Conditions: COPD, Chronic Obstructive Pulmonary Disease
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 23
Healthy volunteers: no

Brief summary:
To assess the effect of treatment with Glycopyronnium (GP) MDI administered twice daily (BID) and Formoterol Fumarate (FF) MDI administered BID on specific image-based airway volumes and resistance in subjects with moderate to severe chronic obstructive pulmonary disease (COPD) following chronic dosing after approximately two weeks treatment.

Detailed description:

Arms:
arm 1: Glycopyrronium arm 2: Formoterol Fumarate

Interventions: intervention 1: GP MDI (PT001) 14.4 μg intervention 2: FF MDI (PT005) 9.6 μg
Intervention descriptions: intervention 1: Glycopyrronium intervention 2: Formoterol Fumarate

Protocol document:
Prot_000.pdf: 
 
 
Revised Clinical Study Protocol 
Study Code 
PT003019 
NCT #  
NCT02937584 
Date: 
   
  10AUGUST2016 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-Blind, Two Treatment, Two Period, 
Chronic Dosing (2 Weeks), Cross-Over, Multi-Center Study to 
Evaluate the Effects of PT001 and PT005 on Specific Image 
Based Airway Volumes and Resistance in Subjects With Moderate 
to Severe COPD 
 
 
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 
22FEBRUARY2016 
Version 2,  Amendment 1 
10AUGUST2016 
 
 


Glycopyrronium Inhalation Aerosol and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc.
Clinical Trial Protocol: PT003019-01 / FLUI-2015-140  
Version 2.0, 10 August 2016
Clinical Trial Protocol: PT003019-01 / FLUI-2015-140
Title:
A Randomized, Double-Blind, Two Treatment, Two Period, 
Chronic Dosing (2 Weeks), Cross-Over, Multi-Center Study to 
Evaluate the Effects of PT001 and PT005 on Specific Image 
Based Airway Volumes and Resistance in Subjects With Moderate 
to Severe COPD.
Study Number:
PT003019-01 / FLUI-2015-140 
Study Phase:
IIIb
Product Name:
PT001: Glycopyrronium Inhalation Aerosol; Glycopyrronium 
Metered Dose Inhaler  (GP MDI)
PT005: Formoterol Fumarate Inhalation Aerosol; Formoterol 
Fumarate Metered Dose Inhaler (FF MDI)
EudraCT 
Number:
Indication:
2015-001744-11 
COPD
Investigators: 
Multi-center
Sponsor:
Sponsor 
Contact:
Version Number
Date
Original Protocol: 
                Version 1.0 
22 February 2016 
Date of Amended 
Protocol #1 
                Version 2.0 
10 August 2016 
Confidentiality Statement
Property of Pearl Therapeutics, Inc.
This document is confidential and may not be used, divulged, published or otherwise 
disclosed without consent of Pearl Therapeutics, Inc. 


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Clinical Trial Protocol: PT003019-01 / FLUI-2015-140   
Version 2.0, 10August 2016
Confidential and Proprietary
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SUMMARY OF CHANGES TO PROTOCOL VERSION 1.0, DATED 22 
FEBRUARY 2016 FOR VERSION 2.0
The amended study protocol, PT003019-01/FLUI-2015-140 (Version 2.0), includes the 
following edits from version 1.0.  Newly added text is shown in bold font and deleted text is 
shown as strikethrough font. 
No.
Description of Change 
Rationale
1
Title Page  
Study Title:
A Randomized, Double-Blind, Two Treatment, 
Two Period, Chronic Dosing (2 Weeks), Cross-
Over, Single Center
Multi-Center
Study to 
Evaluate the Effects of PT001 and PT005 on 
Specific Image Based Airway Volumes and 
Resistance in Subjects With Moderate to Severe 
COPD
Study Title was edited as the study 
will be a multi-center study
2
Title Page
Investigators: Single Center Multi-center
This study will be a multi-center 
study.  This change has been made 
throughout the document where 
reference to Single Center is made
3
Section 4.1 Overall Study Design and Plan
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. At 
Visit 1 (Screening), eligible subjects who are not 
using a prohibited COPD medication (refer to 
Table 5-1) and meet all other entry criteria will 
return to the clinic in 7 to 14 21 days after 
Screening for Visit 2 (Randomization Visit). For 
more details on Visit 1 procedures, refer to Section 
9 8.1 
To provide clarification of wash-
out period of prohibited COPD 
medications 
prior 
to 
Visit 
2 
(Randomization)
4
Section 4.1 Overall Study Design and Plan  
The baseline CT scans (TLC and FRC scan) will be 
taken at least 30 minutes prior to dosing. During the 
To provide clarification that the CT 
scan will be obtained after the -60 
minute FEV1 and prior to the -30 
minutes 
FEV1 
at 
Visit 
2 


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pre-dose assessements an additional assessments a
scan of the upper airway (UA) will be taken. After 
the CT-scans are taken, spirometry and body 
plethysmography will be performed; the 
inhalation profile will be measured with the body 
plethysmograph and respiration belts. and body
plethysmography will be performed. The subject's 
inhalation profile will be measured in order to draw 
an airflow versus time curve. At the moment of this 
measurement the signal from the respiration belt, 
used for the measurement of the inhalation profile 
during the study drug administration, will also be 
logged
(Randomization)
5
Section 4.1 Overall Study Design and Plan
On Visit 3 (Day 15 ± 5 of TP 1) subjects will 
perform a spirometry test and will undergo Visit 3 
protocol-defined pre-dose assessments (refer to 
Table 8-11 and Table 8-13). The site personnel will 
wait 1 hour after the administration of study drug 
before initiating post-dose assessments. Post-dose 
assessments need to be completed within 2.5 hours 
after dosing the subject. Study drug will be collected. 
Prior to discharge from the study clinic, Study 
drug will be collected, subjects will be discharged 
from instructed to undergo a study drug washout 
period of a minimum of 5 days to a maximum of 21 
days, while on Sponsor-provided Atrovent HFA 
MDI administered QID and Ventolin HFA for 
rescue use, as needed (PRN) prior to initiating the 
next treatment in their assigned treatment sequence. 
For more details on Visit 3 procedures, refer to 
Section 8.3 and Table 8-13
Revised to improve readability 
6
Section 4.1 Overall Study Design and Plan
At Visit 4 (Day 1 of TP 2) it is important to ensure 
that the baseline FEV1 is stable and reflective of the
subject’s COPD severity prior to continuing to the 
second treatment period. As such the baseline 
stability criteria will be evaluated (see section 5.1). 
To ensure baseline FEV1 stability at Visit 4 the -
60 minute FEV1 value obtained at Visit 4 will be 
compared to the average predose (-60 and -30 
minute) FEV1
values obtained at Visit 2.  
Revised to provide clarification on 
which  FEV1 values at Visit 4 will 
be used to assess  stability criteria


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Subjects meeting baseline stability criteria will be 
dispensed treatment period 2 study drug according 
to their assigned treatment sequence and will 
administer their first dose in the clinic under site 
personnel supervision. Subjects will undergo all 
protocol-defined assessments (see Table 8-11 and 
Table 8-12), will be discharged from the clinic, and 
will be instructed to continue study 
drug 
administration for approximately 2 weeks (14 days 
± 5 days) until Visit 5. For more details on Visit 4 
procedures, refer to  Table 8-11 and Table 8-12
7
Section 4.1.1 General Considerations for Treatment 
Visit 2 through Visit 5 (in-clinic)
•
At the start of each treatment period (Visit 2 and 
Visit 4), prior to any study procedures being 
performed, site personnel must confirm the 
subject withheld all non study inhaled COPD
medications,
(including ICS and rescue 
medication, 
eg, 
Ventolin 
HFA),
except 
sponsor-provided Atrovent® HFA for at least 
6 hours, by confirming the last time of dosing 
for all COPD medication(s)
Revised to provide clarification on 
the required washout of the inhaled 
COPD medications at the start of 
each Treatment Period
8
Section 4.1.1   General Considerations for 
Treatment Visit 2 through Visit 5 (in-clinic)
•
At the end of each treatment period (Visit 3 and 
Visit 5), prior to any study procedures being 
performed, site personnel must confirm the 
subject withheld all inhaled COPD medications 
(including randomized study medication, ICS 
and rescue medication, eg, Ventolin HFA) for at
least 6 hours, by confirming the last time of 
dosing for all COPD medication(s) 
Revised to provide clarification on 
the required washout of the inhaled 
COPD medications at the end of 
each Treatment Period
9
Section 4.1.1   General Considerations for 
Treatment Visit 2 through Visit 5 (in-clinic)
Note:
Subjects who inadvertently took inhaled
COPD medication(s) within 6 hours of the start of 
study procedures must be rescheduled as soon as is 
practical but within the specified visit window
Revised to provide clarification 
that subjects taking prohibited 
inhaled COPD medications (refer 
to Table 5-1) within 6 hours of the 
start of study procedures must have 
the visit rescheduled


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10
Section 5.1 Inclusion Criteria
8. Stability criteria:
At Visit 4 if the pre-dose -60 minute FEV1 value is 
outside of the ±20% range compared to the average 
(-30 and -60 minute) pre-dose FEV1 value of Visit 
2, the visit may be rescheduled at the Investigator’s 
discretion, or the subject may be discontinued
Edited to provide clarification on 
which FEV1 values at Visit 4 will 
be used to assess stability criteria
11
Section 5.2 Exclusion:  Renal
c) Subjects with a calculated creatinine 
clearance < 30 ml/min/1.73 m^2 estimated 
using  the Modification of Diet in Renal 
Disease Equation (eGRFMDRD) Chronic 
Kidney Disease Epidemiology 
Collaboration (CKD-EPI) formula at Visit 1 
and on repeat testing prior to Visit 2
Formula 
used 
to 
calculate 
creatinine clearance was changed 
from the Modification of Diet in 
Renal Disease (MDRD) Equation to 
the 
Chronic 
Kidney 
Disease 
Epidemiology 
Collaboration 
(CKD-EPI) formula
12
Section 5.2 Exclusion:  Renal
Note: Subjects with a confirmed calculated 
creatinine clearance < 30 ml/min/1.73 m^2 
estimated using the Modification of Diet in Renal 
Disease Equation (eGFRMDRD) Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI)
formula upon repeat testing prior to Visit 2 will 
not be randomized in the study
Note 
was 
added 
to 
provide 
clarification that subjects with a 
calculated creatinine clearance < 30 
ml/min/1.73 
m^2 
upon 
repeat 
testing prior to Visit 2 will not be 
randomized in the study.
13
Table 5-1 Prohibited COPD Medications and 
Required Washout Periods Prior to Visit 2
Prohibited COPD Medications and Required 
Washout Periods Prior to Visit 1 and Visit 2
Table title edited to include Visit 1 
and prohibited COPD medications 
requiring washout prior to Visit 1 
(Screening) added
14
Section 5.4.1 Prohibited COPD Medications
The following medications used for the treatment of 
COPD are not permitted during this study. These 
medications must be discontinued at 6 hours to 24 
hours prior to
Visit 1 (Screening) and are not 
permitted during the run-in period. The minimum 
washout period before Visit 1 and between Visit 1 
and Visit 2 is are shown in Table 5-1.
The only 
COPD medications permitted during the study 
are sponsor-provided Atrovent HFA® for COPD 
Addition of prohibited COPD 
medication washout requirements 
prior to Visit 1 (Screening)


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maintainance during the run-in and wash-out 
period and sponsor-provided Ventolin HFA® for 
rescue of COPD symptoms during the study
15
Table 5-2 Prohibited COPD Medications and 
Required Washout Periods Prior to Visit 2
Edited to provide clarification of 
the prohibited COPD medications 
and the wash-out requirements of 
prohibited COPD medications prior 
to Visit 1 (Screening)
16
Section 5.4.1 Prohibited COPD Medications
•
Subjects taking prohibited inhaled COPD 
medications (listed previously) will discontinue 
these medications 6 hours to 24 hours before 
Visit 1 for the duration of the trial after 
informed consent is obtained. At Visit 1 
subjects will and be switched to sponsor-
provided Atrovent HFA MDI administered QID 
(during the run-in and wash-out periods only) 
and sponsor-provided Ventolin HFA to be 
administered as needed (PRN) throughout the 
study for control of COPD symptoms
Revised to provide clarification of 
the washout requirements of 
prohibited COPD medications prior 
to Visit 1 (Screening)
17
Section 5.4.1 Prohibited COPD Medications
•
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 
To provide clarification on when 
subjects will be switched from a 
fixed dose combination ICS 
therapy to the ICS component 
alone


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prior to Visit 1 (Screening). At Visit 1 Tthese 
subjects will be switched to the corresponding 
dose of fluticasone, mometasone or budesonide 
administered as a single agent BID, with
sponsor-provided Atrovent HFA MDI 
administered QID (during the run-in and 
wash-out periods only), and sponsor-provided 
Ventolin HFA to be administered up to four 
times per day, as needed (PRN) throughout the 
study for control of COPD symptoms during 
the run in period
18
Section 5.4.1 Prohibited COPD Medications
•
Subjects taking prohibited inhaled
COPD 
medications (listed previously) will discontinue 
these medications 6 hours to 24 hours before 
Visit 1 for the duration of the trial after 
informed consent is obtained. At Visit 1 
subjects will and be switched to sponsor-
provided Atrovent HFA MDI administered QID 
(during the run-in and wash-out periods only) 
and sponsor-provided Ventolin HFA to be 
administered as needed (PRN) throughout the 
study for control of COPD symptoms.
To provide clarification on when 
subjects will be instructed to 
discontinue prohibited inhaled 
COPD medications
19
Section 5.4.1 Prohibited COPD Medications
•
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). In 
this case subjects will be asked to withhold
ICS 6 hours before every study visit.
To provide clarification of wash-
out of ICS that is not administered 
as a fixed-dose combination prior 
to each study visit 
20
Section 5.4.1 Prohibited COPD Medications
All subjects treated with either a LABA (salmeterol, 
formoterol, indacaterol) or currently marketed 
LAMA (tiotropium, aclidinium, glycopyrronium, 
[eg, Seebri]) administered alone or as a loose
combination will have these medications 
discontinued and replaced with sponsor-provided 
Atrovent HFA MDI administered QID (during the 
run-in and wash-out periods only), and sponsor-
To provide clarification on when 
subjects will receive COPD 
maintenance Atrovent HFA during 
the study 


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provided Ventolin HFA to be administered up to 
four times per day, as needed (PRN) throughout 
the study for control of COPD symptoms during 
the run in period.
21
Section 5.4.1 Prohibited COPD Medications
•
Subjects taking prohibited inhaled
COPD 
medications (listed previously) at Visit 1 
(screening)  will discontinue these medications 
6 hours to 24 hours before Visit 1 for the
duration of the trial after informed consent is 
obtained. At Visit 1, subjects will and be 
switched to sponsor-provided Atrovent HFA 
MDI administered QID (during the run-in and 
wash-out periods only) and sponsor-provided 
Ventolin HFA to be administered as needed 
(PRN) throughout the study for control of 
COPD symptoms
Revised to provide clarification of 
the washout requirements of 
prohibited COPD medications prior 
to Visit 1 (Screening) and to clarify 
when subjects will be provided 
study Atrovent HFA and Ventolin 
HFA
22
Section 5.7 Reasons and Procedures for Early 
Termination
•
Following dosing, a heart rate increase of 
greater than 40 bpm from the pre-dose value 
obtained on Day 1 of each Treatment Period 2 1
(Visit 2) and Treatment Period 3 2 (Visit 4)
Period and the measured value is also >120 bpm
To provide clarification of the 
definition of baseline 
23
Section 5.7 Reasons and Procedures for Early 
Termination
•
Following dosing, a systolic blood pressure 
(SBP) increase of more than 40 mmHg from the 
pre-dose 
value 
obtained 
on 
Day 
1 
of 
eachTreatment Period 2
1
(Visit 2) and 
Treatment Period 3 2 (Visit 4)  and the 
measured value is also >160 mmHg
To provide clarification of the 
definition of baseline 
24
Section 5.7 Reasons and Procedures for Early 
Termination
•
Initiation of corticosteroids/antibiotics for 
the treatment of exacerbation 
Bullet 12 added to provide 
clarification that the initiation of 
corticosteroids/antibiotics for the 
treatment of an exacerbation will 
be a reason for early termination  


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25
Section 7.1.1 HRCT Scans
A HRCT scan as baseline measurement will be 
taken on Day 1 of each TP (Visit 2 and Visit 4). 
The pre-dose CT-scan of the thorax will be taken on 
two breathing levels, TLC and FRC. During Visit 2 
an additional scan of the UA will be taken. The 
post-dose measurement will only be performed on 
one breathing level, TLC. The Post dose TLC scan 
will be taken after approximately 2 weeks of 
treatment with either GP MDI or FF MDI on Day 
15 (± 5 days) (Visit 3 and Visit 5)
On Day 1 of each TP (Visit 2 and Visit 4) the CT 
scans will be taken at least 30 minutes prior to 
dosing
Post dose HRCT scan on Day 15 (± 5 days) of each 
TP (Visit 3 and Visit 5) should be started 90min ± 
30 minutes after dosing (approximately between 
1pm-2pm). Spirometry followed by body 
plethysmography will be performed after the HRCT 
scans but within 150 minutes after dosing
To provide clarification on the 
duration of each treatment period 
(15 days ± 5 days)
26
Section 7.1.2 Spirometry
At Visit 2 and Visit 4, spirometry will be obtained at 
the beginning of the visit. A second spirometry will 
be obtained before the study drug administration 
after the pre-dose CT-scans are taken. The average 
of the -60 minute FEV1 values value obtained at 
Visit 4 prior to study drug administration will be 
used to check the stability criteria. At Visit 3 and 
Visit 5, spirometry will be obtained before the study 
drug administration, and post-dosing of study drug.
Post-dose spirometry assessments will not be 
conducted before the CT-scan is taken. At Visits 3 
and 5 none of the post dose assessments will start 
before 1 hour after the administration of the study 
drug. All assessments should be completed within 
2.5 hours after dosing
To provide clarification on which 
FEV1 values at Visit 4 will be used 
to assess the stability criteria
27
Section 7.1.2.2 Stability Criteria
At Visit 2, spirometry will be obtained at the 
beginning of the visit. A second spirometry will be 
To provide clarification on which 
FEV1 values at Visit 4 will be used 
to assess the stability criteria


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obtained before the study drug administration after 
the pre-dose CT scans are taken. The average of the 
FEV1
values obtained prior to study drug 
administration (- 60 min and - 30 min) at Visit 2
will be the baseline value used to compare with the 
average of -60 minute FEV1 value obtained at Visit 
4
At Visit 4, if the pre-dose FEV1 is outside of the 
±20% or 200 mL range compared to the average (-
30 and -60 minute) pre-dose FEV1 value of Visit 2, 
at the investigator's discretion, the visit may be 
rescheduled or the subject may be discontinued
28
Section 7.1.9 Recording of Dose Indicator
At each visit Visit 3 and 5, the site staff will 
compare the dose indicator reading from the prior 
entered reading of Day 1 of that TP. For major 
discrepancies (ie, >20 puff difference), the site staff 
will review the major discrepancy with the subject 
and document reason for the major discrepancy in 
the appropriate study source and eCRF. If 
appropriate, site staff will retrain the subject on the 
proper use of the MDI
To provide clarification that the site 
will evaluate and record the dose 
indicator reading at Visit 3 and 5
29
Section 7.2.3 12-lead Electrocardiogram
•
At Visits 3 and 5 (Day 15 ± 5 days of each TP): 
Each subject will undergo a 12-lead ECG 
approximately 60 minutes prior to study drug 
administration and approximately 90 minutes after 
study drug administration
To provide clarification on the 
duration of each treatment period
(15 days ± 5 days)
30
Section 7.2.3 12-lead Electrocardiogram
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 
LQFUHDVHG E\  PVHF RYHU WKH EDVHOLQH YDOXH
obtained on Day 1 of TP 1 (Visit 2) and TP 2 
(Visit 
4) 
just 
prior 
to 
randomization,
the 
Investigator will make a determination on the 
suitability of continuing the subject in the study. 
Refer to Section 5.7 for specific criteria for QTcF 
that prompt subjects to be discontinued from the 
To provide clarification on when 
the baseline value will be obtained. 


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study. If QTcF interval prolongation exceeding 
these limits is verified during treatment, the 
subject’s medical background should be examined 
closely for risk factors that may have contributed to 
the event, including genotyping for hereditary long 
QT syndromes, if appropriate
31
Table 8-9 Schedule of Events
a  Scheduling visits: The maximum run-in period is 
21 days. The earliest a subject can be randomized 
from the Visit 1 date is 7 days (7 days for LABA 
washout), or 14 days if the subject is washing out 
from tiotropium and 15 days if the subject is 
washing out from Indacaterol. The site should 
make every effort to maintain subjects within the 
scheduled visit window
To provide a clarification of 
duration of wash-out required for 
Indacaterol
32
Table 8-9 Schedule of Events
k Sponsor provided Atrovent HFA or Ventolin HFA 
is should be dispensed only after a subject is 
determined to be eligible to proceed to Visit 2 (Day 
1) (i.e., only if a subject meets the definition of 
COPD 
following 
spirometry 
assessments 
at 
Screening)
To provide clarification on when  
Atrovent HFA or Ventolin HFA 
should be dispensed
33
Table 8-9 Schedule of Events
Visit windows during each Treatment Period are 
relative to Day 1 of that Treatment Period. Washout 
period between Visit 3 and Visits 4 is a minimum of 
5 days to a maximum of 21 9 days (7 ± 2 days)
To provide clarification that the 
maximum wash-out period between 
Visit 3 and Visit 4 is 21 days
34
Table 8-9 Schedule of Events
Note: Site should plan to perform these activities 
so as not to interfere with collection of timed 
assessments such as spirometry. Where data 
collection time-points are concurrent,
variables must be collected in the following 
order: On Day 1 of each treatment period: 
Predose: Urine pregnancy test, Spirometry 
(obtain FEV1 to evalutate stability criteria), 
vital signs, ECG, clinical laboratory 
assessments (Abnormal eGFR at Visit 1 
(screening) must be repeated prior to Visit 2 
and have the results available at Visit 2 to 
To provide clarification that repeat 
creatinine clearance testing must be 
completed 
prior 
to 
Visit 
2 
(randomization) 
and 
results
available at Visit 2 to ensure 
subjects meet the eGFR criteria


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confirm eligibility) in case a retest is needed 
during Visit 2 to check eligibility this can be 
performed earlier, Pre-dose CT scans, 
Spirometry, Body Plethysmography,
Inhalation Profile. Postdose: vital signs, ECG. 
On Day 15 (± 5 days) of each TP: Predose: 
Urine pregnancy test, vital signs, ECG, 
clinical laboratory assessments Postdose: 
Vital signs, ECG, post-dose CT Scan, 
Spirometry, Body Plethysmography
35
Table 8-10. Timed Assessments at Visit 2 and Visit 
4
Footnote “b” realigned
To provide clarification on which 
activities are not timed assessments  
36
Table 8-10. Timed Assessments at Visit 2 and Visit 
4
a At the start of each treatment visit, subject must 
withhold all inhaled COPD medications, including 
study medication, rescue Ventolin HFA and ICS for
at least 6 hours prior to start of test day procedures
To provide clarification on COPD 
medications
37
Table 8-9. Timed Assessments at Visit 2 and Visit 4
i After obtaining informed consent is obtained,
prohibited COPD medications will be stopped 6 
hours to 24 hours before Visit 1 (Screening). At 
Visit 1 COPD medications will be changed as 
specified in the protocol (i.e., Sponsor provided 
Atrovent HFA with or without ICS).  At the end of 
Visit 5, return subject to pre-study or other 
appropriate 
inhaled 
maintenance 
COPD 
medications
To 
provide 
clarification 
that 
subjects will be instructed to wash-
out 
of 
prohibited 
COPD 
medications (refer to Table 5-1) 
after providing informed consent 
and at visit 1 subjects will be 
provided with sponsor-provided 
Atrovent HFA and Ventolin HFA
38
Table 8-11. Timed Assessments at Visit 3 and Visit
5
Footnote “b” realigned
To provide clarification on which 
activities are not timed assessments  
39
Table 8-11. Timed Assessments at Visit 3 and Visit 
5
Note: Site should plan to perform these activities so 
as
not to interfere with collection of timed 
assessments such as spirometry. Where data 
collection time-points are concurrent, variables 
Addition of spirometry assessment 
to 
the 
predose 
assessments 
conducted at Visit 3 and Visit 5


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must be collected in the following order: Predose:
Urine pregnancy test, spirometry, vital signs, ECG, 
clinical laboratory assessments Postdose:  Vital 
signs, ECG, post-dose CT scan, spirometry, body 
plethysmography
40
Section 8.1 Visit 1 (Screening)
•
Obtain informed consent prior to or at the 
beginning of Visit 1 prior to conducting any 
study related procedures
Revised to provide clarification 
that informed consent can be 
obtained prior to or at the 
beginning of Visit 1 prior to 
conducting any study related 
procedures
41
Section 8.1 Visit 1 (Screening)
•
Determine time of last dose of prohibited 
COPD medication as defined in table 5-1  
Revised to provide clarification  
that the time of last dose of 
prohibited COPD medication as 
defined in Table 5-1 must be 
determined
42
Section 8.1 Visit 1 (Screening)
x
Stop 
prohibited 
COPD 
medications 
and 
cChange concurrent COPD medications as 
specified in protocol (refer to Section 5.4.1). 
Sponsor will provide Atrovent HFA QID for 
COPD maintenance and Ventolin HFA as 
needed for symptomatic relief
To provide clarification on the 
washout 
requirements 
of 
the 
prohibited 
COPD 
medications
(refer to Table 5-1) prior to Visit 1
43
Section 8.2 Visit 2 (Randomization: Day 1 of TP 1)
•
Determine time of last dose of short-acting 
bronchodilator 
and 
other 
inhaled
COPD 
medications 
other 
than 
sponsor provided 
Atrovent HFA MDI
Correction
44
Section 8.2 Visit 2 (Randomization: Day 1 of TP 1)
Note: Review inclusion/exclusion criteria, repeat 
testing of the creatinine clearance prior to Visit 2
must be known before the HRCT scan can be taken
To provide clarification that the 
results of the repeat creatinine 
clearance 
testing, 
must 
be 
performed prior to Visit 2 prior to 
randomization to ensure subjects 
meet eGFR criteria and that results 
must be known before the HRCT 
scan can be taken
45
Section 8.2 Visit 2 (Randomization: Day 1 of TP 1)
Subjects will be instructed to bring all study 
medication (including used study drug, replacement 
MDI kit, and sponsor provided Atrovent, HFA and
To provide clarification on which 
medications the patient will be 
instructed to bring to the next study 
visit


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rescue Ventolin HFA) and the Diary to the next 
scheduled clinic visit 
46
Section 8.4 Visit 4 (Day 1 of TP 1)
Determine time of last dose of short-acting 
bronchodilator 
and 
other 
inhaled
COPD 
medications other than sponsor provided Atrovent 
HFA MDI
Correction
47
Section 8.4 Visit 4 (Day 1 of TP 1)
x
Review subject diary entries
To clarify that subject diary entries 
should be reviewed at Visit 4 to 
evaluate subject compliance
48
Section 8.4 Visit 4 (Day 1 of TP 2)
Note:
Confirm 
if 
patient 
meets 
stability 
requirments, if not the visit may be rescheduled 
at the Investigator’s discretion, or the subject 
may be discontinued
Note was added to clarify  subjects 
not meeting stability criteria at 
Visit 4 the visit may be rescheduled 
or the subject may be discontinued 
49
Section 9.1 Introduction
This study will be conducted as a single multi-
center, randomized, double-blind (GP and FF 
MDIs), two treatment period, chronic dosing 
(2 weeks), two-treatment, and crossover design 
evaluating 
the 
following 
two treatments 
in 
approximately 20 subjects
Revised as the study will be a 
multi-center study 
50
Minor typographical errors were addressed but not 
captured as individual items in the summary of 
changes
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SYNOPSIS
Sponsor:
Pearl Therapeutics Inc. 
 
Names of Finished Products:
Glycopyrronium Inhalation Aerosol; PT001, Glycopyrronium Metered Dose Inhaler (MDI) 
Formoterol Fumarate Inhalation Aerosol; PT005, Formoterol Fumarate Metered Dose Inhaler 
(FF MDI)  
Name of Active Ingredients:
Glycopyrronium 
Formoterol Fumarate 
Study Title:
A Randomized, Double-Blind, Two Treatment, Two Period, Chronic Dosing (2 Weeks), 
Cross-Over, Multi-Center Study to Evaluate the Effects of PT001 and PT005 on Specific 
Image Based Airway Volumes and Resistance in Subjects With Moderate to Severe COPD. 
Study Number:  PT003019-01  / FLUI-2015-140 
Study Phase: IIIb 
Study Objectives:
Primary Objectives:
x
To assess the effect of treatment with Glycopyronnium (GP) MDI administered twice daily 
(BID) and Formoterol Fumarate (FF) MDI administered BID on specific image-based 
airway volumes and resistance in subjects with moderate to severe chronic obstructive 
pulmonary disease (COPD) following chronic dosing after approximately two weeks 
treatment.
Secondary Objectives:
x
To assess the effects of GP MDI and FF MDI on various Functional Respiratory Imaging 
(FRI) parameters.
x
To assess the effects of GP MDI and FF MDI on lung function parameters.  
Safety Objective:
To assess the safety of GP MDI and FF MDI in subjects with moderate to severe COPD based
on adverse events (AEs), and any clinically relevant findings from vital sign measurements, 
electrocardiograms (ECGs), physical examination findings, and clinical laboratory evaluations. 


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Study Design:
This is a multi-center, double-blind, two treatment, two period, full cross-over, chronic dosing
(2 weeks) study to assess the effects of GP MDI (14.4 μg BID) and FF MDI (9.6 μg BID) on 
specific image-based airway volumes and resistance in subjects with moderate to severe
COPD.  In this study, airway dimension parameters will be calculated for each of the two 
active compounds. 
This multi-center study will be conducted at a minimum of one site.  Across these sites, it is 
planned that approximately 20 subjects with moderate to severe COPD will be randomized 
into this study.
Study design chart:
Computed Tomography (CT)-scans during study: On Day 1 of each Treatment Period (TP 
[Visit 2 and Visit 4]) baseline measurement inspiratory scan (total lung capacity [TLC] scan) 
and expiratory scan (functional residual capacity [FRC] scan) will be conducted.  During Visit 
2 an additional scan of the upper airway (UA) will be taken. Post dose measurement inspiratory 
scan (total lung capacity [TLC] scan) will be taken after approximately 2 weeks of treatment 
with either GP MDI or FF MDI on Day 15 ± 5 days (Visit 3 and Visit 5). Post dose activities 
should be started 1 hour after dosing on Visit 3 and Visit 5 and should be concluded within 2.5 
hours after dosing. Between the Treatment Periods there will be a washout period of 5-21 days. 
Study Duration: 




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FRI Parameters:
x
Specific airway volume (siVaw)
x
Specific airway resistance (siRaw)
Secondary Efficacy Endpoints:
FRI Parameters:
x
Airway volume (iVaw)
x
Airway resistance (iRaw)
Spirometry Parameters:
x
Forced expiratory volume in one second (FEV1)
Body Plethysmography Parameters:
x
FRC
Other Efficacy Endpoints:
FRI Parameters:
x
Lobe volumes (iVlobes)
x
Air trapping
x
Internal lobar airflow distribution
x
Low attenuation or emphysema score
x
Blood vessel density or fibrosis score
x
Airway wall thickness
x
Mass of deposited particles per defined airway section 
Spirometry Parameters:
x
Forced vital capacity (FVC)
x
Tiffeneau index (FEV1/FVC ratio) 
x
Forced expiratory flow 25%-75% (FEF25-75)
x
Inspiratory capacity (IC)
Body Plethysmography Parameters:
x
Residual volume (RV)
x
TLC
x
Airway resistance (Raw)
x
Specific airway resistance (sRaw)
x
Specific airway conductance (sGaw) 
Safety Endpoints:
x
AEs 


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Statistical Methods:
All statistical analysis will be conducted using 
  
For the efficacy analyses, the effects of both GP MDI and FF MDI will be assessed. The effect 
is defined as the difference between the value at Day 15 and the value prior to dosing on Day
1. Effect is thus the change from baseline to GP MDI, for GP MDI treatment and as the change 
from baseline to FF MDI, for FF MDI treatment.
For each parameter in each group (primary efficacy endpoints: FRI; secondary efficacy 
endpoints: FRI, spirometry and body plethysmography; other efficacy endpoints: all FRI 
parameters except the mass of deposited particles, spirometry and body plethysmography), this 
effect will be assessed. Additional analyses will compare the distribution of regional effects 
between the two treatments for the different FRI endpoints. A linear mixed model approach 
will be chosen and specified fully in the statistical analysis plan.
The Intent-to-Treat (ITT) Population will be considered the primary analysis population for 
efficacy. Supportive analyses will be conducted with the Modified Intent-to-Treat (mITT) 
Population. 
Date of Approved Protocol: 22 February 2016 
Date of Protocol Amendment 1 (Version 2.0):  10 August 2016


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TABLE OF CONTENTS
SUMMARY OF CHANGES TO PROTOCOL VERSION 1.0, DATED 22 FEBRUARY
2016 FOR VERSION 2.0 ..................................................................................................2 
SYNOPSIS...............................................................................................................................15 
TABLE OF CONTENTS.........................................................................................................20 
LIST OF IN-TEXT TABLES ..................................................................................................24 
LIST OF IN-TEXT FIGURES.................................................................................................24 
LIST OF APPENDICES..........................................................................................................24 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................25 
TRADEMARK INFORMATION ...........................................................................................29 
1 
INTRODUCTION AND STUDY RATIONALE ...........................................................30 
1.1 
Study Rationale......................................................................................................31 
2 
STUDY OBJECTIVES....................................................................................................32 
2.1 
Primary Objective ..................................................................................................32 
2.2 
Secondary Objectives.............................................................................................32 
2.3 
Safety Objectives ...................................................................................................32 
3 
STUDY ENDPOINTS.....................................................................................................32 
3.1 
Efficacy Endpoints.................................................................................................32 
3.1.1 
Primary Efficacy Endpoints.........................................................................32 
3.1.2 
Secondary Efficacy Endpoints.....................................................................32 
3.1.3 
Other Efficacy Endpoints.............................................................................33 
3.2 
Safety Endpoints....................................................................................................33 
4 
INVESTIGATIONAL PLAN..........................................................................................34 
4.1 
Overall Study Design and Plan ..............................................................................34 
4.1.1 
General Considerations for Treatment Visit 2 through Visit 5 (in-clinic)...36 
4.2 
Rationale of Study Design .....................................................................................40 
4.3 
Rationale of Dose/Regimen, Duration of Treatment.............................................40 
5 
STUDY POPULATION SELECTION AND WITHDRAWAL CRITERIA .................40 
5.1 
Inclusion Criteria....................................................................................................40 
5.2 
Exclusion Criteria ..................................................................................................42 
5.3 
Subject Identification.............................................................................................46 
5.4 
Prior, Concomitant, and Prohibited Medications...................................................46 
5.4.1 
Prohibited COPD Medications ....................................................................46 
5.4.2 
Other Prohibited Medications......................................................................49 
5.5 
Other Restrictions, Illicit Drugs or Drugs of Abuse ..............................................50 
5.5.1 
Illicit Drugs and/or Drugs of Abuse.............................................................50 
5.5.2 
Dietary Restrictions .....................................................................................50 


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5.6 
Smoking Status ......................................................................................................51 
5.7 
Reasons and Procedures for Early Termination.....................................................51 
6 
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES....................................................................................................53 
6.1 
Subject Information ...............................................................................................53 
6.2 
Product Descriptions..............................................................................................53 
6.3 
Primary Packaging and Labeling Information.......................................................54 
6.4 
Secondary Packaging and Labeling Information (Box).........................................55 
6.5 
Emergency Unblinding of Treatment Assignment ................................................56 
6.6 
Storage Requirements ............................................................................................56 
6.7 
Instructions for Preparation of Treatments for Administration and Dispensing....56 
6.7.1 
GP MDI and FF MDI...................................................................................56 
6.7.2 
Atrovent HFA (Ipratropium Bromide).........................................................57 
6.7.3 
Ventolin HFA (Albuterol Sulfate) ...............................................................57 
6.8 
Drug Accountability/Return of Clinical Supplies..................................................57 
7 
STUDY PROCEDURES .................................................................................................59 
7.1 
Efficacy Assessments.............................................................................................59 
7.1.1 
HRCT scans .................................................................................................59 
7.1.2 
Spirometry....................................................................................................60 
7.1.2.1 
Characterization of Reversibility.......................................................60 
7.1.2.2 
Stability Criteria.................................................................................60 
7.1.2.3 
Inspiratory Capacity...........................................................................61 
7.1.2.4 
Standardization of IC and Spirometry Collections ............................61 
7.1.3 
Body plethysmography................................................................................61 
7.1.4 
Diffusion capacity........................................................................................61 
7.1.5 
Inhalation Profile with Body Plethysmography...........................................62 
7.1.6 
Inhalation Profile during administration......................................................62 
7.1.7 
Subject Diary Data Collection .....................................................................62 
7.1.8 
Rescue Ventolin HFA Use...........................................................................63 
7.1.9 
Recording of Dose Indicator Reading..........................................................63 
7.1.10 
Subject Questionnaires.................................................................................64 
7.1.10.1 
COPD Assessment Test.....................................................................64 
7.1.10.2 
Modified Medical Research Council Dyspnea Scale.........................64 
7.1.11 
COPD Exacerbations ...................................................................................65 
7.2 
Safety Assessments................................................................................................65 
7.2.1 
Medical/Surgical History and Physical Examination ..................................65 
7.2.2 
Vital Sign Measurements.............................................................................65 
7.2.3 
12-Lead Electrocardiogram .........................................................................66 
7.2.4 
Clinical Laboratory Tests.............................................................................67 
7.2.4.1 
Hematology........................................................................................67 


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7.2.4.2 
Clinical Chemistry .............................................................................67 
7.2.4.3 
Urinalysis ...........................................................................................68 
7.2.4.4 
Pregnancy Test...................................................................................69 
7.3 
Adverse Events ......................................................................................................69 
7.3.1 
Performing Adverse Events Assessments....................................................69 
7.3.2 
Adverse Event Definitions...........................................................................69 
7.3.3 
Pre-Randomization Adverse Events ............................................................70 
7.3.4 
Severity ........................................................................................................70 
7.3.5 
Relationship .................................................................................................70 
7.3.6 
Clinical Laboratory Adverse Events............................................................71 
7.3.7 
Serious Adverse Events ...............................................................................71 
7.3.7.1 
Reporting Serious Adverse Events ....................................................72 
7.3.7.2 
Supplemental Investigations of SAEs................................................72 
7.3.7.3 
Post-Study Follow-Up of Adverse Events.........................................73 
7.3.7.4 
Notification of Post-Study Serious Adverse Events..........................73 
7.3.7.5 
IRB/IEC Notification of Serious Adverse Events .............................73 
7.3.7.6 
Health Authority Safety Reports........................................................73 
7.3.8 
Overdose ......................................................................................................73 
7.3.9 
Pregnancy.....................................................................................................74 
7.4 
Termination of the Study .......................................................................................74 
8 
STUDY ACTIVITIES .....................................................................................................75 
8.1 
Visit 1 (Screening).................................................................................................81 
8.2 
Visit 2 (Randomization: Day 1 of TP 1)................................................................82 
8.3 
Visit 3 (Day 15 ± 5 days of TP 1)..........................................................................84 
8.4 
Visit 4 (Day 1 of TP 2) ..........................................................................................85 
8.5 
Visit 5 (Day 15 ± 5 days of TP 2)..........................................................................87 
8.6 
Unscheduled Visit/Premature Discontinuation Visit.............................................87 
8.7 
Follow-Up Telephone Call ....................................................................................88 
8.8 
Completion of the Study........................................................................................89 
9 
PLANNED STATISTICAL METHODS ........................................................................90 
9.1 
Introduction............................................................................................................90 
9.2 
Protocol Variables..................................................................................................90 
9.2.1 
Efficacy Endpoints.......................................................................................90 
9.2.1.1 
Primary Efficacy Endpoints on Day 1 and Day 15, except as 
otherwise noted..................................................................................90 
9.2.1.2 
Secondary Efficacy Endpoints measured on Day 1 and Day 15, 
except as otherwise noted ..................................................................90 
9.2.1.3 
Other Efficacy Endpoints measured on Day 1 and Day 15, except as 
otherwise noted..................................................................................91 
9.2.1.4 
Safety Endpoints................................................................................91 
9.3 
Efficacy Analyses ..................................................................................................92 


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9.3.1 
Efficacy Analysis.........................................................................................92 
9.3.2 
Control of Type I error.................................................................................92 
9.3.3 
Safety Analysis ............................................................................................92 
9.3.3.1 
Adverse Events ..................................................................................92 
9.4 
Randomization.......................................................................................................93 
9.5 
Experimental design...............................................................................................93 
9.6 
Sample Size Consideration ....................................................................................93 
9.7 
Data Validation and Transformation .....................................................................93 
9.8 
Analysis Plan .........................................................................................................94 
9.9 
Study Populations ..................................................................................................94 
9.10 
Handling of Missing Data......................................................................................94 
9.11 
Statistical Software ................................................................................................94 
10 ADMINISTRATIVE CONSIDERATIONS....................................................................95 
10.1 
Regulatory Authority Approval .............................................................................95 
10.2 
Ethical Conduct of the Study and Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) Approval....................................................95 
10.3 
Subject Information and Consent...........................................................................95 
10.4 
Laboratory Accreditation.......................................................................................96 
10.5 
Confidentiality .......................................................................................................96 
10.5.1 
Confidentiality of Data ................................................................................96 
10.5.2 
Confidentiality of Subject/Subject Records.................................................96 
10.6 
Quality Control and Assurance..............................................................................96 
10.7 
Data Management ..................................................................................................96 
10.8 
Study Monitoring...................................................................................................97 
10.9 
Retention of Data...................................................................................................98 
10.10 Financial Disclosure...............................................................................................98 
10.11 Investigator's Final Report.....................................................................................98 
10.12 Publication Policy..................................................................................................98 
11 REFERENCE LIST .......................................................................................................100 
12 APPENDICES ...............................................................................................................102 


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LIST OF IN-TEXT TABLES
Table 5-1. Prohibited COPD Medications and Required Washout Periods Prior to Visit 1 and  
Visit 2...........................................................................................................................47 
Table 5-2. Other Respiratory/Nasal Medications: Required Washout Periods.............................49 
Table 5-3.  Non-COPD Medications Allowed Under Certain Condition ......................................49 
Table 5-4. Prohibited Medications...............................................................................................50 
Table 6-5. Study Product Packaging Descriptions.......................................................................54 
Table 6-6. Description of Boxes...................................................................................................55 
Table 7-7. MMRC Dyspnea Scale ...............................................................................................64 
Table 7-8. Lab Parameters............................................................................................................68 
Table 8-9. Schedule of Events.......................................................................................................76 
Table 8-10. Timed Assessments at Visit 2 and Visit 4..................................................................79 
Table 8-11. Timed Assessments at Visit 3 and Visit 5..................................................................80 
Table 9-12. Randomization Schedule............................................................................................93 
LIST OF IN-TEXT FIGURES 
Figure 1. Study Design Chart......................................................................................................39 
Figure A1-1. Indicator at Top of Canister...................................................................................102 
Figure A1-2. Wash Actuator through Top of Actuator...............................................................103 
Figure A1-3. Wash Actuator through Mouthpiece .....................................................................104 
Figure A1-4. Metered Dose Inhaler Parts ...................................................................................105 
LIST OF APPENDICES
Appendix 1. Subject Instructions for Use of GP and FF MDI...................................................102 
Appendix 2. Instructions for Use of Atrovent HFA Inhalation Aerosol Device .......................106 
Appendix 3. Instructions for Use of Ventolin HFA Inhaler.......................................................109 
Appendix 4. COPD Assessment Test.........................................................................................117 
Appendix 5. Modified Medical Research Council Dyspnea Scale Assessment ........................118 
Appendix 6. Dose Indicator Display Reading Instructions........................................................119 
Appendix 7. Protocol of HRCT scan and CFD method.............................................................120 
Appendix 8. Sponsor Signatory .................................................................................................122 
Appendix 9. Investigator’s Agreement and Signature Page ......................................................123 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATS
American Thoracic Society
AV
Atrioventricular block
BID
bis in die, Twice Daily
BiPAP
Bilevel Positive Airway Pressure
Bpm
Beats per minute
BUN
Blood urea nitrogen
CAT
COPD Assessment Test
CFD
Computational fluid dynamics
CFR
Code of Federal Regulations
CHF
Congestive Heart Failure
CHMP
Committee for Medicinal Products for Human Use
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPAP
Continuous Positive Airway Pressure
CT
Computed Tomography
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
Eg
Exempli gratia, for example
ER
Emergency Room
ERS
European Respiratory Society
EU
European Union
ex-actuator
Dose Delivered From The Actuator (ie, mouthpiece) Of The MDI 


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FDA
Food and Drug Administration
FEF25-75
Forced Expiratory Flow between 25% to 75% of FVC
FEV1
Forced Expiratory Volume In 1 Second
FF MDI
Formoterol Fumarate MDI
FRC
Functional Residual Capacity
FRI
Functional Respiratory Imaging
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GFF MDI
Glycopyrronium and Formoterol Fumarate MDI
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GP MDI
Glycopyrronium MDI
H0
Null Hypothesis
H1
Alternative Hypothesis
HCG
Human Chorionic Gonadotropin
HFA
Hydrofluoroalkane
HRCT
High Resolution Computed Tomography
IB
Investigator’s Brochure
IC
Inspiratory Capacity
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
ICS
Inhaled Corticosteroid
ID
Identification
ie
Id est, that is
IEC
Independent Ethics Committee
IPF
Interstitial Pulmonary Fibrosis
iRaw
Image based Airway resistance
IRB
Institutional Review Board
ITT
Intention-to-treat
IUD
Intrauterine device


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iVaw
Image based Airway volume
iVaww
Airway wall volume
iVlobes
Image based Lobe volumes
L
Liter
LABA
Long-acting Beta Agonist
LAMA
Long-acting Muscarinic Antagonist
LTOT
Long Term Oxygen Therapy
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDI
Metered Dose Inhaler
mITT
Modified Intent-to Treat
ml
Milliliter
MMRC
Modified Medical Research Council 
Msec (ms)
Millisecond
NHANES III
Third National Health and Nutrition Examination Survey
NIPPV
Non-invasive Positive Pressure Ventilation Device
NYHA
The New York Heart Association
OTC
Over the counter
PFT
Pulmonary Function Test
PRN
pro re nata, As Needed
QD
quaque die, Once Daily
QID
quater in die; Four Times Daily
QTcF
QT using Fridericia’s correction factor
RANS
Reynolds averaged Navier-Stokes
Raw
Airway resistance
RV
Residual Volume
SABA
Short-acting Beta Agonist
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan


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SBP
Systolic blood pressure
sGaw
Specific airway conductance
siRaw
Image based Specific airway resistance
siVaw
Image based Specific airway volume
SD
Standard Deviation
SOP
Standard Operating Procedure
SNRI
Serotonin and norepinephrine reuptake inhibitors
sRaw
Specific airway resistance
SSRI
Selective Serotonin Reuptake Inhibitors
TC
Telephone Contact
TCO
The single-breath diffusing capacity of the lungs for carbon monoxide
TEAE
Treatment Emergent Adverse Event
TLC
Total Lung Capacity
71)Į
Anti-WXPRU1HFURVLV)DFWRUĮ
TP
Treatment Period
TURP
Trans-urethral Resection of Prostate
UA
Upper Airway
US
United States
VA
Alveolar volume 
Vbv
Blood vessel volume


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TRADEMARK INFORMATION
Trademarks Not Owned By Pearl Therapeutics, Inc.
Aerolizer
Montelukast
Anoro Ellipta
Seebri Breezhaler
Atrovent
Spiriva Respimat
Bretaris Genuair
Spiolto
Combivent 
Tudorza Pressair
Daxas
Ultibro Breezhaler
Duaklir Genuair
Ventolin
Foradil
Zafirlukast
Incruse Ellipta


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1
INTRODUCTION AND STUDY RATIONALE
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality at 
a global level and recent statistics suggest it will become more prevalent as smoking frequencies 
rise and the population ages (Calverley, 2003; Feenstra, 2001; Ferrer, 1997; Murray, 1997;
Sullivan, 2000). In a systematic review and meta-analysis by Halbert and colleagues, the 
SUHYDOHQFHRISK\VLRORJLFDOO\GHILQHG&23'LQDGXOWVDJHG\HDUVZDVREVHUYHGWREH-10% 
(Halbert 2003 and Halbert 2006). The causes behind COPD are multifactorial, where various risk 
factors and environmental stimuli have been identified and include smoking, air pollution, and 
occupational hazards. 
COPD is a disease of the lungs characterized by airflow limitation that is not fully reversible. 
The chronic airflow limitation characteristic of COPD is caused by a mixture of small airways 
disease (obstructive bronchiolitis) and parenchymal destruction (emphysema) the relative 
contributions of which vary from person to person. The airflow limitation tends to be progressive 
in nature and is frequently associated with an abnormal inflammatory response of the lung to 
noxious particles or gases. This disease is characterized by premature loss of ventilator function 
as determined by a decline in forced expiratory volume in the first second of exhalation (FEV1). 
Pathological inflammatory changes are characterized by elevations in activated macrophages, 
neutrophils, elastases, and CD8 lymphocytes. These molecular and cellular changes caused the 
destruction of small airways and surrounding alveoli. As expiratory airflow (FEV1 or forced vital 
capacity [FVC]) is a function of pressure against resistance, airflow in COPD is diminished due 
to a loss of elastic recoil and airway constriction.
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 beta2 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 (ICS)/LABA or a LAMA is 
currently recommended (GOLD, 2015).
Pearl Therapeutics, Inc. (hereafter referred to as Pearl) is conducting a study (PT003018) 
comparing a Pearl combination product, Glycopyrronium and Formoterol Fumarate (GFF) 
Inhalation Aerosol (PT003) metered dose inhaler [MDI] versus placebo MDI evaluating 
Functional Respiratory Imaging (FRI) and lung function parameters. In the current study, the 
effect of glycopyrronium (GP) MDI 14.4 μg (PT001) and formoterol fumarate (FF) MDI 9.6 μg 
(PT005) on FRI and lung function parameters will be evaluated individually.
Glycopyrronium is a LAMA which exerts bronchodilator 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.


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An inhaled formulation of glycopyrronium (Seebri® Breezhaler®
Inhalation Powder, 
glycopyrronium bromide) was recently approved throughout the European Union (EU), 
Australia, Canada, and Japan for the management of adult subjects with COPD. The 
recommended dose is 44 μg (delivered dose of 55 μg of glycopyrronium bromide equivalent to 
44 μg of glycopyrronium) administered once daily (QD) using the Seebri Breezhaler inhaler. 
Additionally, an inhaled formulation of glycopyrrolate (SeebriTM Neohaler® Inhalation Powder, 
glycopyrronium bromide, 15.6 μg twice daily [BID]) was recently approved in the United States 
for the management of COPD in adult subjects. 
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 
bronchodilator. Formoterol fumarDWH VWLPXODWHV ȕ2 adrenoreceptors in the airways, inducing 
airway smooth muscle relaxation and reducing or preventing bronchoconstriction.
A more detailed description can be obtained in the Investigator Brochure (IB).
1.1 Study Rationale
GP is a potent LAMA which exerts it bronchodilatory effect via muscarinic receptors located on 
smooth muscle cells within the trachea and bronchi.  GP is Pearl's glycopyrronium MDI 
monotherapy product under evaluation to treat patients with COPD. GP has been evaluated in 8 
studies conducted by Pearl.  The lower end of the dose response curve has been adequately 
characterized in two chronic-dose, dose-ranging studies (PT001002 and PT001003), and the 
findings from these two studies and the previous Phase II studies support a dose of GP MDI 14.4 
μg.
FF is a potent and selective LABA approved in many countries worldwide for use in asthma and 
COPD.  Pearl Therapeutics has conducted three studies to confirm dose selection and safety for 
FF MDI. These include studies PT0050801, PT0031002, and PT003005. Results demonstrated 
dose proportionality of FF MDI 9.6 ug and bioequivalence to Foradil with no substantial 
differences in terms of safety between the FF MDI treatment groups to placebo or to Foradil 12 
ug, and there were no important trends noted for FF MDI at any dose.
In this study the effects of treatment with Pearl's monotherapy GP and FF MDIs on specific 
image based airway volumes and resistance in subjects with moderate to severe COPD will be 
assessed. This imaging methodology will allow an assessment of the extent of airway changes 
using the monotherapy products GP and FF. Previous studies demonstrated that looking directly 
at airway volumes and resistance is a more sensitive measure as FEV1 to evaluate the acute 
bronchodilating effect of inhaled LABA and/or LAMA (De Backer, 2011; De Backer, 2012;
Vos, 2013).


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2
STUDY OBJECTIVES 
2.1 Primary Objective
•
To assess the effect of treatment with GP MDI, twice daily (BID) and FF MDI, twice daily 
(BID) on specific image-based airway volumes and resistance in subjects with moderate to 
severe chronic obstructive pulmonary disease (COPD) following chronic dosing after 
approximately two weeks treatment.
2.2 Secondary Objectives
•
To assess the effects of GP MDI and FF MDI on various Functional Respiratory Imaging 
(FRI) parameters.
•
To assess the effects of GP MDI and FF MDI on lung function parameters. 
2.3 Safety Objectives
•
To assess the safety of GP MDI and FF MDI in subjects with moderate to severe COPD
based on Adverse Events (AEs), and any clinically relevant findings from vital sign
measurements, electrocardiograms (ECGs), physical examination findings, and clinical
laboratory evaluations.
3 STUDY ENDPOINTS
3.1 Efficacy Endpoints
3.1.1
Primary Efficacy Endpoints
FRI Parameters:
•
Specific airway volume (siVaw)
•
Specific airway resistance (siRaw)
3.1.2
Secondary Efficacy Endpoints
FRI Parameters:
•
Airway volume (iVaw)
•
Airway resistance (iRaw)


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Spirometry Parameters:
•
FEV1
Body Plethysmography Parameters:
•
FRC
3.1.3
Other Efficacy Endpoints
FRI Parameters:
•
Lobe volumes (iVlobes)
•
Air trapping
•
Internal lobar airflow distribution
•
Low attenuation or emphysema score
•
Blood vessel density or fibrosis score
•
Airway wall thickness
•
Mass of deposited particles per defined airway section 
Spirometry Parameters:
•
Forced vital capacity (FVC)
•
Tiffeneau index (FEV1/FVC ratio) 
•
Forced expiratory flow 25%-75% (FEF25-75)
•
Inspiratory capacity (IC)
Body Plethysmography Parameters:
•
Residual volume (RV)
•
TLC
•
Airway resistance (Raw)
•
Specific airway resistance (sRaw)
•
Specific airway conductance (sGaw)
3.2 Safety Endpoints 
•
AEs


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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a multi-center, chronic dosing (approximately 2 weeks) study to assess the effects of GP 
MDI (14.4 μg BID) and FF MDI (9.6 μg  BID) in subjects with moderate to severe COPD on 
specific image based airway volumes and resistance and lung function.
In this study 20 subjects will be included with moderate to severe COPD. Subjects will be 
randomized in two treatment sequences. Subjects in sequence 1 will receive GP MDI in TP 1
followed by FF MDI in TP 2. Subjects in sequence 2 will receive FF MDI in TP 1 followed by 
GP MDI in TP 2. 
Subjects will receive approximately 2 weeks of study treatment with each of their assigned 
treatments for a total of two separate TPs. A washout period of 5-21 days will occur between 
each TP. The entire study period is scheduled to take approximately 13 weeks for each individual
subject from the time of Screening.  
Prior to or at Visit 1 (Screening), all subjects are to sign an informed consent form prior to the 
conduct of any screening assessments. The Investigator or designee 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 for COPD (30% < FEV1 <80% predicted and FEV1/FVC ratio <0.70) at Visit 
1 to qualify for study enrollment. Reversibility of FEV1 approximately 30-60 minutes following 
four puffs of Ventolin® HFA will be assessed and a ventilation-perfusion relationship 
measurement (diffusion capacity) will be performed at Screening (Visit 1) to characterize the 
subject population. 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. . At Visit 1 (Screening), eligible subjects
who are
using a prohibited COPD medication (refer to Table 5-1) and meet all other entry
criteria will return to the clinic in 7
to 21 days for Visit 2 (Randomization Visit). For more 
details on Visit 1 procedures, refer to Section 8.1.
Subjects who meet all entry criteria but are using certain prohibited COPD medications (eg., oral
ȕ2-agonists, LABAs, LAMAs, LABA/LAMA, corticosteroid/LABA combination products, 
cromoglycate or nedocromil inhalers, leukotriene antagonists [eg., zafirlukast, montelukast] or
tiotropium 
[Spiriva], 
glycopyrronium 
[eg., Seebri®], 
and 
aclidinium 
[eg.,Tudorza®
Pressair®/Bretaris® Genuair®], umeclidinium [Incruse® Ellipta®] and fixed dose LAMA/LABA 
combinations; Duaklir® Genuair® (aclidinium and formoterol), Anoro® Ellipta®] (umeclidinium 
and vilanterol), Ultibro® Breezhaler® (indacaterol and glycopyrronium), and Spiolto® Respimat®
(tiotropium and olodaterol) will discontinue these medications for the duration of the study. 
Subjects taking a fixed-dose combination treatment with an ICS plus a LABA must discontinue 


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the combined medication and instead be prescribed an ICS monotherapy at an equivalent dose 
and regimen for the duration of the study. Subjects previously using an ICS and/or 
phosphodiesterase inhibitor may continue using the medications at the same dose as previously 
described. During the Run-in period, and between Visits 3 and 4, subjects will use 
Sponsor-provided Atrovent® HFA [Atrovent, 2012], administered four times daily (QID) (see
Section 6.7.2) and sponsor-provided rescue Ventolin® HFA (albuterol sulfate inhalation aerosol) 
(GlaxoSmithKline), as needed (PRN), to control symptoms (see Section 6.7.3).
At Visit 1 several key assessments (refer to Table 8-11) shall be obtained. Additionally, dyspnea 
will be evaluated with the Modified Medical Research Council (MMRC) questionnaire, and the 
burden of disease will be assessed through the COPD Assessment Test (CAT), therefore, it is 
necessary for all subjects to be appropriately washed out of their inhaled COPD medications 
prior to Visit 1 (refer to Section 5.4.1). 
At Visit 2 (Randomization Visit; Day 1 of TP 1), subjects will return to the clinic. Site staff must 
confirm the subject meets all protocol-specific requirements and ensure adequate washout 
(6 hours or longer) of all inhaled medications (including ICS, and rescue medication), except for 
sponsor-provided Atrovent® HFA. Subjects who continue to meet entry inclusion/exclusion 
criteria and remain eligible for participation in the study will be randomized into one of two 
pre-defined treatment sequences (possible treatment sequences to which a subject can be 
randomized are shown in Section 9.4). All subjects ZLOOUHFHLYH*30',ȝJ%,'GXULQJ
73IRUZHHNV DQG))0',ȝJ%,'GXULQJWKHRWKHU73IRUZHHNVZLWKD:DVKRXW
Period of a minimum of 5 days to a maximum of 21 days between each TP. 
At Visit 2 subjects will complete all pre-dose timed assessments and in the beginning of the visit 
the baseline FEV1 value will be obtained, refer to Table 8-12 prior to receiving their first dose of 
GFF MDI or Placebo MDI in the clinic under site personnel supervision. During the pre-dose 
assessements ascan of the upper airway (UA) will be taken. After the CT-scans are taken, 
spirometry and body plethysmography will be performed; the inhalation profile will be measured 
with the body plethysmograph and respiration belts. The subject's inhalation profile will be 
measured in order to draw an airflow versus time curve. At the moment of this measurement the 
signal from the respiration belt, used for the measurement of the inhalation profile during the 
study drug administration, will also be logged.
Prior to MDI administration on Day 1 of TP 1 and 2, the MDI device will be primed (four 
actuations to waste) at the study site by the study team in a room separated from the patient. 
After administration of the subject’s first dose, all post-dose assessments will be performed, refer 
to Table 8-12. Following completion of all assessments, subjects will be discharged from the
clinic and will be instructed to continue to administer TP 1 study drug for approximately 2 weeks 
at home until Visit 3.
For more details on Visit 2 procedures, refer to Section
8.2.
The subject, clinical site personnel, and Pearl will be unaware of the treatment sequence assigned 
to a subject; it will not be possible to differentiate between GP and FF MDIs since they will be
identical in all aspects. The GP and FF MDIs will be administered BID.


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Subjects will be trained on how to read the dose indicator. See Section 7.1.9 and Appendix 6 for 
instructions on how and when to read the dose indicator.
On Visit 3 (Day 15 ± 5 of TP 1) subjects will perform a spirometry test and will undergo Visit 3 
protocol-defined pre-dose assessments (refer to Table 8-11 and Table 8-13). The site personnel 
will wait 1 hour after the administration of study drug before initiating post-dose assessments. 
Post-dose assessments need to be completed within 2.5 hours after dosing the subject. Study drug 
will be collected. Prior to discharge from the study clinic, subjects will be instructed to undergo a
study drug washout period of a minimum of 5 days to a maximum of 21 days, while on 
Sponsor-provided Atrovent HFA MDI administered QID and Ventolin HFA for rescue use, as 
needed (PRN) prior to initiating the next treatment in their assigned treatment sequence. For 
more details on Visit 3 procedures, refer to Section 8.3 and Table 8-13.
At Visit 4 (Day 1 of TP 2) it is important to ensure that the baseline FEV1 is stable and reflective 
of the subject’s COPD severity prior to continuating to the second TP. As such baseline stability 
criteria will be evaluated (see Section 5.1). To ensure baseline FEV1 stability at Visit 4 the -60
minute FEV1 value obtained at Visit 4 will be compared to the average of the pre-dose (-60 and -
30 minute) FEV1 values obtained at Visit 2.  Subjects meeting baseline stability criteria will be 
dispensed TP 2 study drug according to their assigned treatment sequence and will administer 
their first dose in the clinic under site personnel supervision. Subjects will undergo all
protocol-defined assessments (see Table 8-11 and Table 8-12), will be discharged from the 
clinic, and will be instructed to continue study drug administration for approximately 2 weeks 
(14 days ±5 days) until Visit 5. For more details on Visit 4 procedures, refer to Section 8.4 and 
Table 8-11.
At Visit 5 (Day 15 ± 5 of TP 2) subjects will again return to the clinic for administration of the 
final dose of TP 2 study drug under site personnel supervision. Visit 5 will serve as the final 
clinic visit.  Prior to the administration of the final dose of study drug subjects will perform a 
spirometry test and will undergo Visit 5 protocol-defined pre-dose assessments
(see 
Table 8-11 and Table 8-13).  The site personnel will wait 1 hour after the administration of study 
drug before initiating post-dose assessments. Post-dose assessments need to be completed within 
2.5 hours after dosing the subject. Study drug will be collected, subjects returned to pre-study or 
appropriate maintenance COPD medications, and subjects will be discharged from the study. A
telephone follow-up will be performed within 7 to 10 days following Visit 5. For more details on 
Visit 5 procedures, refer to Section 8.5 and Table 8-13.
Refer to Table 8-11 for the overview of the study procedures and assessments to be performed at 
the study visits. 
4.1.1
General Considerations for Treatment Visit 2 through Visit 5 (in-clinic)
•
At the start of each treatment period (Visit 2 and Visit 4), prior to any study procedures being 
performed, site personnel must confirm the subject withheld all inhaled COPD medications 
(including ICS and rescue medication, eg, Ventolin HFA, except sponsor-provided Atrovent®
HFA for at least 6 hours, by confirming the last time of dosing for all COPD medication(s).


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Note:
Subjects who inadvertently took COPD medication(s) (except for sponsor-
provided Atrovent® HFA) within 6 hours of the start of study procedures must be 
rescheduled as soon as is practical but within the specified visit window.
Note: Before the in-clinic dose is administered, the site must confirm the subject meets 
all other protocol-specified requirements.
Note:
Subjects must administer sponsor-provided Atrovent® HFA the morning of Visit 
2 and Visit 4 5-6 hours prior to the anticipated time of the post-dose CT scan.
•
At the end of each treatment period (Visit 3 and Visit 5), prior to any study procedures being 
performed, site personnel must confirm the subject withheld all inhaled COPD medications 
(including randomized study medication, ICS and rescue medication, eg., Ventolin HFA) for at
least 6 hours, by confirming the last time of dosing for all COPD medication(s). 
Note: Subjects who inadvertently took inhaled COPD medication(s) within 6 hours of 
the start of study procedures must be rescheduled as soon as is practical but within the 
specified visit window.
Note: Before the in-clinic dose is administered, the site must confirm the subject meets 
all other protocol-specified requirements.
•
Subjects must not ingest xanthine-containing foods and beverages for at least 6 hours prior to 
each study visit and for the duration of each study visit (see Section 5.5.2). 
•
Subjects will be required to refrain from smoking (nicotine gums and patches are allowed) 
for at least 4 hours prior to each study visit and throughout the duration of each study visit.
•
To ensure standardization of dosing times, it is recommended that the sites encourage 
subjects to maintain a dosing schedule at home consistent with their in-clinic dosing time.
Subjects will be required to take their study drug BID in the morning between 07:00 and 
11:00 am (breakfast time) and in the evening between 07:00 and 11:00 pm (dinner time).
•
In order to minimize diurnal variance, site should discuss the importance with the subject of 
dosing in a timely manner every 12 hours for blinded study medication.
•
In order to minimize diurnal variance, site should make every effort to assess subjects at the 
same time throughout the study.
Subjects will be required to return to the clinic at approximately the same time for all 
treatment visits and will be required to remain at the clinic until completion of all 
protocol-defined assessments.
•
The site should make every effort to ensure that the in-clinic dosing time for BID treatment
occurs around 11:00 am and within 12±2 hours of the prior at-home evening dosing time. Site 
are encouraged to call the subject on the day before a scheduled visit to remind the subject of the 
following:
To take their last dose of BID treatments the evening before the scheduled visit at 
approximately 11pm.


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To bring their study drugs, sponsor-provided Atrovent® HFA and sponsor-provided 
Ventolin® HFA with them to the clinic. 
To administer sponsor-provided Atrovent® HFA the morning of Visit 2 and Visit 4 5-6
hours prior to the anticipated time of the post-dose CT scan.
To withhold all inhaled COPD medications (including randomized study medication, 
ICS, and rescue medication) for at least 6 hours prior to study assessments with the 
exception of sponsor-provided Atrovent® HFA at Visit 2 and Visit 4. 
To refrain from ingesting xanthine-containing foods and beverages for at least 6 hours 
prior to each study visit and for the duration of each study visit.
To refrain from smoking for at least 4 hours prior to the study visit and throughout the 
duration of each study visit.
•
The in-clinic dosing time will be recorded as the time of administration of the second puff of 
study drug.
•
Site personnel will instruct subjects not to take any non-study COPD medications, without 
site personnel permission, during a visit until all study procedures have been completed and 
the subject is discharged from the clinic. Site personnel should take every precaution to 
prevent use of non-study inhaled COPD medications during a test day. Site personnel may 
request the subject to surrender all non-study COPD medications prior to the start of the visit 
before performing any study procedures and return the medications to the subject at the end 
of the visit when all study procedures are completed if the Investigator is of the opinion this 
is needed.
•
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 for 
use in the subject’s worksheet and all subsequent spirometry assessments should be stopped. 
However, safety assessments should be continued at the discretion of the Investigator.
•
Every effort must be made to ensure that subjects return to the clinic on Day 15 following the
initiation of each treatment period. To accommodate scheduling conflicts, a window of Day 15 ± 
5 days is permitted (i.e., Day 15 procedures must be done within a minimum of 10 days and a 
maximum of 20 days from Day 1).
During each TP (Visits 2 to 3, and Visits 4 to 5), subjects will be permitted to use 
Sponsor-provided Ventolin HFA on an as-needed basis for relief of COPD symptoms.
During the run-in period and washout period, when subjects are not taking study drug (Visits 1 to 
2, and Visits 3 to 4), subjects will use the Sponsor-provided short-acting bronchodilator
(Atrovent HFA) administered QID and may use Ventolin HFA on an as- needed basis.
Protocol-adjusted ICS therapy defined at Screening, if any, should be continued and remain 
stable for the duration of the study (see Section 5.4 for further guidance related to 
phosphodiesterase inhibitors).
A Study Flow Diagram is displayed in Figure 1.


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Figure 1
Study Design Chart


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4.2 Rationale of Study Design
This study will assess the effects of GP MDI 14.4 μg administered BID and FF MDI 9.6 μg 
administered BID on specific image based airway volumes and resistance.
A randomized, double-blind, full cross-over design was adopted in order to increase the 
precision of comparisons between treatment groups.
4.3 Rationale of Dose/Regimen, Duration of Treatment
The selection of the GP MDI (14.4 ȝg BID) and FF MDI (9.6 ȝg BID) dose in this study was 
based on data from the findings of three previous dose-ranging studies with GP MDI
(Studies PT0010801, PT001002, and PT001003), two dose-ranging clinical studies with FF MDI 
(Studies PT0050801 and PT005003), and four studies with GFF MDI (Studies PT0031002, 
PT003003, PT003004, and PT003005). 
These programs identified the optimal doses as 9.6 ȝg BID for FF MDI and 14.4 ȝg BID for GP 
MDI. The aforementioned studies also showed that Glycopyrronium 14.4 μg when added to 
formoterol fumarate 9.6 μg provides a reasonable benefit across all parameters.  GFF MDI 
14.4/9.6 μg was safe and well- tolerated with an AE profile similar to its components and other 
approved products for the management of COPD (ie, Spiriva, Atrovent, and Foradil®
Aerolizer®).
The study will evaluate the individual effects of GP MDI and FF MDI on specific image based 
airway volumes and resistance, other various FRI parameters, and lung function tests 
over 2 weeks.  
5
STUDY POPULATION SELECTION AND WITHDRAWAL CRITERIA 
5.1 Inclusion Criteria
Subjects eligible for enrolment 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 (ie, physiologically incapable of becoming pregnant, 
including any female who is 2 years post-menopausal); or

Child bearing potential, has a negative urine pregnancy test at Visit 1, and agrees to one of 
the following acceptable contraceptive methods used consistently and correctly as outlined 
below (ie, 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 
5.:
-
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


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-
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. A Male is eligible to enter and participate in the study if he is willing not to father a child 
during the study.
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 (eg, 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years represent 
10 pack-years)].
7. Severity of Disease: Subjects with an established clinical history of COPD and severity 
defined as:
 At Visit 1 pre-bronchodilator FEV1/FVC ratio of <0.70.
 At Visit 1 post-bronchodilator FEV1 must be >30% and <80% predicted normal value, 
calculated using The Third National Health and Nutrition Examination Survey 
(NHANES III) reference equations.
8. Stability criteria:
At Visit 4 if the pre-dose -60 minute FEV1 value is outside of the ±20% range compared to the 
average (-30 and -60 minute) pre-dose FEV1 value of Visit 2, the visit may be rescheduled at 
the Investigator’s discretion, or the subject may be discontinued.
9. Subject is willing and, in the opinion of the Investigator, able to adjust current COPD therapy 
as required by the protocol.
10. Screening clinical laboratory tests must be acceptable to the Investigator.
11. Screening ECG must be acceptable to the Investigator.
12. Chest X-ray or 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 at Visit 1 if the most recent chest X-ray or CT 
scan is more than 6 months old at the time of Visit 1.


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13. 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 other than COPD, i.e., disease or condition which, in the opinion of the 
Investigator, may put the subject 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. Pregnancy: Women who are pregnant or lactating.
3. Males who intend to father a child during the study.
4. Respiratory:
a) Asthma: Subjects, who in the opinion of the Investigator, have a current diagnosis of 
asthma.
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 (High Resolution Computed Tomography 
(HRCT) evidence of bronchiectasis that causes repeated acute exacerbations), 
sarcoidosis, idiopathic interstitial pulmonary fibrosis (IPF), primary pulmonary 
hypertension, or 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.
e) Hospitalization: Subjects who have been hospitalized due to poorly controlled COPD 
within 3 months prior to Visit 1 (Screening) or during the run-in period (Visit 1 to Visit 
2).
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 run-in period (Visit 1 to Visit 2).  
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 1 are 
eligible for enrollment providing the dose of oral steroids remains stable during the run-in 
period (Visit 1 through Visit 2).
g) Lower Respiratory Tract Infection: Subjects who had lower respiratory tract infections 
that required antibiotics and/or oral steroids within 6 weeks prior to Visit 1 (Screening) or 
during the run-in period (Visit 1 to Visit 2).
h) Spirometry Performance:
1) Acceptability: Subjects who cannot perform acceptable spirometry, i.e., meet 
ATS/ERS acceptability criteria.


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2) Repeatability: Subjects who cannot perform technically acceptable spirometry with 
at least three acceptable flow-volume curves with two or more meeting ATS 
repeatability criteria for FEV1 during the pre- bronchodilator assessments at Visit 1 
and at the post-bronchodilator assessment at Visit 1.
i) Oxygen: Subjects receiving long-term-oxygen therapy (LTOT) or nocturnal oxygen 
therapy required for greater than 12 hours a day.  
Note: PRN oxygen use is not exclusionary.
j) Subject use of any non-invasive positive pressure ventilation device (NIPPV).
Note: Subjects using continuous positive airway pressure (CPAP) or bilevel positive airway 
pressure (BiPAP) for Sleep Apnea Syndrome are allowed in the study.
k) Change in smoking status (ie, start or stop smoking,) or initiation of a smoking cessation 
program within 6 weeks of Visit 1 and throughout the run-in period (Visit 1 to Visit 2).
l) 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.
m)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 run-in period (Visit 1 to Visit 2)
5. Cardiac disease:
a) Subjects who have unstable ischemic heart disease, left ventricular failure, or 
documented myocardial infarction within 12 months of Screening (Visit 1). 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) The New York Heart Association (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:
1) Clinically significant conduction abnormalities [eg, left bundle branch block, 
Wolff-Parkinson-White syndrome or evidence of second degree (Mobitz Type II) or 
third degree atrioventricular (AV) block].
2) Clinically significant arrhythmias (eg, atrial fibrillation with irregular ventricular 
response, atrial flutter, ventricular tachycardia).
Note: Atrial fibrillation that has been clinically stable for at least 6 months is 
appropriately treated with anticoagulation and controlled with a rate control strategy 
(ie, 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 
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3) A mean corrected QT interval using Fridericia’s correction factor (QTcF) value at 
screening >450 msec for males and >470 msec for females or an ECG that is not 
suitable for QT measurements (eg, poorly defined termination of the T wave) at 
Visit 1 that remains elevated on repeat testing prior to Visit 2.
4) Ventricular rate <45 bpm.
5) PathRORJLFDO4ZDYHVRI\HDU
6) 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.
7) Any other ECG abnormalities not listed above that in the opinion of the Investigator 
are clinically significant.
8) Clinically Uncontrolled Hypertension: Subjects who have clinically significant 
uncontrolled hypertension.
6. 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 
four weeks prior to Visit 1 or is altered at any point during the Run-in Period (Visit 1 to 
Visit 2), or exceeds the maximum recommended dose.
7. Renal
a) Subjects with symptomatic prostatic hypertrophy that is clinically significant in the 
opinion of the Investigator. Subjects with a trans-urethral resection of prostate 
(TURP) or full resection of the prostate within 6 months prior to Visit 1 are excluded 
from the study.
b) Subjects with bladder neck obstruction or urinary retention that is clinically significant 
in the opinion of the Investigator.
c) Subjects with a calculated creatinine clearance < 30 ml/min/1.73 m^2 estimated 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 a confirmed calculated creatinine clearance < 30 ml/min/1.73 m^2 
estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
formula upon repeat testing prior to Visit 2 will not be randomized in the study.
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.
8. Endocrine
a) Subjects, who in the opinion of the Investigator, have uncontrolled hypo-or 
hyperthyroidism, hypokalemia or hyperadrenergic state.


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b) Subjects, who in the opinion of the Investigator, have uncontrolled Type I or II diabetes.
9. Liver: Subjects with abnormal liver function tests defined as Alanine aminotransferase (AST), 
$VSDUWDWHDPLQRWUDQVIHUDVH$/7RUWRWDOELOLUXELQWLPHVXSSHUOLPLWRIQRUPDODW9LVLW
1 and on repeat testing prior to Visit 2.
10. 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 evaluated, is clinically controlled and the subject’s participation in the study 
would not represent a safety concern.
11. Glaucoma: Subjects with a diagnosis of angle closure glaucoma will be excluded, regardless 
of whether or not they have been treated. Subjects with a diagnosis of open angle glaucoma 
who have intraocular pressure controlled with medication(s) are eligible. All medications 
approved for control of intraocular pressures are allowed including topical ophthalmic non-
seleFWLYHȕ-blockers such as betaxolol, carteolol, levobunolol, metipranolol, or timolol.
12. 'UXJ $OOHUJ\ 6XEMHFWV ZKR KDYH D KLVWRU\ RI K\SHUVHQVLWLYLW\ WR ȕ-agonists, 
glycopyrronium or other muscarinic anticholinergics, or any component of the MDI.
13. Substance Abuse: Subjects, who in the opinion of the Investigator, significantly abuse 
alcohol or drugs (refer to Exclusion Criterion 1).
14. 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.
15. 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 Section 5.4).
16. Vaccinations: Subjects who received a live attenuated vaccination within 30 days prior to 
Visit 1 (Screening) or during the Run-in Period (between Visit 1 and Visit 2). 
Note: Inactivated influenza vaccination, pneumococcal vaccination or any other inactivated 
vaccine is acceptable provided it is not administered within 48 hours prior to Visit 
1(Screening) or Visit 2 (Randomization).
17. Non-compliance: Subjects unable to comply with study procedures. 
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. 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 (ie, studies that do not require change to 
medication or an additional intervention) is not exclusionary.


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21. 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.
22. Previous Participation:  Subjects who were previously enrolled in any trial 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 1). Only subjects continuing to meet entry inclusion/exclusion criteria at 
Visit 2 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 
electronic Case Report Form (eCRF). Any additions, deletions, or changes in the dose of these 
medications while in the study should be entered on the eCRF. Any current ongoing medications, 
including OTC drugs and herbal supplements, will be allowed provided they are not prohibited 
by the protocol (refer to Section 5.4.2) 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 eCRF with indication, dose, dose regimen, and dates of drug administration.
5.4.1
Prohibited COPD Medications
The following medications used for the treatment of COPD are not permitted during this study. 
These medications must be discontinued 6 hours to 24 hours prior to  Visit 1 (Screening) and are 
not permitted during the run-in period. The minimum washout period before Visit 1 and between 
Visit 1 and Visit 2 are shown in Table 5-1.  The only COPD medications permitted during the 
study are sponsor-provided Atrovent HFA® for COPD maintainance during the run-in and wash-
out period and sponsor-provided Ventolin HFA® for rescue of COPD symptoms during the 
study.


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Table 5-1
Prohibited COPD Medications and Required Washout Periods 
Prior to Visit 1 and  Visit 2
Minimum Washout Period Prior to:
Class of Medication
Visit 1
Visit 2
LAMAs
24 hours
Tiotropium: 14 days
Aclidinium: 7 days
Glycopyrronium: 7 days
Umeclidinium: 7 days 
Short-acting muscarinic antagonists 
(SAMA)a
6 hours
6 hours
LABAs (inhaled)
24 hours
48 hours (Indacaterol: 15 days) 
Fixed-combinations of LABA/LAMA
24 hours
7 days 
(15 days for 
indacaterol/glycopyrronium  
and olodaterol/tiotropium)
Fixed-combinations of LABA/ICS
24 hours
7 days 
Fixed-combinations of SABAs and SAMAs 6 hours
6 hours
SABAsb
6 hours
6 hours
2UDOȕ-agonists
2 days 
Theophylline (total daily dose 
>400 mg/day)c
7 days
Monotherapy of ICSd
6 hours
Abbreviations:  COPD=chronic obstructive pulmonary disease; HFA=hydrofluoroalkane; ICS=inhaled 
corticosteroid; LABA=long-DFWLQJȕ-agonist; LAMA=long-acting muscarinic antagonist; SABA=short-acting 
ȕ-agonist
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 run-in and washout period 
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.
d. Protocol adjusted ICS therapy defined at Screening, if any, should be continued and remain stable for the 
duration of the study.
Subjects that have received depot corticosteroids including, intra-articular or intraocular 
corticosteroids require a 3 month washout prior to Visit 1. Subjects that have received oral, 
intravenous or intramuscular corticosteroids for any reason require a 6 week washout prior 
to Visit 1. Any subject that requires use of systemic corticosteroids during the run-in period 
(Visit 1 to Visit 2) will be screen failed.


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Note:
•
Subjects who DUH VWHURLG GHSHQGHQW DQG PDLQWDLQHG RQ DQ HTXLYDOHQW RI  mg oral 
SUHGQLVRQHSHUGD\RUPJRUDOSUHGQLVRQHHYHU\RWKHUGD\IRUDWOHDVW months prior to 
Visit 1 are eligible providing the dose of oral steroids remains stable during the run-in period
(Visit 1-Visit 2).
•
During the TP 1 and 2 (Visit 2 to Visit 3 and Visit 4 to Visit 5), subjects treated with oral 
corticosteroids and/ or antibiotics for exacerbation should be discontinued from the study.
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 prohibited inhaled COPD medications (listed previously) will discontinue 
these medications 6 hours to 24 hours before Visit 1 for the duration of the trial after 
informed consent is obtained. At Visit 1 subjects will be switched to sponsor-provided 
Atrovent HFA MDI administered QID (during the run-in and wash-out periods only) and 
sponsor-provided Ventolin HFA to be administered as needed (PRN) throughout the study 
for control of COPD symptoms.
•
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). At Visit 1 these subjects will be switched to the corresponding dose of
fluticasone, mometasone or budesonide administered as a single agent BID and may continue 
the ICS during the study, sponsor-provided Atrovent HFA MDI administered QID (during 
the run-in and wash-out periods only), and sponsor-provided Ventolin HFA to be 
administered as needed (PRN) throughout the study for control of COPD symptoms.
•
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). In this case 
subjects will be asked to withhold ICS 6 hours before every study visit.
•
All subjects treated with either a LABA (salmeterol, formoterol, indacaterol) or currently 
marketed LAMA (tiotropium, aclidinium, glycopyrronium, [eg, Seebri]) administered alone
or as a loose combination will have these medications discontinued and replaced with 
sponsor-provided Atrovent HFA MDI administered QID (during the run-in and wash-out 
periods only), and sponsor-provided Ventolin HFA to be administered as needed (PRN)
throughout the study for control of COPD symptoms.
The following respiratory medications are not permitted during this study (Table 5-4)


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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 (eg, zafirlukast, 
montelukast) 
7 days
Cromoglycate
7 days
Nedocromil
7 days
Ketotifen *
7 days
*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 5-5). Each concomitant drug must be individually assessed against all exclusion criteria.  
If in doubt, the Investigator should contact the sponsor 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
Treatment regimen has been stable for at least four 
weeks prior to Visit 1 and not altered during the run-in 
period and does not exceed the maximum recommended 
dose
Intranasal corticosteroids, intranasal antihistamines or 
combination thereof
Administered at constant dose and dosing regimen for at 
least 7 days prior to Visit 1 (Screening) and during the 
run-in period
Subjects requiring the following medications are prohibited from this study (Table 5-6). 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, they should be discontinued.


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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 DQWLERGLHV HJ
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/or 
designee 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.
5.5 Other Restrictions, Illicit Drugs or Drugs of Abuse
5.5.1
Illicit Drugs and/or Drugs of Abuse
Illicit drugs or drugs of abuse will not be allowed from the start of Screening (Visit 1) to the end 
of Visit 5 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.  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 are encouraged to refrain from consuming grapefruits or grapefruit juice throughout the 
study. Subjects must not ingest xanthine (ie, caffeine)-containing foods and beverages for at least 


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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 (ie, 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 (ie, whether a subject’s status has changed from smoker to non-smoker or 
vice versa). Any change in smoking status during the run-in period (Visit 1 to Visit 2) will result 
in a screen failure. Smoking status changes during the 2 week TPs will be captured in the eCRF, 
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-years to determine cigarette smoking 
history.
5.7 Reasons and Procedures for Early Termination
Subjects may be withdrawn from the study at any time at their own request, at the request of the 
Investigator, or by Pearl at any time or for any reason. 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 being randomized, regardless of the cause, should undergo the 
assessments outlined in Section 8.6 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 determination as to the suitability of continuing the 
subject in the study. The changes of concern include:
•
Following dosing, a heart rate increase of greater than 40 bpm from the pre-dose value 
obtained on Day 1 of Treatment Period 1 (Visit 2) and Treatment Period 2 (Visit 4) and the 
measured value is also >120 bpm.
•
Following dosing, a systolic blood pressure (SBP) increase of more than 40 mmHg from the 
pre-dose value obtained on Day 1 of Treatment Period 1 (Visit 2) and Treatment Period 2 
(Visit 4) and the measured value is also >160 mmHg.
•
Decrease in creatinine clearance to a value below 30 ml/minute/1.73m2 using CKD-EPI
equation or a clinically relevant change from baseline as determined by the Investigator.
•
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times upper limit of normal on repeat testing
•
Calculated QTcF intervals >500 millisecond (msec), and have increased by 60 msec or more 
over baseline value obtained at Day 1 of Treatment Period 1 (Visit 2) and Treatment Period 2 
(Visit 4).


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•
Subjects who suffer a mild exacerbation will remain in the study and continue to take their 
assigned study drug unless the Investigator decides that it is in the best interest of the subject 
to discontinue early from the study. Any subject who suffers a moderate or severe 
exacerbation will be discontinued.  
An exacerbation will be defined as a change in the subject’s baseline dyspnea, cough, and/or 
sputum (increase in volume or change in color towards purulence) that lasts 3 or more days, is 
beyond normal day-to-day variations, is acute in onset and may warrant a change in regular 
medication. The severity of 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 requires treatment with systemic steroids and/or antibiotics, and 
do not result in hospitalization or death.
•
Severe: exacerbations that result in hospitalization or death.
If a subject requires the following prohibited medications they should be discontinued from the 
study:
•
Initiation of maintenance therapy with any prohibited medications as listed in
Table 5-6.
•
Initiation of maintenance therapy with a marketed LABA (eg, salmeterol, formoterol, 
indacaterol) administered alone or in combination with an ICS or a marketed LAMA
(eg, tiotropium, aclidinium, or glycopyrronium bromide [Seebri]).
•
Initiation of corticosteroids/antibiotics for the treatment of exacerbation 
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 7.3.9).


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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.  Clinical supplies will be 
packaged according to a component schedule generated by a specialized company.  The 
unblinded study pharmacist will assign the study drug to subjects according to a separate 
randomization schedule and will manage the distribution of clinical supplies.  All other study 
personnel will remain blinded.
6.2 Product Descriptions
Investigational materials will be provided by Pearl as summarized in Table 6-7.
Treatments will be blinded in terms of GP MDI or FF MDI administered; these products are 
identical in form and function and indistinguishable from each other. Ventolin and Atrovent are 
open-label products.




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Blinded Supplies: Each MDI will be labeled with a single label.  The MDI actuator will be 
labeled with a single label. The foil pouch will be labeled with a single label. 
Open-label Supplies: Open-label Atrovent HFA and Ventolin HFA will be provided as
individually labeled MDIs. Each MDI will contain a single label.  The MDI actuator will be 
labeled with a single label. The foil pouch will be labeled with a single label.
Both single and two-part labels will be printed with black ink and may include the following 
text:
Packaging Lot Trace ID #
Space for entry of screening #
Component ID #
Space for entry of randomization #
Fill Count & Dosage Form
Space for entry of Interval ID (Visit # only)
Re-evaluation/Expiration date (if applicable)
Dosing Instructions
Storage Conditions
Compound ID - Protocol #
Country regulatory requirements
Sponsor address (If applicable)
Translation Key (If applicable)
Abbreviation:  ID=identification
6.4 Secondary Packaging and Labeling Information (Box)
Blinded investigational drug and open-label (Atrovent HFA and Ventolin HFA) supplies will be
packaged in individual boxes as outlined in Table 6-8. Box configuration is subject to change as 
a result of packaging constraints.
Table 6-6
Description of Boxes
Drug supplies
Individual box contents
Blinded
Atrovent HFA
Ventolin HFA 
1 MDI
1 MDI
1 MDI
Each box will be labeled with a two-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)
Abbreviation:  ID=identification


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6.5 Emergency Unblinding of Treatment Assignment
The individual subject emergency code break sealed envelopes should be used in order to 
unblind subjects and to unmask drug identity. When the Investigator needs to unblind a subject, 
he/she must confirm the necessity to unblind the subject. 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 appropriate clinical management or welfare 
of the subject. Whenever possible, the Investigator must first discuss options with the Sponsor 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: Store below 25° C (77° F) in a dry place. Excursions permitted up to 30° C (86°
F).
Ventolin HFA supplies: Store between 15° and 25°C (59° 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°-30°C (59°-86°F). 
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 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 this protocol or in the 
product label. Documentation of temperature monitoring should be maintained.
6.7 Instructions for Preparation of Treatments for Administration and 
Dispensing
6.7.1
GP MDI and FF MDI
Individual GP MDI and FF MDI will be packaged in a foil pouch and contained in an individual 
visit treatment box. Both the visit treatment box and the foil overwrap will have a label with a 
component identification number. Confirm that the identifier given by the randomization lists 
and the component identification number written on the label are the same. The visit treatment 
box is labeled with a two-part label. Write the subject number and treatment visit number on 
each of the two-part labels. The ‘tear-off’ part of the label is to be placed onto the subjects 
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All MDIs must be primed before the first use. Priming involves releasing 4 sprays 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.
The MDI must be primed in a separate room from the subject treatment area.  Each dose will 
consist of 2 puffs from the MDI. Subjects will be dispensed the MDI and instructed to continue 
taking study medication twice daily, 2 puffs in the morning and 2 puffs in the evening 
approximately 12 hours apart, until subject returns to the clinic. The MDI should be stored 
upright at room temperature by the subject, avoiding temperature extremes, and storage in direct 
sunlight. Refer to Appendix 1 for instructions on the administration of GP MDI and FF MDI.  
Cleaning instructions are provided in Appendix 1.
6.7.2
Atrovent HFA (Ipratropium Bromide) 
Open-label Atrovent HFA will be provided by Pearl and stored in a secured location within the 
clinic or pharmacy facilities.  
Atrovent HFA is a solution aerosol that does not require shaking. However, as with any other 
MDI, some coordination is required between actuating the canister and inhaling the medication. 
Atrovent HFA should be primed per manufacturer’s instructions prior to dispensing to subject 
(ie, "prime" or actuate Atrovent HFA before using for the first time by releasing 2 test sprays 
into the air away from the face). In cases where the inhaler has not been used for more than 3 
days, prime the inhaler again by releasing 2 test sprays into the air away from the face. Subjects 
should avoid spraying Atrovent HFA into their eyes.
Subjects will be dispensed the Atrovent HFA for COPD maintenance therapy during the run-in 
period (between Visit 1 and 2) and during the washout period (between Visit 3 and 4) per the 
manufacturer’s instruction, 2 puffs with each administration four times a day, divided over the 
daytime. The MDI should be stored at room temperature by the subject, avoiding temperature 
extremes and storage in direct sunlight. Refer to Appendix 2 for the manufacturer’s instructions 
on the administration of Atrovent HFA.
6.7.3
Ventolin HFA (Albuterol Sulfate)
Open-label Ventolin HFA will be provided by Pearl and stored in a secured location within the 
clinic or pharmacy facilities. Ventolin HFA should be stored at room temperature by the subject. 
Ventolin HFA should be primed per manufacturer’s instructions prior to dispensing to subject. 
Refer to Appendix 3 for the manufacturer’s instructions on the administration of Ventolin HFA. 
Study personnel will record number on the dose counter at the time of dispensing (following 
priming and characterization of reversibility) and upon return. 
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 


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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. 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 each site’s investigator file. 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
The ICF must be obtained prior to performing any and all study-related activities. The ICF must 
be approved by the Independent Ethics Committee (IEC)/ Institutional Review Board (IRB) 
that is reviewing the study documents. Informed consent will be obtained for all subjects 
participating in the study. Subjects may withdraw consent at any time. Participation in the study
may be terminated at any time without the subject’s consent at the discretion of the Principal
Investigator.
A schedule of events is provided in Table 8-11. Detailed schedules for pre and post-dose 
procedures to be performed on visit days are provided in Table 8-12 and Table 8-13.
7.1
Efficacy Assessments
7.1.1
HRCT scans
A HRCT scan as baseline measurement will be taken on Day 1 of each TP (Visit 2 and Visit 4). 
The pre-dose CT-scan of the thorax will be taken on two breathing levels, TLC and FRC. During 
Visit 2 an additional scan of the UA will be taken. The post-dose measurement will only be 
performed on one breathing level, TLC. The Post dose TLC scan will be taken after 
approximately 2 weeks of treatment with either GP MDI or FF MDI on Day 15 (± 5 days) (Visit 
3 and Visit 5). 
On Day 1 of each TP (Visit 2 and Visit 4) the CT scans will be taken at least 30 minutes prior to 
dosing.
Post dose HRCT scan on Day 15 (± 5 days) of each TP (Visit 3 and Visit 5) should be started 
90min ± 30 minutes after dosing (approximately between 1pm-2pm). Spirometry followed by 
body plethysmography will be performed after the HRCT scans but within 150 minutes after 
dosing.
Between the two TPs there will be a washout period of a minimum of 5 days up to a maximum 
of 21 days.
Whenever possible the same scanner should be used at all the study visits.
HRCT scan is performed with a low radiation protocol. These images are made to perform 
Computational fluid dynamics (CFD) in order to obtain more information on regional lung 
function characteristics. For more details of the protocol of CT scan and CFD please refer to the 
addendum in Appendix 7.


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7.1.2
Spirometry
Forced expiratory spirometry maneuvers for derivation of FEV1, FVC, FEF25-75, FEV1/FVC ratio 
and IC will be assessed using a spirometer that meets or exceeds minimum performance 
recommendations of the ATS.
Spirometry will be conducted at all visits. At Visit 1, Spirometry will be conducted
approximately 60 minutes and 30 minutes prior to bronchodilator administration and 
approximately 30-60 minutes post-bronchodilator (refer to Section 7.1.2.1). 
Note: Spirometry must meet the severity and both acceptability and repeatability criteria (refer to 
Section 5.1 and Section 5.2).
At Visit 2 and Visit 4, spirometry will be obtained at the beginning of the visit. A second 
spirometry will be obtained before the study drug administration after the pre-dose CT-scans are 
taken. The -60 minute FEV1 value obtained at Visit 4 prior to study drug administration will be 
used to check the stability criteria. At Visit 3 and Visit 5, spirometry will be obtained before the 
study drug administration, and post-dosing of study drug. Post-dose spirometry assessments will 
not be conducted before the CT-scan is taken At Visit 3 and 5 none of the post dose assessments 
will start before 1 hour after the administration of the study drug. All assessments should be 
completed within 2.5 hours after dosing.
7.1.2.1
Characterization of Reversibility
Reversibility to Ventolin HFA (SABA) will be evaluated at Visit 1.  
The procedure will be, as follows:  Reversibility testing to Ventolin HFA:
x
Perform pre-bronchodilator PFTs (approximately -60 minutes and -30 minutes) prior to 
administration of Ventolin HFA (albuterol).
x
Administer 4 puffs of Ventolin HFA (albuterol).
x
Perform post-bronchodilator PFT 30-60 minutes after the administration of Ventolin HFA.
Reversibility will be a comparison of the average best FEV1 effort obtained at approximately 
-60 minutes and -30 minutes pre-bronchodilator to the best FEV1
effort obtained at 
approximately 30-60 minutes post-bronchodilator. A subject is determined to be reversible to 
Ventolin HFA if the improvement in FEV1
approximately 30-60 minutes following 
administration of 4 SXIIVRI9HQWROLQ+)$UHVSHFWLYHO\LVDQG ml. Reversibility to 
Ventolin HFA (obtained at Visit 1) will be used to characterize the population.
7.1.2.2
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 TP.
At Visit 2, spirometry will be obtained at the beginning of the visit. A second spirometry will be 
obtained before the study drug administration after the pre-dose CT scans are taken. The average 


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of the FEV1 values obtained prior to study drug administration (- 60 min and - 30 min) at Visit 2 
will be the baseline value used to compare with the -60 minute FEV1 value obtained at Visit 4. 
At Visit 4, if the pre-dose FEV1 is outside of the ±20% or 200 mL range compared to the average 
(-30 and -60 minute) pre-dose FEV1 value of Visit 2, at the investigator's discretion, the visit 
may be rescheduled or the subject may be discontinued.
7.1.2.3
Inspiratory Capacity
Visit 1 to Visit 5: IC assessments will be conducted with every spirometry. 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 TLC with no hesitation. From at least three acceptable trials, 
the two largest IC measurements should agree within 5% or 150 ml, both of these IC values will 
be captured and analyzed. 
7.1.2.4
Standardization of IC and Spirometry Collections
All pulmonary function tests including FEV1, FVC, FEF25-75, FEV1/FVC ratio, as well as all IC 
assessments, as defined in ATS/ERS guidelines will be performed in accordance with ATS 
criteria (Miller, 2005).
The volume accuracy of the spirometer is to be checked daily using a 3 L syringe across 3 flow 
ranges (ie, low, medium and high flows), 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 of the calibration 
factor will be maintained on site, which will be available if the sponsor wants to check for 
compliance or an audit.
7.1.3
Body plethysmography
Visit 2 to Visit 5: RV, TLC, FRC, Raw,
sRaw,
sGaw will be measured using body 
plethysmography.
On Day 1 of each TP (Visit 2 and Visit 4) the body plethysmography measurement will be 
performed after the CT-scan before the IP administration.
On Day 15 (± 5 days) of each TP (Visit 3 and Visit 5) the body plethysmography measurement 
will be performed after the CT-scan and after the post-dose spirometry measurement.
Post dose activities on Day 15 (± 5 days)  of each TP (Visit 3 and Visit 5) will be started 1 hour 
after dosing on and will be concluded within 2.5 hours after dosing. 
7.1.4
Diffusion capacity
The single-breath diffusing capacity of the lungs for carbon monoxide (TCO), alveolar volume 
(VA) and TCO/VA will be measured at Visit 1. TCO measurement will be used to characterize 


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the subjects enrolled in the trial and will not be used to determine subject eligibility to participate 
in the study. 
7.1.5
Inhalation Profile with Body Plethysmography
Visit 2 and Visit 4: In order to draw an airflow versus time curve, the subject’s inhalation profile 
will be measured. The subject will be asked to inhale and exhale maximally through a 
mouthpiece without a nose clip. This measurement is performed with a body plethysmograph. At 
the moment of this measurement the signal from the respiration belt, used for the measurement 
of the inhalation profile during the study drug administration, will also be logged. 
7.1.6
Inhalation Profile during administration
Visit 2 and Visit 4: During IP administration on Day 1 of both active compounds, the inhalation 
profile will be recorded while the subject inhales through the device to generate a subject 
specific inhalation profile by using a respiration belt. The thorax and abdomen expansion will be 
measured with the 
 diagnostic device. This inhalation profile which represents the lung 
expansion during inhalation of the medication can be coupled with the values of the 
corresponding lung volume expansion (RV – TLC) measured with the body plethysmography 
wearing the respiration belts. 
Sensor cables transmit the appropriate signals to the 
. The signals are stored on the 
removable memory card, or if configured to do so, the signals can be displayed from the 
 
 on a computer running the 
 software application.  
7.1.7
Subject Diary Data Collection
At Visit 1, subjects will be provided with a Diary to be completed twice daily (morning and 
evening).  Study personnel will train subjects on Diary completion and will instruct subjects to 
return Diary responses to the clinic for all in-clinic study visits.  
•
At Visit 1, subjects will be instructed to record in the Diary Atrovent HFA four time daily 
use and rescue Ventolin HFA use during the Run-in Period prior to Visit 2.   
•
At Visit 2, subjects will be instructed to record in the Diary study medication administration 
and the use of rescue Ventolin HFA. 
•
At Visit 3, subjects will be instructed to record in the Diary Atrovent HFA four time daily 
use and rescue Ventolin HFA) use during the Wash-out Period between Visit 3 and Visit 4.   
•
At Visit 4, subjects will be instructed to record in the Diary study medication administration 
and the use of rescue Ventolin HFA.  
Diary Compliance Requirement: Subject participation may be terminated at any time during the 
study for the following reason: 
Chronic failure, in the judgment of the Investigator, to comply with diary completion, despite 
documentation at the site of repeated efforts to reinforce compliance. As defined for this study, 


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compliance requires >70% subject completion of diary assessments.  The Sponsor may also 
instruct a site to discontinue a subject based on consistent noncompliance.
Subjects who are unable to meet the compliance requirement (>70% subject completion of diary 
assessments) in the last 7 days preceding the Randomization Visit (Visit 2) must be retrained. 
When retraining is required due to non compliance the Randomization Visit (Visit 2) must be 
rescheduled.
In-clinic dosing times and dose indicator readings will be documented in the eCRF by the site 
staff and will not be entered by the subject into their Diary.
During the treatment periods, each subject will record his/her symptoms in the study-provided 
Diary, twice daily (morning and evening).  The subject will record his/her use of rescue Ventolin 
HFA twice daily, morning and evening.  In addition, the subject will record study medication 
usage.
7.1.8
Rescue Ventolin HFA Use 
Subjects requiring more than 8 puffs per day on 3 consecutive days with worsening symptoms 
should contact the site. The number of “puffs” of rescue Ventolin HFA is the number of 
actuations of the canister. For example, when rescue Ventolin HFA is required and 2 actuations 
are inhaled, this should be counted as 2 “puffs.” In the event the subject requires 4 actuations, 
this should be counted as 4 “puffs”.  
At Visit 2 to 5 the subject will be asked to bring the rescue Ventolin HFA and the site personnel 
will record the number of actuations of the canister.
7.1.9
Recording of Dose Indicator Reading
The GP MDI and FF MDI are fitted with a dose indicator to track use of the MDI.
Site personnel will be instructed to record the dose indicator reading from the MDI after priming 
(prior to the first dosing Day 1) and after the first dosing Day 1 of both the TPs (Visit 2 and Visit 
4). All MDIs 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 (For more details refer to Section 6.7).
Prior to dosing at Day 15 (± 5 days)  of each TP Visit (Visit 3 and Visit 4) or at a Premature 
Discontinuation Visit, site personnel will observe the dose indicator reading on the study drug 
returned by the subject and record the dose indicator reading in the source. 
Note: The dose indicator reading recorded by the site staff on Day 15 (± 5 days) of each TP 
(Visit 3 and Visit 5) will be the dose indicator reading observed prior to subject dosing.  
At Visit 3 and 5, the site staff will compare the dose indicator reading from the prior entered 
reading of Day 1 of that TP. For major discrepancies (ie, >20 puff difference), the site staff will 


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review the major discrepancy with the subject and document reason for the major discrepancy in 
the appropriate study source and eCRF. If appropriate, site staff will retrain the subject on the 
proper use of the MDI.
7.1.10
Subject Questionnaires
The following subject questionnaires will be completed by subjects using the study supplied 
questionnaire at Visit 1: CAT, and MMRC.
7.1.10.1 COPD Assessment Test
The CAT is a self-administered questionnaire designed to assess the condition of subjects and 
overall impact of COPD. 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 MMRC Dyspnea Scale.
Subjects will complete the CAT (refer to Appendix 4) at Visit 1. 
The CAT score will describe the burden and symptomatic impact of COPD in subjects enrolled 
in the trial and will not be used to determine subject eligibility to participate in the study.
7.1.10.2 Modified Medical Research Council Dyspnea Scale
The MMRC Dyspnea Scale uses a simple grading system to assess a subject's level of dyspnea,
shortness of breath (Table 7-9 and Appendix 5).
Table 7-7:
MMRC Dyspnea Scale
Grade
Description of Breathlessness
0
I only get breathless with strenuous exercise.
1
I get short of breath when hurrying on level ground or walking up a slight hill.
2
On level ground, I walk slower than people of the same age because of breathlessness, or have to stop for 
breath when walking at my own pace.
3
I stop for breath after walking about 100 meters or after a few minutes on level ground.
4
I am too breathless to leave the house or I am breathless when dressing.
The MMRC scale is a five-point scale published in 1959 that considers certain activities, such as 
walking or climbing stairs, which provoke breathlessness (Fletcher 1959). In one minute, the 
subject selects a grade on the MMRC scale that most closely matches his/her severity of 
dyspnea. The MMRC scale is considered a discriminative instrument that can categorize subjects 
with COPD in terms of their disability. The MMRC scale is not satisfactory as an evaluative
instrument to measure changes in dyspnea, and its broad grades are generally unresponsive to 
interventions such as pharmacotherapy. 
Subjects will complete the MMRC scale at Visit 1, as a description of the symptomatic burden in 
study subjects. The MMRC scale will not be used to determine subject eligibility to participate in 
the study.


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7.1.11
COPD Exacerbations
Site personnel will evaluate whether the subject has experienced a worsening of their COPD that 
meets the definition of a COPD exacerbation since their last visit. An exacerbation will be 
defined as a change in the subject’s baseline dyspnea, cough, and/or sputum (increase in volume 
or change in color towards purulence) that lasts 3 or more days, is beyond normal day-to-day 
variations, is acute in onset and may warrant a change in regular medication.
All COPD exacerbations will be reported as AEs unless considered a serious adverse event 
(SAE).
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.
7.2 Safety Assessments
The safety assessments include physical examination findings, vital signs, ECGs, clinical 
laboratory tests in addition to recording of AEs and SAEs. 
7.2.1
Medical/Surgical History and Physical Examination
Medical history, including smoking history details, will be collected at Visit 1 (Screening) and 
updated during the run-in period (Visit 1 to Visit 2). The number of COPD exacerbations 
requiring oral steroids and/or oral antibiotics, or hospitalization within 12 months of Visit 1 
(Screening) will be collected. A complete physical examination will be performed at Visit 1 
(Screening) and at Visit 5. A complete physical examination will include evaluation of relevant 
body parts, general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), 
lymph nodes, chest, heart, abdomen, extremities, and nervous system. Weight, assessed in 
ordinary indoor clothing with shoes removed and height will be recorded at Visit 1 (Screening).
At all visits (including the follow-up telephone call [TC]) the subject will be asked about any 
recent change in their smoking status (ie, whether a subject’s status has changed from smoker to 
non-smoker or vice versa).  
7.2.2
Vital Sign Measurements
Heart rate, systolic and diastolic blood pressure, and temperature (‘vital signs’) will be assessed 
as outlined below; assessments may be obtained in either the supine or seated position obtained 
after the subject has been in the supine or seated position for 5 minutes. 
If, in the opinion of the Investigator, a clinically significant vital sign change occurs, then the 
measurement will be repeated at medically appropriate intervals until the value returns to within 


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an acceptable range. Temperature will be collected at Screening (Visit 1) and at pre-dose at all 
visits and will not be repeated post-dose.
Obtain heart rate and SBP/Diastolic blood pressure (DBP), as directed below:  
•
At Screening (Visit 1): Baseline measures will be obtained.
•
At Day 1 of each TP (Visits 2 and 4): Prior to study drug administration and after study 
drug administration. 
•
At Day 15 (± 5 days) of each TP (Visits 3 and 5): Prior to study drug administration and 
after study drug administration. 
Note: Any clinically relevant findings from vital sign measurements will be reported as adverse 
events.
7.2.3
12-Lead Electrocardiogram 
Twelve-lead ECGs will be performed as described below: 
Twelve-lead ECGs will be obtained during Screening (Visit 1), at Day 1 of each TP (Visit 2 
(Randomization) and Visit 4), and at Day 15 (± 5 days) of each TP, (Visits 3 and 5), as follows:
x
At Visit 1 (Screening): Each subject will undergo a 12-lead ECG 
x
At Visit 2 (Randomization) and Visit 4: Each subject will undergo a 12-lead ECG obtained 
approximately 60 min prior to study drug administration and approximately 90 min after study 
drug administration.
x
At Visits 3 and 5 (Day 15 ± 5 days of each TP): Each subject will undergo a 12-lead ECG 
approximately 60 minutes prior to study drug administration and approximately 90 minutes 
after study drug administration.
Note: Baseline ECG values are defined as the last value obtained prior to dosing on Day 1 of 
Treatment Period 1 (Visit 2) and Treatment Period 2 (Visit 4).  Electrocardiogram parameter 
assessments include: heart rate, PR interval, QRS duration, QT interval, and QTcF.
Note: The study team is encouraged to maintain study timepoints.
Note: Any clinically relevant findings from ECGs will be reported as adverse events.
ECG values will be checked by the investigator or designee.
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, 
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TP 2 (Visit 4), the Investigator will make a determination on the suitability of continuing the 
subject in the study. Refer to Section 5.7 for specific criteria for QTcF that prompt subjects to be 
discontinued from the study. If QTcF interval prolongation exceeding these limits is verified 
during treatment, the subject’s medical background should be examined closely for risk factors 


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that may have contributed to the event, including genotyping for hereditary long QT syndromes, 
if appropriate.  
Every clinical significant deviation after the subject is randomized in this study must be recorded 
as an AE and reported to the Sponsor.
The decision to continue the treatment of any subject with prolonged QT or QTcF interval must 
be discussed and agreed upon by the Investigator and the Sponsor. 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 Sponsor must be contacted.
7.2.4
Clinical Laboratory Tests
Clinical safety laboratory tests will be analyzed by 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 Visit 1 (Screening) and prior to dosing at Visit 2 (Day 1 of TP 
1), Visit 3 (Day 15 ± 5 days of TP 1), Visit 4 (Day 1 of TP 2) and Visit 5 (Day 15 ± 5 days of TP 
2) or Premature Discontinuation Visit.
7.2.4.1
Hematology
Hemoglobin, Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin 
concentration (MCHC), Mean corpuscular volume (MCV), hematocrit, red blood cell count, 
white blood cell count with differential, and platelet count will be measured at 
Visit 1 (Screening) and prior to dosing at Visit 2 (Day 1 of TP 1), Visit 3 (Day 15 ± 5 days of TP 
1), Visit 4 (Day 1 of TP 2) and Visit 5 (Day 15 ± 5 days of TP 2) or Premature Discontinuation 
Visit.
Note: Any clinically relevant findings from Hematology will be reported as adverse events.
7.2.4.2
Clinical Chemistry
Albumin, alkaline phosphatase, total bilirubin, calcium, total cholesterol, magnesium, phosphate, 
sodium, potassium, chloride, creatinine, Gamma-glut amyl transferase (Ȗ-GT), bicarbonate, 
triglycerides, blood glucose, total protein, blood urea nitrogen (BUN), AST and ALT will be 
measured at Visit 1 (Screening) and prior to dosing at Visit 2 (Day 1 of TP 1), Visit 3 (Day 15 ± 
5 days of TP 1), Visit 4 (Day 1 of TP 2) and Visit 5 (Day 15 ± 5 days of TP 2) or Premature 
Discontinuation Visit.  
The Laboratory will supply material for the collection of these samples (refer to Table 7-10 for 
an overview of the lab parameters for the blood investigations).
Note: Any clinically relevant findings from clinical chemistry tests will be reported as adverse 
events.


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Table 7-8:
Lab Parameters
Hematology
Hemoglobin 
MCH
Hematocrit 
MCHC
White Blood Cell count with differential 
MCV
Red Blood Cell count 
Platelet Count 
Clinical Blood Chemistry
Liver Enzyme and Other Function Tests
Other Clinical Blood Chemistry
ALT 
Albumin
AST
Calcium
Alkaline phosphatase 
Chloride
Bilirubin, total 
Cholesterol 
Ȗ-GT
Bicarbonate
Creatinine
Glucose
Magnesium 
Potassium
Phosphate
Protein, total 
Sodium
Triglycerides 
BUN
Other Tests:
Creatinine clearance will be estimated by the GFR CKD-EPI formula.
7.2.4.3
Urinalysis
Urine dipstick: red blood cell count, nitrite, white blood cell count, pH, bilirubin, protein, 
ketones, glucose, density.
Microscopic analysis will only be performed if dipstick is positive.
Urinalysis will be measured at Visit 1 (Screening) and prior to dosing at Visit 2 (Day 1 of TP 1), 
Visit 3 (Day 15 ± 5 days of TP 1), Visit 4 (Day 1 of TP 2) and Visit 5 (Day 15 ± 5 days of TP 2) 
or Premature Discontinuation Visit.


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7.2.4.4
Pregnancy Test
A urine pregnancy test will be performed in women of childbearing potential only at 
Visit 1 (Screening) and prior to dosing at Visit 2 (Day 1 of TP 1), Visit 3 (Day 15 ± 5 days of TP 
1), Visit 4 (Day 1 of TP 2) and Visit 5 (Day 15 ± 5 days of TP 2) or Premature Discontinuation 
Visit.
If any of these tests are positive, the subject must be discontinued from the study. The pregnancy 
test should be performed at the beginning of the visit.
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 case report form. If the AE is “alarming,” the Investigator must report 
the 
AE 
immediately 
to 
Pearl. 
In 
addition, 
certain 
AEs 
(as 
described 
in 
Section 7.3.7) are classified as "serious" and must be reported no later than 24 hours after the 
Investigator recognizes/classifies the event as a SAE to Pearl or its designee.
In the case of SAEs, after discussing the details of the AE, the Investigator and the Sponsor may 
discontinue the subject prematurely.
7.3.2
Adverse Event Definitions
The following definitions of terms are guided by the International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the US 
Code of Federal Regulations (21 CFR 312.32) and EU 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 AE 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:
•
Any symptom or condition not previously reported by the subject (medical history).
•
An exacerbation of a pre-existing symptom or condition.
•
A significant increase in frequency or intensity of a pre-existing episodic event or condition.
•
A drug interaction.
•
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:
•
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, blood 
transfusion); the condition that results in the procedure is considered an AE (eg, bleeding 
esophageal varices, dental caries).
•
Overdose of either study drug or concurrent medication without any clinical signs or 
symptoms.
•
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
AEs that occur between the time subject signs the ICF for the study and the time when that 
subject is randomized will be summarized as medical history and not as a Treatment Emergent 
AE (TEAE) unless the event meets the definition of a SAE as defined in 
Section 7.3.7.
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 AE 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 
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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
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 (eg, elevated BUN and creatinine in the setting of an 
AE of renal failure, or decreased hemoglobin in a case of bleeding esophageal varices).  In such 
cases, the laboratory abnormality itself (eg, elevated creatinine in a setting of renal failure) does 
not need to be recorded as an AE. However, isolated laboratory abnormalities should be reported 
as AEs if they are considered to be clinically significant by the Investigator.
Criteria for a "clinically significant" laboratory abnormality are:
•
A laboratory abnormality that leads to a dose-limiting toxicity (eg, an abnormality that results 
in study drug dose reduction, suspension, or discontinuation)
•
A laboratory abnormality that results in any therapeutic intervention (ie, concomitant 
medication or therapy)
•
Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (eg, significant fall in hemoglobin not requiring transfusion)
For laboratory abnormalities that do not meet the above criteria but are outside of normal range 
(eg, < or > normal reference range), the Investigator should indicate whether the value is 
clinically significant or not clinically significant for the subject.
7.3.7
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:
•
Death
•
A life-threatening AE
•
In subject hospitalization or prolongation of existing hospitalization 
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
•
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 


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jeopardize the subject and 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 (ER) 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 a SAE.
An AE or suspected adverse reaction is considered “life-threatening’ if, in the view of the 
Investigator or Sponsor, its occurrence places the subject or subject 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 or is not listed at the specificity or severity that has been observed.
7.3.7.1
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 
Pharmacovigilance or designee no later than 24 hours after the Investigator recognizes/classifies 
the event as a SAE. 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 (eg, SAE 
Report Form). After the initial report, as necessary, the Investigator must provide any additional 
information on a SAE to Pearl Pharmacovigilance or designee within 2 working days after he/she 
receives additional follow-up information this follow-up information will be a detailed written 
report that may include copies of hospital records, case reports, and autopsy reports, and other 
pertinent documents.
Post-study SAEs following the last dose of study drug must be reported to Pearl as described in 
Section 7.3.7.3.
The Investigator is responsible for continuing to report any new or relevant follow-up
information that he/she learns about the SAE.
7.3.7.2
Supplemental Investigations of SAEs
The Investigator and supporting personnel responsible for subject care should discuss with the 
Medical Monitor 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 Pharmacovigilance.


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7.3.7.3
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. 
7.3.7.4
Notification of Post-Study Serious Adverse Events
The follow up telephone call will be performed 7 – 10 days after Visit 5 so post-study SAEs 
occurring up to 10 days following the last dose of study drug 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 a SAE.
7.3.7.5
IRB/IEC Notification of Serious Adverse Events
The Investigator is responsible for notifying her/his 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 a SAE report.
7.3.7.6
Health Authority Safety Reports
Pearl or its representatives will submit a safety report to the Belgium Health Authority ‘Federal 
Agency for Medicines and Health Products Department of Research & Development’ for any 
suspected adverse reaction that is both serious and unexpected within the appropriate time frame. 
Pearl or its representatives will send copies of each safety report submitted to the Belgium 
Health Authority ‘Federal Agency for Medicines and Health Products Department of Research & 
Development’ 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 as 
described in Section 7.3.7.5.
7.3.8
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) 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. The Investigator should refer to the 
relevant 
document(s) 
for 
detailed 
information 
regarding 
warnings, 
precautions, 
contraindications, AEs, 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 IB.


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7.3.9
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 Report Form and reported by the Investigator to Pearl Pharmacovigilance or 
designee. Pregnancy follow-up including pregnancy outcome should be recorded on the same 
form and should include an assessment of the possible relationship to the Pearl Therapeutics 
study drug. Any SAE experienced during pregnancy must be reported on the SAE Report Form.
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 8-11, Table 8-12 and 
Table 8-13 present details about activities conducted pre and post dose at Visits 2 through 5.


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Table 8-9:
Schedule of Events
Clinical Variable
Screening
Treatment Period 1
Treatment Period 2
Follow-up
Visit 1
Visit 2n
Day 1
Visit 3n
Day 15
Visit 4n
Day 1
Visit 5n
Day 15
Telephone
Call
Study Day
-7 up to -21a
Day 1a
Day 15
±5 Days
Day 1
Day 15
±5 Days
7 to10 days
Informed Consent
X
Review of Inclusion/Exclusion 
Criteria
X
X
X
Diary Training
X
Review of Diary
Xu
X
X
X
Chest X-rayh
X
Reversibility
X
Demographics and 
Medical/Surgical History
Xs
COPD Assessment Test (CAT)
X
MMRC
X
Smoking Status
X
X
X
X
X
X
Prior/Concomitant Medicationsb
Xr
X
X
X
X
X
Diffusion Capacity
X
Spirometryc
X
X
X
X
X
Body Plethysmography
X
X
X
X
Physical Examinationd
X
X
Vital Signse
X
X
X
X
X
12-lead ECGf
X
X
X
X
X
Pregnancy Testp
X
X
X
X
X
Clinical Laboratory Testingg
X
X
X
X
X
Adjust COPD Medicationsi
X
X


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Clinical Variable
Screening
Treatment Period 1
Treatment Period 2
Follow-up
Visit 1
Visit 2n
Day 1
Visit 3n
Day 15
Visit 4n
Day 1
Visit 5n
Day 15
Telephone
Call
Study Day
-7 up to -21a
Day 1a
Day 15
±5 Days
Day 1
Day 15
±5 Days
7 to10 days
Adverse Eventsq
X
X
X
X
X
Inhalation Device Trainingj
X
Inhalation Profile 
X
X
Recording of Inhalation Profile 
with Respiration Belto
X
X
HRCT scant
X
X
X
X
Study Drug Dispensing/Collectionk
X
X
X
X
X
Randomization
X
Study Drug Administrationl
X
X
X
X
Review/Record Study Drug Dose 
Indicator Readingm
X
X
X
X
Review/Record Ventolin Dose 
Indicator Reading
X
X
X
X
X
Telephone contact
X
Abbreviations:  CAT=COPD assessment test; MMRC= Modified Medical Research Council; ECG=electrocardiogram; 
COPD=Chronic obstructive pulmonary disease; HRCT=High-resolution computed tomography; ICS=inhaled corticosteroids; 
MDI=metered dose inhaler; FRC= functional residual capacity; TLC=total lung capacity
a
Scheduling visits: The maximum run-in period is 21 days. The earliest a subject can be randomized from the Visit 1 date is 7 days (7 days for 
LABA washout), or 14 days if the subject is washing out from tiotropium and 15 days if the subject is washing out from Indacaterol. The site 
should make every effort to maintain subjects within the scheduled visit window. 
b
At all visits beyond Visit 1 (Screening), note the time of last dose of COPD medications, including rescue medication and ICS (if <6 hours, visit 
should be rescheduled, except for sponsor-provided Atrovent® HFA at Visit 2 and Visit 4).
c
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d
Includes evaluation of height and weight at Visit 1.
e
Refer to Section 7.2.2 for vital sign assessments and specific timepoints to be performed at each visit.
f
Refer to Section 7.2.3 for ECG assessments and specific timepoints to be performed at each visit.
g
Refer to Section 7.2.4 for clinical laboratory assessments (hematology, chemistry and urinalysis and specific timepoints at each study visit).  
h
Obtain a new chest x-ray if the chest x-ray or CT scan performed within 6 months of Visit 1 (Screening) is not available.
i
After informed consent is obtained, prohibited COPD medications will be stopped 6 hours to 24 hours before Visit 1 (Screening). At Visit 1 COPD 
medications will be changed as specified in the protocol (i.e., Sponsor provided Atrovent HFA with or without ICS).  At the end of Visit 5, return 
subject to pre-study or other appropriate inhaled maintenance COPD medications.
j
Site should use the sponsor provided placebo MDI to train subjects on the use of MDIs.
k
Sponsor provided Atrovent HFA or Ventolin HFA should be dispensed only after a subject is determined to be eligible to proceed to Visit 2 (Day 
1) (i.e., only if a subject meets the definition of COPD following spirometry assessments at Screening).
l
In-clinic dosing time is recorded as time of the second puff/inhalation.  
m
Refer to Appendix 6 for details and instructions on recording dose indicator readings.
n
Visit windows during each Treatment Period are relative to Day 1 of that Treatment Period. Washout period between Visit 3 and Visits 4 is a
minimum of 5 days to a maximum of 21 days. 
o
The inhalation profile with the use of the respiration belt will be measured simultaneously with the drug administration.
p
Only in female of childbearing potential.
q
AEs that occur before randomization will be summarized as medical history and not as a TEAE unless the event meets the definition of a SAE 
(Refer to Section 7.3.3).
r
All prescription and OTC medications taken by the subject within 30 days before Visit 1 (Screening) will be recorded.
s
The number of COPD exacerbations requiring oral steroids and/or oral antibiotics, or hospitalization within 12 months of Visit 1 (Screening) will 
be collected.  
t
At Visit 2 and 4 two breathing levels: TLC and FRC. During Visit 2 an additional scan of the UA will be taken. At Visit 3 and 5 one breathing 
level: TLC.
u
Subjects who are unable to meet the compliance requirement (>70% subject completion of diary assessments) in the last 7 days preceding the 
Randomization Visit (Visit 2) must be retrained. When retraining is required due to non compliance the Randomization Visit (Visit 2) must be 
rescheduled.
Note: Site should plan to perform these activities so as not to interfere with collection of timed assessments such as spirometry. Where data collection 
time-points are concurrent, variables must be collected in the following order: On Day 1 of each treatment period: Predose: Urine pregnancy 
test, Spirometry (obtain FEV1 to evalutate stability criteria), vital signs, ECG, clinical laboratory assessments (Abnormal eGFR at Visit 1 
[screening] must be repeated prior to visit 2 and have the results available at Visit 2 to confirm eligibility), Pre-dose CT scans, Spirometry, 
Body Plethysmography, Inhalation Profile. Postdose: vital signs, ECG. On Day 15 (± 5 days) of each TP: Predose: Urine pregnancy test, vital 
signs, ECG, clinical laboratory assessments Postdose: Vital signs, ECG, post-dose CT Scan, Spirometry, Body Plethysmography.


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Table 8-10. Timed Assessments at Visit 2 and Visit 4
Visit 2 (Day 1 TP 1)
Visit 4 (Day 1 TP 2)
Clinical Variablea
Pre-dosing
Post-
dosing
Pre-dosing
Post-
dosing
-60 minh
-30
minh
90 minh
-60
minh
-30 minh
90 minh
Vital Signsb,c,d
X
X
X
X
ECGb,c
X
X
X
X
Clinical Laboratory Testingb,c
X
X
Urine pregnancy teste
X
X
Spirometryc
Xi
Xf
Xi
Xf
HRCT Scansc
X
X
Body Plethysmographyc
Xf
Xf
Inhalation Profilec
Xg
Xg
a.
At the start of each treatment visit, subject must withhold all inhaled COPD medications, including study 
medication, rescue Ventolin® HFA and ICS for at least 6 hours prior to start of test day procedures (except for 
sponsor provided Atrovent® HFA at Visit 2 and Visit 4).
b.
This is not a timed assessment.  Site should plan to perform these activities so as not to interfere with 
collection of timed assessments such as spirometry.
Note: Subjects with a calculated creatinine clearance < 30 ml/min/1.73 m^2 CKD-EPI at Visit 1 must have 
a eGFR CKD-EPI > 30 ml/min/1.73 m^2 on the repeat testing prior to Visit 2 to be randomized in this study.
c.
Refer to Section 7.2.3 for specific assessments and specific time points to be performed at each treatment 
visit.
d.
Pre-dose vital signs include the temperature measurement.
e.
Urine pregnancy test should be performed at the beginning of the visit
f.
Spirometry and body plethysmography will be measured after the HRCT scan is taken.
g.
At the moment of this measurement the signal from the respiration belt, used for the measurement of the 
inhalation profile during the study drug administration, will also be logged.
h.
The timepoints are preferred timepoints, the site should make every effort to respect the timepoints as close
as possible. 
i.
Will be performed at the beginning of the visit. At Visit 4 the obtained FEV1 value will be used to check the 
stability criteria 
Note: Site should plan to perform these activities so as not to interfere with collection of timed assessments such 
as spirometry. Where data collection time points are concurrent, variables must be collected in the following 
order:  Predose: Urine pregnancy test, spirometry (obtaining FEV1 to check stability criteria), vital signs, ECG, 
clinical laboratory assessments, pre-dose CT scans, spirometry, body plethysmography, inhalation profile.  
Postdose: Vital signs, ECG.


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Table 8-11. Timed Assessments at Visit 3 and Visit 5
Visit 3 (Day 15 TP 1)
Visit 5 (Day 15 TP 2)
Clinical Variablea
Pre-dosing
Post-
dosing
Pre-dosing
Post-
dosing
-60 ming
-30 ming
90 ming
-60 ming
-30 ming
90 ming
Vital Signsb,c,d
X
X
X
X
ECGb,c
X
X
X
X
Clinical Laboratory Testingb,c
X
X
Urine pregnancy test
Xh
Xh
HRCT Scansc
Xe
Xe
Body Plethysmographyc
Xf
Xf
Spirometryc
X
Xf
X
Xf
a.
At the start of each treatment visit, subject must withhold all inhaled COPD medications, including study 
medication, rescue Ventolin HFA and ICS for at least 6 hours prior to start of test day procedures.
b.
This is not a timed assessment.  Site should plan to perform these activities so as not to interfere with 
collection of timed assessments such as spirometry.
c.
Refer to Section 7 for specific assessments and specific time points to be performed at each treatment visit.
d.
Pre-dose vital signs include the temperature measurement.
e.
At one breathing level: TLC. Will be performed before the post-dose spirometry and body plethysmography.
f.
Spirometry followed by body plethysmography will be performed after the HRCT scans but within 150min 
after dosing.
g.
The timepoints are preferred timepoints, the site should make every effort to respect the timepoints as good  
as possible. None of the post dose assessments will start before 1 hour after the administration and all 
assessmenst will be concluded within 2.5hours after dosing.
h.
Urine pregnancy test should be performed at the beginning of the visit.
Note: Site should plan to perform these activities so as not to interfere with collection of timed assessments such 
as spirometry. Where data collection time-points are concurrent, variables must be collected in the following 
order: Predose: Urine pregnancy test, spirometry, vital signs, ECG, clinical laboratory assessments Postdose:
Vital signs, ECG, post-dose CT scan, spirometry, body plethysmography.


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8.1 Visit 1 (Screening)
•
Obtain informed consent prior to or at the beginning of Visit 1
•
Determine time of last dose of prohibited COPD medication as defined in Table 5-1
•
Site will assign subject screening number
•
Review inclusion/exclusion criteria
•
Obtain demographic data, including age, race, smoking history, medical/surgical history, and 
age of onset of COPD 
•
Obtain medication history, including COPD medications.
•
Conduct a urine pregnancy test for all female subjects of childbearing potential 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.
•
Conduct a complete physical examination of relevant body parts.
•
Obtain height, weight, and vital signs (heart rate and blood pressure after being supine or 
seated for 5 minutes, and oral or tympanic temperature).
•
Obtain a 12-lead ECG.
•
Obtain CAT and MMRC
•
Conduct spirometry assessments including IC and diffusion capacity. 
•
Perform reversibility test to Ventolin HFA (refer to Section 7.1.2.1 for instructions)
Note: Confirm subject continues to meet entry criteria based on pre- and post-dose spirometry 
quality (refer to Section 5.1).
•
Confirm subject’s ability to use MDI correctly, provide coaching with sponsor-provided 
Placebo MDI.
•
If subject qualifies to continue to Visit 2 perform the following:
x
Obtain laboratory samples (hematology, chemistry and urinalysis).
x
If Chest X-ray or CT within 6 months of Visit 1 (Screening) is not available, obtain a new 
Chest X-ray.
x
Change concurrent COPD medications as specified in protocol (refer to Section 5.4.1). 
Sponsor will provide Atrovent HFA QID for COPD maintenance and Ventolin HFA as 
needed for symptomatic relief.
x
Schedule Visit 2.
•
In order to allow for an adequate washout of previous maintenance medications, subjects will 
undergo a run-in period of at least 1 week, but not greater than 21 days (2 weeks if subject is 
taking Spiriva or other Long-acting anticholinergics) in duration prior to returning to the 
clinic for Visit 2 (see Table 5-1).
•
Dispense and train subject on Diary use.


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•
Ensure subject has adequate supply of sponsor-provided Atrovent®
HFA and 
sponsor-provided rescue Ventolin® HFA.
•
Record the number of actuations of the Ventolin® canister at the time of dispensing 
(following priming and characterization of reversibility).
•
Subjects will be instructed to bring the Diary, the sponsor-provided Ventolin® HFA and 
Atrovent® HFA to the next scheduled clinic visit.
•
Subjects will be instructed to administer sponsor-provided Atrovent® HFA the morning of 
Visit 2 5-6 hours prior to the anticipated time of the post-dose CT scan.
•
AEs must be recorded during the run-in period, that is, from the time of consent to the start of 
study treatment. 
Note: AEs that occur between the time the subject signs the ICF 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 
AE, unless the event meets the definition of a SAE.
8.2 Visit 2 (Randomization: Day 1 of TP 1) 
•
Review subject diary entries and retrain subject if subject has not met diary compliance 
requirement of >70% subject completion of diary assessments.
•
Collect sponsor-provided Atrovent HFA and sponsor-provided Ventolin HFA dispensed 
during the Screening run-in period.
•
Record the number of actuations of the Atrovent HFA and Ventolin HFA canisters.
•
Determine time of last dose of short-acting bronchodilator and other inhaled COPD 
medications.
•
Review all prior medications and ensure adherence to COPD regimen.
•
Review inclusion/exclusion criteria and confirm subject eligibility to continue.
•
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.
Note: Subjects with a calculated creatinine clearance < 30 ml/min/1.73 m^2 estimated using the 
Modification of Diet in Renal Disease Equation (eGFR CKD-EPI)  at Visit 1 and on repeat 
testing prior to Visit 2 will be excluded. 
•
Record AEs (if any).
Note: AEs that occur during the run-in period (Visit 1 to Visit 2) will be summarized as medical 
history and not as a study AE unless the event meets the definition of a SAE.
x
Update medical history if needed.
x
Update smoking status if needed.
x
Conduct a urine pregnancy test for all female subjects of childbearing potential unless it is 
documented in the medical history that the subject has been irreversibly surgically sterilized 


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(hysterectomy, oophorectomy, or bilateral tubal ligation) or they are at least 2 years post-
menopausal.
x
Perform all pre-dose assessments (refer to Table 8-10):
x
Obtain Spirometry (baseline FEV1 will be obtained)
x
Obtain Vital signs (heart rate and blood pressure after being supine or seated for 5 
minutes, and oral or tympanic temperature).
x
Obtain 12-lead ECG.
x
Obtain laboratory samples (hematology, chemistry and urinalysis).
x
Obtain HRCT scans: TLC + FRC + UA.
Note: Review inclusion/exclusion criteria, repeat testing of the creatinine clearance prior to Visit 
2 must be known before the HRCT scan can be taken.
x
Obtain Spirometry (including IC).
x
Obtain body plethysmography
x
Obtain Inhalation Profile (body plethysmograph while wearing respiration belts)
x
Obtain subject randomization number and treatment assignment information. The subject 
is to be considered randomized after receiving a randomization number.
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. Refer to Section 6.7 for detailed instructions for 
preparation of treatments for administration. These instructions are to be adhered to and are 
relevant to all study treatment visits.
•
Record/document the dose indicator reading. The dose indicator count recorded by the site 
staff on Day 1 of the TP will be after priming the medication (prior to the the first dosing) 
and after the first dosing. Refer to Section 7.1.9 for more details.
•
Subject will administer first dose of newly assigned study drug at the clinic. During dosing 
the inhalation profile with the respiration belts will be recorded.
•
Record/document the dose indicator reading after subject dosing.  
•
Subject will be instructed to dose while at home from the site-primed MDI only, unless all of 
the following replacement conditions are met:
•
Dose indicator is in the red zone (refer to Appendix 6 for dose indicator reading instructions).
•
7KHGRVHLQGLFDWRUUHJLVWHUVSXIIVUHPDLQLQJand their next scheduled study clinic visit 
is not the following day.
If these replacement conditions are met, subjects will be instructed to open their replacement kit, 
prime the MDI and start using for at home dosing until the next scheduled study clinic visit.
•
Perform all post-dosing assessments (refer to Table 8-10):
•
Obtain post-dose Vital signs (heart rate and blood pressure after being supine or seated for 5 
minutes).
•
Obtain post-dose 12-lead ECG.


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•
Schedule Visit 3.
Note: Visit 3 should be scheduled at minimum 10 days after Visit 2 and no later than 20 days 
after Visit 2. 
•
Ensure subject has adequate supply of study medication (including sponsor-provided rescue 
Ventolin HFA).
•
Subjects will be instructed to bring all study medication (including used study drug, 
replacement MDI kit, and sponsor provided rescue Ventolin HFA) and the Diary to the next 
scheduled clinic visit.
8.3 Visit 3 (Day 15 ± 5 days of TP 1)
•
Determine time of last dose of short-acting bronchodilator and other inhaled COPD 
medications (if <6 hours, the visit must be rescheduled).
•
Confirm the subject took their last dose of randomized study medication as scheduled the 
prior evening.  
•
Record/document the dose indicator reading of the used MDI.  
•
Record the number of actuations of the Ventolin HFA canister.
•
Record COPD exacerbations and AEs (if any).
•
Review all concomitant medications and ensure adherence to COPD regimen.
•
Update smoking status if needed.
•
Review subject diary entries.
•
Conduct a urine 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.
•
Perform all pre-dose assessments (refer to Table 8-11):
x
Obtain Vital signs (heart rate and blood pressure after being supine or seated for 5 
minutes, and oral or tympanic temperature).
x
Obtain 12-lead ECG.
x
Obtain laboratory samples (hematology, chemistry and urinalysis).
x
Obtain Spirometry (including IC).
x
Administer last in-clinic study drug dose of TP 1.
x
Perform all post-dosing assessments (refer to Table 8-11). All post-dose assessments must be 
performed between 1 to 2.5 hours after drug administration.
x
Obtain Vital signs (heart rate and blood pressure after being supine or seated for 5 
minutes).
x
Obtain 12-lead ECG.
x
Obtain HRCT scan: TLC.


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x
Obtain Spirometry (including IC).
x
Obtain body plethysmography.
•
Schedule Visit 4.
Note: Visit 4 should be scheduled at minimum 5 days after Visit 3 and no later than 21 days after 
Visit 3.
x
Ensure subject has adequate supply of sponsor-provided Atrovent HFA and sponsor-provided 
rescue Ventolin HFA.
•
Subjects will be instructed to bring the Diary, the sponsor-provided Atrovent HFA and
Ventolin HFA to the next scheduled clinic visit. Subjects will be instructed to administer 
sponsor-provided Atrovent® HFA the morning of Visit 4 5-6 hours prior to the anticipated 
time of the post-dose CT scan.
8.4 Visit 4 (Day 1 of TP 2)
•
Collect sponsor-provided Atrovent HFA and sponsor-provided Ventolin HFA dispensed 
during the washout period.
•
Record the number of actuations of the Atrovent HFA and Ventolin HFA canisters.
•
Determine time of last dose of short-acting bronchodilator and other inhaled COPD 
medications.
•
Review all concomitant medications and ensure adherence to COPD regimen.
•
Update smoking status if needed.
•
Review subject diary entries.
•
Review inclusion/exclusion criteria and confirm subject eligibility to continue.
•
Record COPD exacerbations and AEs (if any).
x
Conduct a urine pregnancy test for all female subjects of childbearing potential 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
Complete all pre-dose assessments (refer to Table 8-10):
x
Obtain Spirometry
Note: Confirm if patient meets stability requirments, if not the visit may be rescheduled 
at the Investigator’s discretion, or the subject may be discontinued.
x
Obtain Vital signs (heart rate and blood pressure after being supine or seated for 5 
minutes, and oral or tympanic temperature).
x
Obtain 12-lead ECG.
x
Obtain laboratory samples (hematology, chemistry and urinalysis).
x
Obtain HRCT scans: TLC + FRC.
Note: Review inclusion/exclusion criteria, before the HRCT scan can be taken.


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x
Obtain Spirometry (including IC).
x
Obtain body plethysmography.
x
Obtain inhalation profile (body plethysmograph while wearing respiration belts).
•
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. Refer to Section 6.7 for detailed instructions for 
preparation of treatments for administration. These instructions are to be adhered to and are 
relevant to all study treatment visits.
•
Record/document the dose indicator reading. The dose indicator count recorded by the site 
staff will be dose indicator count observed after priming the medication and prior to subject 
dosing. Refer to Section 7.1.9 for more details.
•
Subject will administer first dose of newly assigned study drug at the clinic. During dosing 
the inhalation profile with the respiration belts will be recorded.
•
Record/document the dose indicator reading after subject dosing.  
•
Subject will be instructed to dose while at home from the site-primed MDI only, unless all of 
the following replacement conditions are met:
•
Dose indicator is in the red zone (refer to Appendix 6 for dose indicator reading instructions)
•
The dose iQGLFDWRUUHJLVWHUVSXIIVUHPDLQLQJand their next scheduled study clinic visit 
is not the following day.
If these replacement conditions are met, subjects will be instructed to open their replacement kit, 
prime the MDI and start using for at home dosing until the next scheduled study clinic visit.
•
Perform all post-dosing assessments (refer to Table 8-10):
•
Obtain Vital signs (heart rate and blood pressure after being supine or seated for 5 minutes).
•
Obtain 12-lead ECG.
•
Schedule Visit 5.
Note: Visit 5 should be scheduled at a minimum 10 days after Visit 4 and no later than 20 days 
after Visit 4.
•
Ensure subject has adequate supply of all study medication (including sponsor-provided  
rescue Ventolin HFA).
•
Subjects will be instructed to bring all study medication (including used study drug, 
replacement MDI kit, and sponsor provided rescue Ventolin HFA) and the Diary to the next 
scheduled clinic visit.


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8.5 Visit 5 (Day 15 ± 5 days of TP 2)
•
Determine time of last dose of short-acting bronchodilator and other inhaled COPD 
medications (if <6 hours, the visit must be rescheduled).
•
Confirm the subject took their last dose of randomized study medication as scheduled the 
prior evening.  
•
Record/document the dose indicator reading of the used MDI. 
•
Record the number of actuations of the Ventolin HFA canister.
•
Record COPD exacerbations and AEs (if any).
•
Review all concomitant medications and ensure adherence to COPD regimen.
•
Update smoking status if needed.
•
Review subject diary entries.
•
Conduct a urine 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.
•
Perform all pre-dose assessments (refer to Table 8-11):
x
Obtain Vital signs (heart rate and blood pressure after being supine or seated for 5 minutes, 
and oral or tympanic temperature).
x
Obtain 12-lead ECG.
x
Obtain laboratory samples (hematology, chemistry and urinalysis).
x
Obtain Spirometry (including IC).
x
Administer in-clinic last study drug dose of TP 2
x
Perform all post-dosing assessments (refer to Table 8-11). All post-dose assessments must be 
performed between 1 to 2.5 hours after drug administration.
x
Obtain Vital signs (heart rate and blood pressure after being supine or seated for 5 minutes).
x
Obtain 12-lead ECG.
x
Obtain HRCT scan: TLC.
x
Obtain Spirometry (including IC).
x
Obtain body plethysmography.
x
Conduct a complete physical examination of relevant body parts.
x
Schedule a follow-up telephone contact (TC) 7 to 10 days post last study drug dosing.
x
Collect all study medication including sponsor-provided Ventolin HFA.
x
At completion of all Visit 5 assessments, return subject to pre-study or appropriate 
maintenance COPD medications.
8.6
Unscheduled Visit/Premature Discontinuation Visit
Repeat assessments, if needed, will be captured in unscheduled visits.


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Premature Discontinuations Visits will be captured as unscheduled visits. The following 
minimum procedures should be completed at the Premature Discontinuation Visit:
•
Record COPD exacerbations and AEs (if any).
•
Review concomitant medications.
•
Conduct a physical examination, including vital signs (heart rate and blood pressure after 
being supine or seated for 5 minutes, and oral or tympanic temperature).
•
Perform ECG and collect blood samples for hematology and chemistry.
•
Collect a urine sample for urinalysis for lab safety.
•
Conduct a urine pregnancy test for all female subjects of childbearing potential.
•
Collect all study drugs. 
•
Inform subject about reporting all SAEs up to 10 days following the last dose of study drug.
•
Return subject to pre-study or appropriate maintenance COPD medications.
•
Capture the subject discontinuation reason.
•
Schedule a follow-up TC 10 days post last study drug dosing.  If the discontinuation visit is 
performed >10 days post last study drug dosing a follow-up TC will not be required.
8.7
Follow-Up Telephone Call
Subjects will be followed-up through telephone contact 7 to 10 days post last study drug dosing.  
The following information will be requested:
•
Review previously on-going SAEs, and record new SAEs (if any).
•
Review concomitant medications.
•
Review smoking status.


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8.8
Completion of the Study
The Investigator will document the completion or the reason for early withdrawal by a subject in 
the eCRF. The following categories should be used to describe these events in the eCRF:
•
Subject discretion (document reason).
•
Investigator considers it to be in the best interest of the subject.
•
AEs.
•
Administrative reasons (eg, early termination of the study).
•
Subject lost-to-follow-up.
•
Lack of efficacy.
•
Major protocol violation.
•
Death.
•
Completion of the study.
•
Protocol specified criteria such as heart rate, systolic or diastolic blood pressure, or use 
of prohibited medications (refer to Section 5.7).


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9
PLANNED STATISTICAL METHODS
9.1
Introduction
This study will be conducted as a multi-center, randomized, double-blind (GP and FF MDIs), 
two treatment period, chronic dosing (2 weeks), two-treatment, and crossover design evaluating 
the following two treatments in approximately 20 subjects:
•
GP MDI 14.4 μg BID
•
FF MDI 9ȝJ%,'
The primary objective of this study is to assess the effect of treatment with GP MDI, 14.4 ȝg ex-
actuator, BID and FF MDI 9.6 ȝg ex-actuator, BID on specific image based airway volumes and 
resistance in subjects with moderate to severe COPD.
9.2
Protocol Variables
9.2.1
Efficacy Endpoints
The first day of treatment in each TP is Day 1. Each TP is planned to contain 15 days between 
the first and last dose corresponding to a span of 15 calendar days. Therefore, assessments 
collected on Day 15 (Visits 3 and 5) will occur following 14 days of treatment. All FRI, 
spirometry and body plethysmography endpoints will utilize changes from baseline.
9.2.1.1
Primary Efficacy Endpoints on Day 1 and Day 15, except as otherwise noted
FRI Parameters:
•
Specific airway volume (siVaw)
•
Specific airway resistance (siRaw)
9.2.1.2
Secondary Efficacy Endpoints measured on Day 1 and Day 15, except as 
otherwise noted
FRI Parameters:
•
Airway volume (iVaw)
•
Airway resistance (iRaw)
Spirometry Parameters:
•
Forced expiratory volume in one second (FEV1)


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Body Plethysmography Parameters:
•
FRC
9.2.1.3
Other Efficacy Endpoints measured on Day 1 and Day 15, except as otherwise 
noted
FRI Parameters:
•
Lobe volumes (iVlobes)
•
Air trapping
•
Internal lobar airflow distribution
•
Low attenuation or emphysema score
•
Blood vessel density or fibrosis score
•
Airway wall thickness
•
Mass of deposited particles per defined airway section 
Spirometry Parameters:
•
Forced vital capacity (FVC)
•
Tiffeneau index (FEV1/FVC ratio) 
•
Forced expiratory flow 25%-75% (FEF25-75)
•
Inspiratory capacity (IC)
Body Plethysmography Parameters:
•
Residual volume (RV)
•
TLC
•
Airway resistance (Raw)
•
Specific airway resistance (sRaw)
•
Specific airway conductance (sGaw)
9.2.1.4
Safety Endpoints
•
AEs


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9.3
Efficacy Analyses
9.3.1
Efficacy Analysis
For the efficacy analyses, the individual effects of both GP MDI and FF MDI will be assessed. 
The effect is defined as the difference between the value at Day 15 and the value at Day 1. Effect 
is thus the change from baseline to GP MDI, for a GP MDI treatment and as the change from 
baseline to FF MDI, for a FF MDI treatment.
For each parameter in each group (primary efficacy endpoints: FRI; secondary efficacy endpoints: 
FRI, spirometry and body plethysmography; other efficacy endpoints: all FRI parameters except the 
mass of deposited particles, spirometry and body plethysmography), this effect will be assessed. 
Additional analyses will compare the distribution of regional effects between the two treatments 
for the different FRI endpoints. A linear mixed model approach will be chosen and specified 
fully in the statistical analysis plan.
In order to gain extra insights in the mode of action of the product, additional exploratory 
analyses can be executed using (robust) linear regression or mixed-models. The results of the 
PT003019-00 study can be combined with the results of the PT003018-00 (EudraCT: 2015-
001743-36) for further examination.
The Intent-to-Treat (ITT) Population will be considered the primary analysis population for 
efficacy. Supportive analyses will be conducted with the Modified Intent-to-Treat (mITT) 
Population.
9.3.2
Control of Type I error
For the primary outcome parameters, Hochberg's step-up procedure will be used as multiplicity 
adjustment within each product. No correction will be performed for the secondary or other 
endpoints.
9.3.3
Safety Analysis 
9.3.3.1
Adverse Events
Adverse events during each TP will be summarized by the number of subjects experiencing an 
event. 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.
Note: Any clinically relevant findings from ECGs, clinical laboratory tests (e.g. Hematology, 
Clinical Chemistry), or vital sign measurements will be reported as adverse events.


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9.4
Randomization
Subjects will be randomly assigned to one of two treatment sequences in a block size of 4 for the 
two sequences. Each sequence will include exactly one of the two treatment groups included in 
this study per TP. All subjects will receive GP MDI 14.4 ȝg and FF MD I9.6 ȝg.
The two treatment sequences are shown below:
Table 9-12. Randomization Schedule
Treatment Period 1
Treatment Period 2
Treatment sequence 1 
GP MDI (PT001)
14.4 μg ex-actuator
FF MDI (PT005)
9.6 μg ex-actuator
Treatment sequence 2
FF MDI (PT005)
9.6 μg ex-actuator
GP MDI (PT001)
14.4 μg ex-actuator
9.5
Experimental design
The experimental design was chosen to be balanced with respect to period and first-order 
carryover effects.
9.6
Sample Size Consideration
In a double-blind, cross-over study where 10 COPD Global Initiative for Chronic Obstructive 
Lung Disease (GOLD) III subjects received a budesonide/formoterol combination; FRI was able 
to quantify the effects of the active compound relative to baseline. A sample size calculation 
(power goal 90%, alpha 0.05) revealed that in order to have a well-powered study with change in 
imaging based airway volume as primary outcome parameter, a total of 16 subjects would be 
required (De Backer, 2012). If the significance level for the volume is set to 0.025 by the 
Hochberg's step-up procedure, 20 subjects would be required. It can be assumed that sufficient 
power will be obtained when including 20 subjects.
9.7
Data Validation and Transformation
All measured values will be included in the analyses. Depending on the plots of the standardized 
residuals versus fitted values of the mixed-effect models, data transformations will be considered 


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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: 
•
The ITT Population is defined as all subjects who are randomized to treatment. Treatment is 
assigned as randomized regardless of the treatment actually received. 
•
The modified Intent-to-Treat (mITT Population) is a subset of the ITT Population 
including subjects who received treatment and have post-treatment efficacy data from 
both TPs. 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.
•
The Safety Population is defined as all subjects who are randomized to treatment and 
receive at least one dose of the study treatment. Statistical analyses and tabulations will be by 
the treatment actually received.
Analyses will be performed as follows: 
Demographics will be summarized for the ITT, mITT and Safety populations. Extent of exposure 
will be summarized for the Safety Population. The Safety Population will be used to summarize 
safety data.
Efficacy analyses will be performed for the ITT and mITT Populations, with the ITT Population 
being considered the primary population for these analyses. 
9.10 Handling of Missing Data 
No imputation for missing values is planned. 
9.11 Statistical Software 
All analyses will be performed using the open-source statistical environment


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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 (ICH of Technical 
Requirements for the Registration of Pharmaceuticals for Human Use, May 1996).
•
US 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 ICF, and any other information that will be presented to potential subjects (eg, 
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/Subject 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/subject agrees to this 
process. If study documents will be photocopied during the process of verifying worksheet/case 
report form information, the subject/subject will be identified by unique code only; full 
names/initials and full birth year 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
 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’ Quality Assurance auditors, and authorized representatives of the FAGG 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 Pearls' 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. 
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
Pearl intends to publish the results of all of the clinical studies that it sponsors in compliance 
with the Declaration of Helsinki (http://www.wma.net/en/10home/index.html). Consistent with 
the recommendations of the editors of several leading medical journals, the International 
Committee of Medical Journal Editors (ICMJE), authorship of publications resulting from Pearl -
sponsored studies should fairly recognize the activities of those that have made a significant 
contribution to the study. Thus, it is anticipated that authorship will reflect the contribution made 
by Pearl personnel, the Investigators and others involved, such as statisticians.
In recent years, issues about conflicts of interest and accuracy of the study data have been raised 
in the medical press. Accordingly, Pearl has developed publication guidelines as described 
below:
1. Responsibility: Each principal Investigator is responsible for the accuracy and completeness 
of all data from their site. Pearl (or its representatives) is responsible for the accuracy of the 
data entered into the study databases and for the accuracy of the analyses conducted.
2. Authorship and Publication Committee: Pearl, in collaboration with the Investigators, will 
establish the appropriate authorship and responsibility for drafting study documents in 
accordance with the principles of the ICMJE. It is anticipated that a publication committee 
will be formed to assume oversight of these activities. All manuscripts will be reviewed and 
agreed upon before submission for publication by all authors.
3. Sponsor Review of External Manuscripts: Consistent with the previous bullet point, drafts 
of any and all publications or presentations that may arise from this study must be submitted 
at least 30 days prior to submission for publication or presentation to Pearl for review, 


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approval, and to ensure consistency with the policy in this protocol. Pearl will have the right 
to request appropriate modification to correct facts and to represent its opinions, or the 
opinions of the publication committee, if these differ with the proposed publication.
4. Confidentiality: Investigators will conduct all interactions with Pearl and with third parties 
consistent with the executed confidentiality agreements. While publication, by intention, 
presents the critical scientific data in a public forum, some information (such as future plans, 
results of nonclinical studies, or chemical formulae) may still need to remain confidential.
5. Medical Journal Review: Consistent with the intention of Pearl to publish the study in a fair 
and accurate manner, Pearl supports diligence in the publication review process of medical 
journals. Accordingly, upon request, all pertinent study data and information will be made 
available as supplemental information for journal editors and reviewers to evaluate and audit, 
eg, protocol and amendments, data tabulations, etc. The journal and reviewers will need to 
make arrangements to maintain the confidentiality of such supplemental information, where 
relevant, and Pearl will make suitable arrangements to ensure that the identity of journal 
reviewers is kept confidential. Records will be maintained of reviewers and the respective 
documents and datasets that were reviewed by each of them.
6. Reporting of Clinical Trials Results: To provide transparency in the conduct and reporting 
of randomized clinical trials, Pearl reports clinical findings based on the guidance of The 
CONSORT (Consolidated Standards of Reporting Trials) Statement [CONSORT, 2010] and 
a 25-item checklist which is intended to improve the reporting of a randomized controlled 
trial, and to facilitate reader understanding of the trial design, conduct, analysis and 
interpretation, and to support their ability to assess the validity of its results.
7. Internet Clinical Trial Listing: In addition, also consistent with the recommendations of the 
ICMJE, Pearl will make available appropriate information regarding the study via the 
internet.  This will include registration and listing of the study on www.clinicaltrials.gov, the 
US National Institutes of Health listing of clinical trials, and other clinical trial listings as 
appropriate.


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11 REFERENCE LIST
Atrovent Prescribing Information (US), 
, 2012. 
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.
Consolidated Standards of Reporting Trials (CONSORT) Statement 2010.  Accessed on 17 July 
2014.  Available online at: http://www.consort-statement.org/consort-2010 
COPD Assessment Test (CAT) (http://www.catestonline.org/).
Celli B, MaNee W, Agusti A, et al. Standards for the diagnosis and treatment of subjects with 
COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004; 23:932-946. 
De Backer L, Vos W, De Backer J, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD: a multi-slice computed tomography and lung function 
study. Eur Respir J. 2012 Aug 1;40(2):298–305. 
De Backer L, Vos W, Salgado R, De Backer J, Devolder A, Verhulst S, et al. Functional imaging 
using computer methods to compare the effect of salbutamol and ipratropium bromide in subject-
specific airway models of COPD. Int J Chron Obstruct Pulmon Dis. 2011;6:637–46. 
European Medicines Agency. EMA/CHMP/508029/2012 Committee for Medicinal Products for 
Human Use (CHMP). Assessment Report Seebri Breezhaler. Accessed on 24 July 2014, 
online:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/002430/WC500133771.pdf 
Feenstra TL, van Genugten ML, Hoogenveen RT, et al. The impact of aging and smoking on the 
future burden of chronic obstructive pulmonary disease: a model analysis in the Netherlands. Am 
J Respir Crit Care Med 2001;164:590-596. 
Ferrer, Alonso J,Morera J, et al. Chronic obstructive pulmonary disease Part and health related 
quality of life. Ann Intern Med. 1997;127:1072-1079. 
Fletcher CM, Elmes PC, Fairbairn MB, et al. The significance of respiratory symptoms and the 
diagnosis of chronic bronchitis in a working population. Br Med J. 1959; 2:257-266. 
GOLD (Global Initiative for Chronic Obstructive Lung Disease). Global strategy for the 
diagnosis, management, and prevention of chronic obstructive pulmonary disease. National 
Institutes of Health, updated 2015 (www.goldcopd.com).  
Halbert RJ, Isonaka S, George D, Iqbal A. Interpreting COPD prevalence estimates: what is the 
true burden of disease? Chest 2003;123:1684-1692. 


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Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systemic review and meta-
analysis. Eur Respir J 2006;28:523-532. 
Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. 
Annals of Internal Medicine. 2009; 150 (9): 604–12.
Miller MR, Crapo R, Hankinson J, et al. ATS/ERS Task Force. General considerations for lung 
function testing. Eur Respir J. 2005; 26:153-61 Eur Respir J. 2005; 26:153-61. 
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: 
Global Burden of Disease Study. Lancet 1997;349:1498-1504. 
National Health and Nutrition Examination Survey (NHANES III), 2011. Accessed on 14 July 
2014.  Available online at: http://www.cdc.gov/niosh/topics/spirometry/nhanes.html 
New York Heart Association NYHA 2011 NYHA Classification, the Stages of Heart Failure. 
Accessed on 14 July 2014.  Available online at Heart Failure Society of America: 
http://www.abouthf.org/questions_stages.htm 
R Development Core Team, 2003] R Development Core Team (2003). R: A language and 
environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.
Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest 2000;117:5S-9S. 
van Noord JA. Comparison of tiotropium once daily, formoterol twice daily and both combined 
once daily in subjects with COPD. European Respiratory Journal. 2005; 26(2):214–222. 
van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A, Cornelissen PJG. 
Effects of Tiotropium With and Without Formoterol on Airflow Obstruction and Resting 
Hyperinflation in Subjects With COPD. Chest 2006;129;509-517. 
Ventolin (albuterol sulfate) inhalation aerosol HFA. Highlights of Prescribing Information 
(
Vogelmeier C, Kardos P, Harari S, Gans SJM,Stenglein S, Thirlwell J. Formoterol mono- and 
combination therapy with tiotropium in subjects with COPD: A 6-month study. Respiratory 
Medicine (2008) 102, 1511-1520. 
Vos W, De Backer J, Poli G, De Volder A, Ghys L, Van Holsbeke C, et al. Novel functional 
imaging 
of 
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beclomethasone/formoterol. Respiration. 2013; 86(5):393–401. 


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12 APPENDICES
Appendix 1
Subject Instructions for Use of GP and FF MDI
Before using GP MDI and FF 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 A1-1.
Figure A1-1. 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 GP MDI and FF 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 GP MDI and FF 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.


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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.
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 GP MDI and FF 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 
(see Figure A1-2).  
Figure A1-2. Wash Actuator through Top of Actuator
3. Then wash the actuator again through the mouthpiece (see Figure A1-3).


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Figure A1-3. 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 A1-4. Metered Dose Inhaler Parts


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Appendix 2
Instructions for Use of Atrovent HFA Inhalation Aerosol Device


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Appendix 3
Instructions for Use of Ventolin HFA Inhaler
Instructions for Use
For Oral Inhalation Only
Your VENTOLIN HFA inhaler
•
The metal canister holds the medicine. See Figure A.
Figure A
Figure A
The canister has a counter to show how many sprays of medicine you have left. The number 
shows through a window in the back of the actuator. See Figure B.


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Figure B
•
The counter starts at either 204 or 064, depending on which size inhaler you have. The 
number will count down by 1 each time you spray the inhaler. The counter will stop counting 
at 000.
•
Do not try to change the numbers or take the counter off the metal canis ter. The counter 
cannot be reset, and it is permanently attached to the canister.
•
The blue plastic actuator sprays the medicine from the canister. The actuator has a protective 
cap that covers the mouthpiece. See Figure A. Keep the protective cap on the mouthpiece 
when the canister is not in use. The strap keeps the cap attached to the actuator.
•
Do not use the actuator with a canister of medicine from any other inhaler.
•
Do not use a VENTOLIN HFA canister with an actuator from any other inhaler.
Before using your VENTOLIN HFA inhaler
Before you use VENTOLIN HFA for the first time, you must prime the inhaler so that 
you will get the right amount of medicine when you use it.
To prime the inhaler, take the cap off the mouthpiece and shake the inhaler well. Then spray 
the inhaler 1 time into the air away from your face. See Figure C. Avoid spraying in eyes.


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Figure C
•
Shake and spray the inhaler like this 3 more times to finish priming it. The counter should 
now read 200 or 060, depending on which size inhaler you have. See Figure D.
Figure D


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You must prime your inhaler again if you have not used it in more than 14 days or if you 
drop it. Take the cap off the mouthpiece and shake and spray the inhaler 4 times into the air 
away from your face.
How to use your VENTOLIN HFA inhaler
Follow these steps every time you use VENTOLIN HFA.
Step 1. Make sure the canister fits firmly in the actuator. The counter should show through the 
window in the actuator.
Shake the inhaler well before each spray.
Take the cap off the mouthpiece of the actuator. Look inside the mouthpiece for foreign objects, 
and take out any you see.
Step 2. Hold the inhaler with the mouthpiece down. See Figure E.
Figure E
Step 3. Breathe out through your mouth and push as much air from your lungs as you can. Put 
the mouthpiece in your mouth and close your lips around it. See Figure F.


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Figure F
Step 4. Push the top of the canister all the way down while you breathe in deeply and slowly 
through your mouth. See Figure F.
Step 5. After the spray comes out, take your finger off the canister. After you have breathed in 
all the way, take the inhaler out of your mouth and close your mouth.
Step 6. Hold your breath for about 10 s econds, or for as long as is comfortable. Breathe out 
slowly as long as you can.
If your healthcare provider has told you to use more sprays, wait 1 minute and shake the 
inhaler again. Repeat Steps 2 through Step 6.
Step 7. Put the cap back on the mouthpiece after every time you use the inhaler. Make sure it 
snaps firmly into place.
Cleaning your VENTOLIN HFA inhaler
Clean your inhaler at least 1 time each week. You may not see any medicine build-up on the 
inhaler, but it is important to keep it clean so medicine build-up will not block the spray. See 
Figure G.


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Figure G
Step 8. Take the canister out of the actuator, and take the cap off the mouthpiece. The strap on 
the cap will stay attached to the actuator.
Step 9. Hold the actuator under the faucet and run warm water through it for about 30 seconds. 
See Figure H.
Figure H
Step 10. Turn the actuator upside down and run warm water through the mouthpiece for about 
30 seconds. See Figure I.


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Figure I
Step 11. 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 build-up,
repeat Steps 9 and 10.
Step 12. Let the actuator air-dry overnight. See Figure J.
Figure J


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Step 13. When the actuator is dry, put the protective cap on the mouthpiece and then put the 
canister in the actuator and make sure it fits firmly. Shake the inhaler well, remove the cap, and 
spray the inhaler once into the air away from your face. (The counter will count down by 1 
number.) Put the cap back on
the mouthpiece.
If you need to use your inhaler before the actuator is completely dry:
•
Shake as much water off the actuator as you can.
•
Put the cap on the mouthpiece and then put the canister in the actuator and make sure it fits 
firmly.
•
Shake the inhaler well and spray it 1 time into the air away from your face.
•
Take your VENTOLIN HFA dose as prescribed.
•
Follow cleaning Steps 8 through 13 above.






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Appendix 6
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 7
Protocol of HRCT scan and CFD method  
1 Protocol of CT scan 
For small airways scanning thorax HRCT scans are taken at Visit 2, Visit 3, Visit 4 and Visit 5. 
The scans on Visit 2 and Visit 4 are taken at two different lung volumes, i.e. TLC and FRC, 
during breath hold. The scans on Visit 3 and Visit 5 are only taken at TLC level. In order to 
control the lung volume, the subjects’ breathing signal is monitored. During Visit 2 an additional 
scan of the upper airway will be taken. The scans will be taken with a 
 64-
slice scanner or a scanner yielding equivalent results.
Monitoring the breathing signal: 
In order to monitor the breathing signal, the subject breaths through a mouthpiece. This 
mouthpiece is connected with a laptop (via a networkcable long enough to bridge the distance 
between subject in the CT room and the control room) on which specialized software is running. 
Through a pneumotach in the mouthpiece the flow pattern can be followed. For TLC we ask the 
subject to breath in fully and to hold his breath for the duration of the scan. When we see the 
subject is correctly holding his breath, a CT scan is taken. The same procedure is repeated at 
FRC. We ask the subject to breath in a bit and to slowly blow out until FRC and to hold his 
breath. At that moment the second CT scan is taken. For the upper airway scan we ask the 
subject to breath in slowly while the scan is taken. 
Scanning protocols: 
For the TLC Scan and FRC scan:
•         Rotation time of 0.6 s 
•         Detector coverage of 40 mm 
•         Helical thickness of 0.625 mm 
•         Pitch and speed of 1.375:1 and 55 mm/s. 
•         Tube voltage: 100 kV 
•         Tube current: variable between 10 and 200 mAs 
•         Noise index: 45 
The field of view is set as small as possible, but the lung should be seen completely in all axial 
slices. Scan time lies around 5 seconds. Images are reconstructed at 0.3 mm interval using a lung 
filter. The resulting data set has 700-1200 images with a pixel size of 0.4-0.65 mm2. 
UA scan
•         Rotation time of 0.5 s 
•         Detector coverage of 40 mm 
•         Helical thickness of 1.250 mm 
•         Pitch and speed of 0.984:1 and 39.37 mm/s. 
•         Tube voltage: 100 kV 






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Appendix 9
Investigator’s Agreement and Signature Page
Study Title:
A Randomized, Double-Blind, Two Treatment, Two Period, Chronic 
Dosing (2 Weeks), Cross-Over, Multi-Center Study to Evaluate the 
Effects of PT001 and PT005 on Specific Image Based Airway 
Volumes and Resistance in Subjects With Moderate to Severe COPD.
Study Number:
PT003019-01 / FLUI-2015-140
Final Date:
10 August 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 
Therapeutics, Inc.
•
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, Inc. 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 Therapeutics, Inc. 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 Therapeutics, Inc.
•
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 Therapeutics, Inc. 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:

SAP_001.pdf: 
 
Statistical Analysis Plan 
 
Study Code 
PT003019  
NCT #  
NCT02937584 
Date 
16APRIL2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-Blind, Two Treatment, Two Period, 
Chronic Dosing (2 Weeks), Cross-Over, Multi-Center Study to 
Evaluate the Effects of PT001 and PT005 on Specific Image 
Based Airway Volumes and Resistance in Subjects With Moderate 
to Severe COPD 


1
Statistical Analysis Plan
Study Code
PT003019
Edition Number
1.0
Date
16 Apr 2018
A Randomized, Double-Blind, Two Treatment, Two Period, Chronic 
Dosing (2 Weeks), Cross-Over, Multi-Center Study to Evaluate the Effects 
of PT001 and PT005 on Specific Image Based Airway Volumes and 
Resistance in Subjects With Moderate to Severe COPD.








Statistical Analysis Plan 
Study Code PT003019
Edition Number 1.0
Date 16 Apr 2018
5
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
TABLE OF CONTENTS.....................................................................................5
LIST OF ABBREVIATIONS ..............................................................................7
AMENDMENT HISTORY..................................................................................9
1.
STUDY DETAILS............................................................................................. 10
1.1
Study objectives................................................................................................. 10
1.1.1
Primary objectives ............................................................................................. 10
1.1.2
Secondary objectives.......................................................................................... 10
1.1.3
Safety Objective................................................................................................. 10
1.2
Study design ...................................................................................................... 10
1.3
Number of subjects ............................................................................................11
2.
ANALYSIS SETS ............................................................................................. 12
2.1
Definition of analysis sets .................................................................................. 12
2.1.1
Intent-To-Treat (ITT) population........................................................................ 12
2.1.2
Modified Intent-To-Treat (mITT) population ..................................................... 12
2.1.3
Safety population ...............................................................................................12
2.1.4
Population for analyses ......................................................................................12
2.2
Violations and deviations ................................................................................... 13
3.
PRIMARY AND SECONDARY VARIABLES................................................. 13
3.1
Efficacy Endpoints............................................................................................. 13
3.1.1
Definition of baselines ....................................................................................... 13
3.1.2
Treatment periods and visit windows .................................................................14
3.1.3
Primary Efficacy Endpoints ...............................................................................14
3.1.4
Secondary Efficacy Endpoints............................................................................ 16
3.1.4.1
FRI Parameters ..................................................................................................16
3.1.4.2
Spirometry Parameters....................................................................................... 17
3.1.4.3
Body Plethysmography Parameters .................................................................... 17
3.1.5
Other Efficacy Endpoints................................................................................... 18
3.1.5.1
FRI Parameters ..................................................................................................18
3.1.5.2
Spirometry Parameters....................................................................................... 20
3.1.5.3
Body Plethysmography Parameters .................................................................... 21
3.2
Safety Endpoints................................................................................................ 21


Statistical Analysis Plan 
Study Code PT003019
Edition Number 1.0
Date 16 Apr 2018
6
3.3
Handling of missing data.................................................................................... 21
4.
ANALYSIS METHODS....................................................................................23
4.1
General principles.............................................................................................. 23
4.1.1
Treatment Effect Assessment ............................................................................. 23
4.1.2
Hypothesis Testing.............................................................................................23
4.1.3
Control of Type I error....................................................................................... 24
4.1.4
Software............................................................................................................. 24
4.2
Analysis methods............................................................................................... 24
4.2.1
Disposition, demographics and baseline characteristics ......................................24
4.2.2
Concomitant medications................................................................................... 25
4.2.3
Exposure............................................................................................................ 25
4.2.4
Analysis of FRI data ..........................................................................................25
4.2.5
Spirometry / Body Plethysmography data........................................................... 28
4.2.6
Assumptions Checks and Removal of Outliers in Sensitivity Analyses............... 28
4.2.7
Exploratory analyses..........................................................................................29
4.2.8
Safety data ......................................................................................................... 29
5.
INTERIM ANALYSES (NOT APPLICABLE).................................................. 30
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 30
7.
REFERENCES ..................................................................................................30
8.
APPENDIX ....................................................................................................... 31
8.1
List of efficacy analyses..................................................................................... 31


Statistical Analysis Plan 
Study Code PT003019
Edition Number 1.0
Date 16 Apr 2018
7
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
AT
ATC
ATS
BID
CFD
COPD
CSR
CT
ECG
eCRF
ERS
FEF25-75
FEV1
FRC
FRI
FVC
GFF
GOLD
HFA
IAD
IC
IPD
iRaw
ITT
iVaw
iVlobe
LUL
LL
LLL
MDI
mITT
PFT
Raw
RLL
Adverse Event
Air Trapping
Anatomic Therapeutic Class
American Thoracic Society
Bis In Die, twice daily
Computational Fluid Dynamics
Chronic Obstructive Pulmonary Disease
Clinical Study Report
Computed Tomography
Electrocardiograms
electronic Case Report Form
European Respiratory Society
Forced Expiratory Flow between 25% to 75% of FVC
Forced Expiratory Volume In 1 Second
Functional Residual Capacity
Functional Respiratory Imaging
Forced Vital Capacity
Glycopyrronium and Formoterol Fumarate
Global initiative for chronic Obstructive Lung Disease
Hydrofluoroalkane
Internal Airflow Distribution
Inspiratory Capacity
Important Protocol Deviation
Image based Airway Resistance
Intent-To-Treat
Image based Airway Volume
Image based Lobar Volume
Left Upper Lobe
Lower Lobe
Left Lower Lobe
Metered Dose Inhaler
Modified Intent-To-Treat
Pulmonary Function Test
Airway Resistance
Right Lower Lobe


Statistical Analysis Plan 
Study Code PT003019
Edition Number 1.0
Date 16 Apr 2018
8
Abbreviation or 
special term
Explanation
RML
RUL
Right Middle Lobe
Right Upper Lobe
RV
sGaw
siRaw
siVaw
sRaw
TEAE
TLC
TP
UA
UL
WHO-DD
Residual Volume
Specific Airway Conductance
Specific Image based Airway Resistance
Specific Image based Airway Volume
Specific Airway Resistance
Treatment Emergent Adverse Event
Total Lung Capacity
Treatment Period
Upper Airway
Upper Lobe
World Health Organization Drug Dictionary


Statistical Analysis Plan 
Study Code PT003019
Edition Number 1.0
Date 16 Apr 2018
9
AMENDMENT HISTORY
Date
Brief description of change
N/A


Statistical Analysis Plan 
Study Code PT003019
Edition Number 1.0
Date 16 Apr 2018
10
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objectives
!
To assess the effect of treatment with Glycopyrronium (GP) MDI administered twice 
daily (BID) and Formoterol Fumarate (FF) MDI administered BID on specific image-
based airway volumes and resistance in subjects with moderate to severe chronic 
obstructive pulmonary disease (COPD) following chronic dosing after approximately 
two weeks treatment.
1.1.2
Secondary objectives
!
To assess the effects of GP MDI and FF MDI on various Functional Respiratory 
Imaging (FRI) parameters.
!
To assess the effects of GP MDI and FF MDI on lung function parameters.
1.1.3
Safety Objective
To assess the safety of GP MDI and FF MDI in subjects with moderate to severe COPD based 
on adverse events (AEs), and any clinically relevant findings from vital sign measurements, 
electrocardiograms (ECGs), physical examination findings, and clinical laboratory 
evaluations.
1.2
Study design
This is a multi-center, double-blind, two-treatment, two-period, full cross-over, chronic dosing
(2 weeks) study to assess the effects of GP MDI (14.4 μg BID) and FF MDI (9.6 μg BID) on 
specific image-based airway volumes and resistance in subjects with moderate to severe 
COPD. In this study, airway dimension parameters will be calculated for each of the two 
active compounds.
This multi-center study will be conducted at two sites. Across these sites, it is planned that 
approximately 20 subjects with moderate to severe COPD will be randomized into this study.
Study Duration: 
Each subject will receive in total study treatment for approximately four weeks (two separate
Treatment Periods (TP) of approximately two weeks, separated by a washout period of 5-21 
days). The entire study period is scheduled to take approximately 13 weeks for each individual 
subject from the time of screening through follow-up.


Statistical Analysis Plan 
Study Code PT003019
Edition Number 1.0
Date 16 Apr 2018
11
Study design chart
Computed Tomography (CT)-scans during study: 
On Day 1 of each Treatment Period (TP [Visit 2 and Visit 4]), baseline measurement 
inspiratory scan (total lung capacity [TLC] scan) and expiratory scan (functional residual 
capacity [FRC] scan) will be conducted. During Visit 2, an additional scan of the upper airway 
(UA) will be taken. Post-dose measurement inspiratory scan (total lung capacity [TLC] scan) 
will be taken after approximately 2 weeks of treatment with either GP MDI or FF MDI on 
Day 15 ± 5 days (Visit 3 and Visit 5). Post-dose activities should be started 1 hour after dosing 
on Visit 3 and Visit 5, and should be concluded within 2.5 hours after dosing. Between the 
Treatment Periods there will be a washout period of 5-21 days.
1.3
Number of subjects
Approximately 20 subjects with moderate to severe COPD will be randomized into the study.
In a double-blind, cross-over study where 10 COPD Global Initiative for Chronic Obstructive
Lung Disease (GOLD) III subjects received a budesonide/formoterol combination (De Backer 
2012); FRI was able to quantify the effects of the active compound relative to baseline. The 
percentage change from baseline in airway volume was 6.48% (SD=7.46%), giving an effect 


Statistical Analysis Plan 
Study Code PT003019
Edition Number 1.0
Date 16 Apr 2018
12
size of 0.869. Assuming a similar effect size for the improvements from baseline in airway 
volume parameters with active treatments in this study, a sample size calculation (power goal 
90%, alpha 0.05) revealed that in order to have a well-powered study with change in imaging 
based airway volume as primary outcome parameter, a total of 16 subjects would be required. 
If the significance level for the volume is set to 0.025 by the Hochberg's step-up procedure, 20 
subjects would be required. It can be assumed that sufficient power will be obtained when 
including 20 subjects.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
The following analysis populations are defined in this study:
2.1.1
Intent-To-Treat (ITT) population
The ITT Population is defined as all subjects who are randomized to treatment. Patients will 
be analysed according to the treatment they were assigned to at randomization, regardless of 
the treatment actually received.
2.1.2
Modified Intent-To-Treat (mITT) population
The modified Intent-to-Treat (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.
2.1.3
Safety population
The Safety Population is defined as all subjects who are randomized to treatment and
receive at least one dose of the study treatment. Statistical analyses and tabulations will be by
the treatment actually received.
2.1.4
Population for analyses
Analyses will be performed as follows:
Given that the ITT, mITT and Safety Populations are expected to only differ slightly, 
demographics and other characteristics will be summarized only for the ITT 
population. Extent of exposure will be summarized for the Safety Population. The 
Safety Population will be used to summarize safety data.
Efficacy analyses will be performed for the ITT Population. The mITT Population is a 
subset of the ITT Population, but if the data contributing to the mITT analyses differs 
from the data contributing to the ITT analyses, then the mITT Population will be used 
to conduct sensitivity analyses for the co-primary endpoints.


Statistical Analysis Plan 
Study Code PT003019
Edition Number 1.0
Date 16 Apr 2018
13
2.2
Violations and deviations
Only Important Protocol Deviations (IPDs) will be listed or tabulated. These are defined as 
those protocol deviations that may significantly affect the completeness, accuracy, and/or 
reliability of the study data or that may significantly affect a patient's rights, safety, or well-
being. These will be identified based upon blinded data, before database lock.
The following will be considered important protocol deviations:
!
Patient randomized despite not meeting key inclusion criteria, including:
o
Patients not meeting COPD diagnosis (as defined by ATS/ERS) and severity 
criteria (FEV1/FVC ratio of <0.70 and post-bronchodilator FEV1 >30% and <80% 
of predicted normal) as per inclusion criteria 5 and 7.
o
Patients meeting exclusion criteria for other respiratory disease as per 
exclusion criteria 4, including diagnoses of asthma.
!
Patient received incorrect study drug
!
Prohibited concomitant COPD medication taken during the study, defined as the
classes of medications listed in table 5-1 of the protocol, received after visit 2, other 
than those provided by the sponsor.
!
Developed discontinuation criteria but not withdrawn from study or discontinued 
investigational product 
Randomization errors
If a subject is given a treatment pack for a different patient or is randomized out of 
chronological order, they will be included in the statistical analysis. If a subject would receive 
the same treatment twice, this will be considered an important protocol deviation and 
sensitivity analyses will be conducted using the mITT population.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Efficacy Endpoints
3.1.1
Definition of baselines
Efficacy baseline assessments are taken pre-dose at Day 1 of each Treatment Period (TP) 
(Visits 2 and 4). The primary efficacy analyses involve a paired comparison to baseline, for 
each treatment separately, and the relevant period-dependent baseline (defined below) will be 
used as the Day 1 value for a subject.
Where linear mixed models are applied, the mean of the available pre-dose assessments across 
both visits will be taken as the subject-average baseline. As well, the mean of the available 
pre-dose assessments at each of Visits 2 and 4 respectively will be taken as the period-
dependent baseline for that respective TP.


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For the analysis of spirometry and plethysmography endpoints, the subject-average baseline 
will be derived as follows. For spirometry, the mean of the pre-dose -60 and -30-minute 
values will be obtained, at each of Visits 2 and Visit 4, then averaged over visits. In patients 
missing either of these assessments, the single value from that visit will be used. For 
plethysmography, the -30-minute assessments at Visits 2 and 4 will be obtained and averaged 
over these visits. Period-dependent baselines will be derived similarly based upon either Visit 
2 or Visit 4 respectively for spirometry and plethysmography analyses, and used for paired 
tests of baseline to Day 15 within treatment.
FRI parameters allow for estimates by lobe. Subject-average baseline for individual lobes is 
derived for each subject as the mean of the -30-minute lobe-specific baseline (Day 1) across 
periods (Visits 2 and 4), and these will be used in the individual lobe descriptive statistics. 
Subject-average baseline “across-lobes” is derived for each subject as the mean of all 
available baselines across all lobes and periods, and will be used in descriptive statistics, and 
statistical analyses that include a baseline. 
Period-dependent baseline for individual lobes is defined for each subject as the lobe-specific 
value on Day 1 of the respective treatment period (Visit 2 or 4). Period-dependent baseline 
“across lobes” is defined for each subject as the mean over all lobes on the first day of the
respective treatment period (Visit 2 or 4).
For FRI parameters that allow estimates by generation, subject-average baselines will be 
derived as described in the preceding paragraph (using “generation” instead of “lobe”), and 
included in descriptive statistics. Period-dependent baselines will not be required for analyses 
involving generation.
3.1.2
Treatment periods and visit windows
There will be two treatment periods in this study. The first day on which a study treatment is 
received is Treatment Day 1 (for that study treatment and period). Treatment day is numbered 
sequentially thereafter until washout is begun or a subsequent study treatment is received. 
Each treatment period is intended to last until Day 15. Visit windows during each Treatment 
Period are relative to Day 1 of that Treatment Period. Washout period between Visit 3 and 
Visits 4 is a minimum of 5 days to a maximum of 21 days.
No study time windows will be derived for the reporting of data. Data will be reported 
according to the protocol-scheduled day. Efficacy data obtained during unscheduled visits 
after Day 1 will be allocated to Day 15 within the same treatment period if the Day 15 visit is 
missing. For analysis of spirometry data by time point, if multiple values are collected the last 
available assessment will be used for a given nominal time point.
3.1.3
Primary Efficacy Endpoints
FRI Parameters:
The PT003019 Data Transfer Agreement describes the physiology of the lung in terms of the 
FRI endpoints described here, and should be read in conjunction with this (PT003019) SAP.


Statistical Analysis Plan 
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The co-primary endpoints of this study are as follows:
!
Specific Image based airway volume (siVaw): Absolