher M, Pfeifer M, Jörres RA. Co-morbidities and Hyperinflation Are
Independent Risk Factors of All-cause Mortality in Very Severe COPD. COPD. 2013 Oct 10. 
[Epub ahead of print] PubMed PMID: 24111878.
Calverley P, Lee A, Towse L, et al. Effect of tiotropium bromide on circadian variation in 
airflow limitation in chronic obstructive pulmonary disease. Br Medical J. 2003;58(10):855–
860.
Calverley P, Anderson J, Celli B, Ferguson G, Jenkins C, Jones P, Yates J, and Vestbo J, 
Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary 
Disease: New England Journal of Medicine 2007;356:775-89.
Campbell M, Elias A, Johansson G, et al. Formoterol for maintenance and as-needed 
treatment of chronic obstructive pulmonary disease. Respiratory Medicine 2005; 99:1511 
1520.
Campbell, SC, Crier, GJ, Levine, BE, Simon, SJ, Smith, JS, Orevillo, C. et al. Cardiac safety 
of formoterol 12 μg twice daily in patients with chronic obstructive pulmonary disease. 
Pulmonary Pharmacology and Therapeutics 2007; 20:571-579.
Casaburi R, Mahler DA, Jones PW, Wannerz A, San Pedro G, ZuWallack RL, Menjoge SS, 
Serby CW, Witek T.  A long-term evaluation of once-daily inhaled tiotropium in chronic 
obstructive pulmonary disease. Eur Respir J 2002; 19: 217–224.
Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise
tolerance with the combination of tiotropium and pulmonary rehabilitation in subjects with 
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12
APPENDICES


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Appendix 1
Spirometry Performance Recommendations
Spirometry data of the highest quality must be obtained for proper interpretation of the 
results of this protocol.  To these ends, a standard spirometer will be used (provided by 
Pearl), central training provided, qualification will be required, and specific operating 
instruction will also be provided.
Series “ATS/ERS Task Force: Standardization of Lung Function Testing:  Number 2 in 
Series.  European Respiratory Journal 2005; 26(2):319-338.
FEV1 AND FVC MANEUVERS
Equipment Requirements
The spirometer must be capable of accumulating volume for >15 s (longer times are 
recommended) and measuring volumes of >8 L (body temperature (ie, 37°C), ambient 
pressure, saturated with water vapor, BTPS) with an accuracy of at least +3% of reading or 
+0.050 L, whichever is greater, with flows between 0 and 14 L-s-1.  The total resistance to 
airflow at 14.0 L-s-1 must be <1.5 cmH2O L-1s-1 (0.15 kPa L-1s-1).  The total resistance must 
be measured with any tubing, valves, pre-filter, etc. included that may be inserted between 
the subject and the spirometer.  Some devices may exhibit changes in resistance due to water 
vapor condensation, and accuracy requirements must be met under BTPS conditions for up to 
eight successive FVC maneuvers performed in a 10-minute period without inspiration from 
the instrument.
Display
For optimal quality control, both flow–volume and volume–time displays are useful, and test 
operators should visually inspect the performance of each maneuver for quality assurance 
before proceeding with another maneuver.  This inspection requires tracings to meet the 
minimum size and resolution requirements set forth in this standard.  Displays of flow versus 
volume provide more detail for the initial portion (first 1 s) of the FVC maneuver.  Since this 
portion of the maneuver, particularly the peak expiratory flow (PEF), is correlated with the 
pleural pressure during the maneuver, the flow–volume display is useful to assess the 
magnitude of effort during the initial portions of the maneuver.  The ability to overlay a 
series of flow–volume curves registered at the point of maximal inhalation may be helpful in 
evaluating repeatability and detecting sub-maximal efforts.  However, if the point of maximal 
inhalation varies between blows, then the interpretation of these results is difficult because 
the flows at identical measured volumes are being achieved at different absolute lung 
volumes.  In contrast, display of the FVC maneuver as a volume–time graph provides more 
detail for the latter part of the maneuver.  A volume–time tracing of sufficient size also 
allows independent measurement and calculation of parameters from the FVC maneuvers.  In 
a display of multiple trials, the sequencing of the blows should be apparent to the user.  For 
the start of test display, the volume–time display should include >0.25 s, and preferably 1 s, 
before exhalation starts (zero volume).  This time period before there is any change in 
volume is needed to calculate the back extrapolated volume (EV) and to evaluate effort 
during the initial portion of the maneuver. Time zero, as defined by EV, must be presented as 


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the zero point on the graphical output. The last 2 s of the maneuver should be displayed to 
indicate a satisfactory end of test.
When a volume–time curve is plotted as hardcopy, the volume scale must be >10 mm L-1
(BTPS). For a screen display, 5 mm L-1 is satisfactory (Table A1-1).  
Table A1-1
Recommended Minimal Scale Factors for Time, Volume and Flow on 
Graphical Output
Parameter
Instrument Display
Hardcopy Graphical 
Output
Resolution Required
Scale Factor
Resolution Required
Volume*
0.050 L
5 mm-L-1
0.050 L
Flow*
0.200 L-s-1
2.5 mm L-1 s-1
0.200 L-s-1
Time
0.2 s
10 mm-s-1
0.2 s
*The correct aspect ratio for flow versus volume display is two units of flow per one unit of volume
The time scale should be >20 mm-s-1, and larger time scales are preferred (>30 mm-s-1) when 
manual measurements are made.  When the volume–time plot is used in conjunction with a 
flow–volume curve (ie, both display methods are provided for interpretations and no hand 
measurements are performed), the time scale requirement is reduced to 10 mm-s-1 from the 
usually required minimum of 20 mm-s-1 (Table A1-1). The rationale for this exception is that 
the flow–volume curve can provide the means for quality assessment during the initial 
portion of the FVC maneuver.  The volume–time curve can be used to evaluate the latter part 
of the FVC maneuver, making the time scale less critical.
Validation
It is strongly recommended that spirometry systems should be evaluated using a computer-
driven mechanical syringe or its equivalent, in order to test the range of exhalations that are 
likely to be encountered in the test population.  Testing the performance of equipment is not 
part of the usual laboratory procedures.
Quality Control
Attention to equipment quality control and calibration is an important part of good laboratory 
practice.  At a minimum, the requirements are as follows: 1) a log of calibration results is 
maintained; 2) the documentation of repairs or other alterations which return the equipment 
to acceptable operation; 3) the dates of computer software and hardware updates or changes; 
and 4) if equipment is changed or relocated (eg, industrial surveys), calibration checks and 
quality-control procedures must be repeated before further testing begins.
Key aspects of equipment quality control are summarized in Table A1-2.


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Table A1-2
Summary of Equipment Quality Control
Test
Minimal 
Interval
Action
Volume
Daily
Calibration check with a 3 L syringe
Leak
Daily
2 cm H2O (0.3 kPa) constant pressure for 1 minute
Volume 
Linearity
Quarterly
1 L increments with a calibrating syringe measured over 
the entire volume range
Flow Linearity
Weekly
Test at least three different flow ranges
Time
Quarterly
Mechanical recorder check with stop watch
Software
New versions
Log installation date and perform test using “known” 
subject
Calibration is the procedure for establishing the relationship between sensor-determined 
values of flow or volume and the actual flow or volume.  A calibration check is different 
from calibration and is the procedure used to validate that the device is within calibration 
limits, eg, +3% of true. If a device fails its calibration check, then a new calibration 
procedure or equipment maintenance is required.  Calibration checks must be undertaken 
daily, or more frequently, if specified by the manufacturer.  The syringe used to check the 
volume calibration of spirometers must have an accuracy of +15 mL or +0.5% of the full 
scale (15 mL for a 3-L syringe), and the manufacturer must provide recommendations 
concerning appropriate intervals between syringe calibration checks.  Users should be aware 
that a syringe with an adjustable or variable stop may be out of calibration if the stop is reset 
or accidentally moved.  Calibration syringes should be periodically (eg, monthly) leak tested 
at more than one volume up to their maximum; this can be done by attempting to empty them 
with the outlet corked.  A dropped or damaged syringe should be considered out of 
calibration until it is checked.
With regard to time, assessing mechanical recorder time scale accuracy with a stopwatch 
must be performed at least quarterly.  An accuracy of within 2% must be achieved.
Quality Control for Volume-Measuring Devices
The volume accuracy of the spirometer must be checked at least daily, with a single 
discharge of a 3-L calibrated syringe.  Daily calibration checking is highly recommended so 
that the onset of a problem can be determined within 1 day, and also to help define day-to-
day laboratory variability.  More frequent checks may be required in special circumstances, 
such as: 1) during industrial surveys or other studies in which a large number of subject 
maneuvers are carried out, the equipment’s calibration should be checked more frequently 
than daily; and 2) when the ambient temperature is changing (eg, field studies), volume 
accuracy must be checked more frequently than daily and the BTPS correction factor 
appropriately updated.  


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The accuracy of the syringe volume must be considered in determining whether the measured 
volume is within acceptable limits.  For example, if the syringe has an accuracy of 0.5%, a 
reading of +3.5% is appropriate.
The calibration syringe should be stored and used in such a way as to maintain the same 
temperature and humidity of the testing site. This is best accomplished by keeping the 
syringe in close proximity to the spirometer, but out of direct sunlight and away from heat 
sources.
Volume-type spirometer systems must be evaluated for leaks every day.  The importance of 
undertaking this daily test cannot be overstressed.  Leaks can be detected by applying a 
constant positive pressure of >3.0 cmH2O (0.3 kPa) with the spirometer outlet occluded 
(preferably at or including the mouthpiece).  Any observed volume loss of 30 mL after 1 
minute indicates a leak and needs to be corrected.
At least quarterly, volume spirometers must have their calibration checked over their entire 
volume range using a calibrated syringe or an equivalent volume standard.  The measured 
volume should be within +3.5% of the reading or 65 mL, whichever is greater. This limit 
includes the 0.5% accuracy limit for a 3-L syringe.  The linearity check procedure provided 
by the manufacturer can be used if it is equivalent to one of the following procedures: 1) 
consecutive injections of 1-L volume increments while comparing observed volume with the 
corresponding cumulative measured volume, eg, 0–1,1–2, 2–3,…6–7 and 7–8 L, for an 8-L
spirometer; and 2) injection of a 3-L volume starting at a minimal spirometer volume, then 
repeating this with a 1-L increment in the start position, eg, 0–3, 1–4, 2–5, 3–6, 4–7 and 5–8
L, for an 8-L spirometer.  The linearity check is considered acceptable if the spirometer 
meets the volume accuracy requirements for all volumes tested.
Quality Control for Flow-Measuring Devices
With regards to volume accuracy, calibration checks must be undertaken at least daily, using 
a 3-L syringe discharged at least three times to give a range of flows varying between 0.5 and 
12 L-s-1 (with 3-L injection times of 6 s and 0.5 s).  The volume at each flow should meet the 
accuracy requirement of +3.5%.  For devices using disposable flow sensors, a new sensor 
from the supply used for patient tests should be tested each day.
For linearity, a volume calibration check should be performed weekly with a 3-L syringe to 
deliver three relatively constant flows at a low flow, then three at a mid-range flow and 
finally three at a high flow.  The volumes achieved at each of these flows should each meet 
the accuracy requirement of +3.5%.
VC MANEUVERS
Equipment
For measurements of VC, the spirometer or flow meter must comply with the requirements 
for FVC (as described previously) and be capable of accumulating volume for >30 s.  
Expiratory maneuvers or, ideally, both inspiratory and expiratory maneuvers should be 
included in the display of VC maneuver.  Regardless of whether the inspiratory or expiratory 


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maneuver is used for deriving measurements, a display of the entire recorded VC maneuver 
must be provided.  The maximal expiratory volume must be assessed to determine whether 
the subject has obtained a plateau in the expiratory effort. For display of the slow VC, the 
time scale may be reduced to 5 mm-s-1.
TECHNICAL CONSIDERATIONS
Minimal recommendations for spirometry systems
Accurate results require accurate equipment.  Spirometer equipment recommendations apply 
to all spirometers and are minimal requirements. In some circumstances, it may be 
appropriate to exceed these requirements (ie, in some research/surveillance applications).  
Instrumentation recommendations should be followed to provide accurate spirometric data 
and information that is comparable from laboratory to laboratory and from one time period to 
another.  The accuracy of a spirometry system depends on characteristics of the entire 
system, from the volume or flow transducer and the use of an in-line filter, to the recorder, 
display or processor.  Changes in any aspect of the equipment or errors at any step in the 
process can affect the accuracy of the results. For example, if the BTPS correction factor is 
wrong, an accurately measured FVC will be incorrectly reported.  Spirometers are not 
required to measure all of the indices in Table A1-1, but must meet the recommendations for 
those that are measured. Accuracy and repeatability recommendations apply over the entire 
volume range of the instrument. 
Table A1-3.
Range and Accuracy Recommendations Specified for Forced Expiratory 
Maneuvers
Test
Range/Accuracy 
(BTPS)
Flow 
Range
(L-s-1)
Time 
(s)
Resistance and 
Back Pressure
Test Signal
VC
0.5–8 L, +3% of reading 
or +0.050 L, whichever is 
greater
0-14
30
3-L Calibration 
syringe
FVC
0.5–8 L, +3% of reading 
or +0.050 L, whichever is 
greater
0-14
15
<1.5 cm H2O L-1 s-1 
(0.15 kPa L-1s-1)
24 ATS 
waveforms, 3-
L Cal Syringe
FEV1
0.5–8 L, +3% of reading 
or +0.050 L, whichever is 
greater
0-14
1
<1.5 cm H2O L-1 s-1 
(0.15 kPa L-1s-1)
24 ATS 
waveforms
Time 
Zero
The timepoint from 
which all FEVt
measurements are taken. 
Back extrapolation
FEVt: forced expiratory volume in t seconds


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BTPS correction
All spirometry values should be reported at BTPS by any method (measuring temperature 
and barometric pressure) proven effective by the manufacturer. For volume-type spirometers, 
the temperature inside the spirometer should be measured for each breathing maneuver.  
Regardless of the BTPS correction technique used, the ambient temperature must always be 
recorded with an accuracy of +1°C.  In situations where the ambient air temperature is 
changing rapidly (>3°C in <30 min), continuous temperature corrections may be necessary.  
Spirometer users should be aware of potential problems with testing performed at lower 
ambient temperatures: 17°C is the lower limit for ambient temperature, unless a manufacturer 
states that their spirometer will operate accurately at lower ambient temperatures.  If 
barometric pressure is not used in calculating the BTPS correction factor, the range of 
barometric pressures over which the BTPS correction factor is valid must be published.


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Appendix 2
Spirometry Assessment Criteria
Acceptable Versus Usable Tests
Acceptable Tests must meet the following 7 Criteria:
1. Acceptable start of exhalation with brisk upstroke, no hesitation or false start, and back 
extrapolation volume (EV) < 5% of FVC or 0.150 L, whichever is the greater. (Refer to
example in Figure A2-1)
2. No cough during the first second.
3. No valsalva maneuver.
4. No leak.
5. No obstruction of mouthpiece.
6. No extra breaths.
7. Plateau achieved, ie, the volume-WLPHFXUYHVKRZVQRFKDQJHLQYROXPH/IRU
1s, and the patient has tried to exhale for at least 6 seconds.
An acceptable test meets all 7 criteria listed.  This is to be considered the “gold standard”.
Useable spirometry tracings are those that only meet criteria 1 and 2.  When this occurs, 
repeat testing up to 8 attempts in an effort to obtain 3 acceptable spirograms.  If only Usable 
tests are obtained, report results based on the 3 best Usable trials with observed limitations.
Figure A2-1
Example of a Usable Spirogram
The expanded version of the early part of a subject’s volume-time spirogram, illustrating 
back extrapolation through the steepest part of the curve, where flow is peak expiratory flow 
(PEF), to determine the new “time zero”. Forced vital capacity (FVC)-4.291 L; back 
extrapolated volume (EV) – 0.123 L (2.9% FVC): back extrapolation line through PEF.
Between-Maneuver FEV 1 Baseline Stability Criteria
After three acceptable spirograms have been obtained, apply the following tests


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The two largest values of FVC must be within 0.150 L of each other
The two largest values of FEV1 must be within 0.150 L of each other
If these criteria are met, the spirometry testing for that time-point may conclude.  The highest 
FEV1 and the highest FVC obtained at each testing time-point (even if from different 
reproducible tracings), will be collected. 
If acceptability criteria are not met, continue testing until they are met or the patient cannot/ 
should not continue (Maximum of 8 attempts). 


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Appendix 3
Subject Instructions for Use of GFF and Placebo MDI
Before using GFF MDI and Placebo MDI
1. Take the inhaler out of the foil pouch.  Safely throw away the pouch and the drying 
packet that comes inside the pouch.  Check the indicator at the top of the canister; the 
indicator should read as shown in Figure 2.
Figure 2. Indicator at Top of Canister
2. Take the cap off the inhaler and inspect the front of the inhaler and make sure there is 
nothing inside the mouthpiece of the inhaler.  Make sure the canister is fully and firmly 
inserted into the actuator.
3. The inhaler should be stored at room temperature.
How to prime GFF MDI and Placebo MDI
1. The inhaler must be primed before the first use.  Priming involves releasing a certain 
number of sprays (4) into the air before the first use of the inhaler.  Shaking and priming 
the inhaler fills a chamber inside the canister with the correct dose and mix of medication 
so that the inhaler is ready to use.  
2. Take the cap off the mouthpiece of the actuator.
3. To prime the inhaler, gently shake the inhaler for 5-10 seconds and then spray once into 
the air away from yourself and others.  
4. Wait approximately 5-10 seconds and repeat the process three more times.
How to take a dose from GFF MDI and Placebo MDI
Steps 3-6 below should be done one after the other.
1. Take the cap off the mouthpiece of the actuator.
2. Hold the inhaler with the mouthpiece down.
3. Shake the canister for 5-10 seconds.
4. Breathe out fully through mouth, expelling as much air from the lungs as possible. 
5. Tilt head back slightly, place the mouthpiece into mouth, and close lips around it.  To 
allow the medication to enter the lungs, keep tongue flat on the floor of your mouth.  
Keep the mouthpiece at the bottom and the dose indicator at the top.


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6. While breathing in deeply and slowly, press down on the center of the dose indicator with 
finger.  Fully depress the canister until it stops moving in the actuator while delivering
the dose.  Note: It is normal to hear a soft click from the indicator as it counts down 
during use.
7. Hold breath as long as possible, up to 10 seconds, and then breathe normally.
8. Repeat steps 3 to 7, with gentle shaking for 5-10 seconds before the second spray.
9. Put the cap back on the mouthpiece after every time the inhaler is used, and make sure it 
is firmly seated in place.
How to clean GFF and Placebo MDI
It is very important to keep the plastic actuator clean so the medicine does not build-up and 
block the spray.  The inhaler may stop spraying if it is not cleaned correctly.  Do not clean 
the metal canister or let it get wet.
Wash the actuator once a week for the first three weeks as directed below.
1. Take the canister out of the actuator, and take the cap off the mouthpiece. 
2. Wash the actuator through the top of the actuator with warm running water for 
30 seconds (Refer to Figure 3).  
Figure 3. Wash Actuator through Top of Actuator
3. Then wash the actuator again through the mouthpiece (Refer to Figure 4).


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Figure 4. Wash Actuator through Mouthpiece
4. Shake off as much water from the actuator as you can.  Look into the mouthpiece to make 
sure any medicine build-up has been completely washed away.  If there is any visible 
build-up, repeat steps 2 and 3.
5. Let the actuator air dry completely, such as overnight.
6. When the actuator is dry, put the canister in the actuator, making sure the canister is fully 
and firmly fitted into the actuator.  Shake the inhaler gently for 5-10 seconds and spray it 
2 times into the air away from your face, shaking gently 5-10 seconds before each spray.  
Put the cap back on the mouthpiece.
If the actuator becomes blocked
Blockage from medicine build-up is more likely to happen if the actuator is not routinely 
cleaned and the actuator is not air-dried completely.  If the actuator gets blocked so that little 
or no medicine comes out of the mouthpiece, wash the actuator as described in cleaning steps 
1-6.
If the inhaler is needed before the actuator is completely dry, shake as much water off the 
actuator as possible.  Put the canister in the actuator and make sure it fits firmly.  Shake the 
inhaler gently for 5-10 seconds and spray it 2 times into the air away from your face, shaking 
gently 5-10 seconds before each spray. Then take the dose as prescribed and described 
above.  Then clean and air-dry it completely.
How to read the inhaler dose indicator
The inhaler is fitted with a dose indicator which shows how much medicine is left during use.  
The dose indicator display will move after every tenth puff.  The dose indicator pointer will 
start to point to the red area when there are 20 puffs remaining.  This means that the inhaler 
needs to be replaced soon. 


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Figure 5. Metered Dose Inhaler Parts


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Appendix 4
Instructions for Use of Atrovent HFA Inhalation Aerosol 
Device


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Clinical Trial Protocol: PT003017-02
Version 3.0, 26 September 2016
Confidential and Proprietary
Page 112 of 121


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Appendix 5
Instructions for Use of Ventolin HFA Inhaler
The Parts of Your VENTOLIN HFA Inhaler


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Clinical Trial Protocol: PT003017-02
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Confidential and Proprietary
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Pearl Therapeutics, Inc.
Clinical Trial Protocol: PT003017-02
Version 3.0, 26 September 2016
Confidential and Proprietary
Page 116 of 121


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Pearl Therapeutics, Inc.
Clinical Trial Protocol: PT003017-02
Version 3.0, 26 September 2016
Confidential and Proprietary
Page 117 of 121


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Clinical Trial Protocol: PT003017-02
Version 3.0, 26 September 2016
Confidential and Proprietary
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Appendix 6
COPD Assessment Test


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Appendix 7
Dose Indicator Display Reading Instructions
For the purposes of this study, when recording the dose indicator display value, review the 
indicator display at the top of the MDI and record the number of inhalations remaining that 
matches the chart below: 
130 Count (Actuation) Version Shown 
 
If your dose 
indicator 
display looks 
like this record 
120+  
 
If your dose 
indicator 
display looks 
like this record 
120 
 
If your dose 
indicator 
display looks 
like this record 
110 
 
If your dose 
indicator 
display looks 
like this record 
100 
 
If your dose 
indicator display 
looks like this 
record 90 
 
If your dose 
indicator 
display looks 
like this record 
80 
 
If your dose 
indicator 
display looks 
like this record 
70 
 
If your dose 
indicator 
display looks 
like this record 
60 
 
If your dose 
indicator 
display looks 
like this record 
50 
 
If your dose 
indicator display 
looks like this 
record 40 
 
If your dose 
indicator 
display looks 
like this record 
30 
 
If your dose 
indicator 
display looks 
like this record 
20 
 
If your dose 
indicator 
display looks 
like this record 
10 
 
If your dose 
indicator 
display looks 
like this record 
0  
 




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Appendix 9 Investigator’s Agreement and Signature Page
Study Title:
A Randomized, Phase IIIb, Two-period, Double-blind, Two-
treatment, Chronic-dosing (7 Days), Single-center Crossover Study 
to Evaluate the Treatment Effect of PT003 on Cardiovascular 
Hemodynamics in Subjects With Moderate to Severe Chronic 
Obstructive Pulmonary Disease, Compared with Placebo
Study Number:
PT003017-02
Final Date:
26 September 2016
I agree:
To assume responsibility for the proper conduct of the study at this site.
To conduct the study in compliance with the protocol and with any other study conduct procedures provided by 
Pearl.
Not to implement any changes to the protocol without agreement from the Sponsor and prior review and written 
approval from the IRB/IEC, except where necessary to eliminate an immediate hazard to the subjects, or for 
administrative aspects of the study (where permitted by all applicable regulatory requirements).
That I am aware of, and will comply with good clinical practices (GCP) and all applicable regulatory 
requirements.
That I am thoroughly familiar with the appropriate use of the investigational product(s), and other information 
provided by the Sponsor including, but not limited to, the following: the protocol and the current Investigator’s 
Brochure (IB).
To ensure that all persons assisting me with the study are qualified, adequately informed about the 
investigational product(s) and of their study-related duties and functions.
To supply Pearl Therapeutic with any necessary information regarding ownership interest and financial ties; to 
promptly update this information if any relevant changes occur during the course of the study and for 1 year 
following completion of the study; and agree that Pearl may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.
I agree to report all information or data in accordance with the protocol and any other study conduct procedures 
provided by Pearl
That since the information in this protocol and IB is confidential, I understand that its disclosure to any third 
parties, other than those involved in approval, supervision or conduct of the study is prohibited.
To accurately transfer all required data from each subject’s source document to the case report forms (CRFs).  
The CRFs will be provided to the Sponsor in a timely manner at the completion of the study, or as otherwise 
specified by the Sponsor.
To allow authorized representatives of Pearl or regulatory authority representatives to conduct on-site visits to 
review, audit and copy study documents.  I will personally meet with these representatives to answer any study-
related questions.
Signature:
Date:
Name:
Affiliation: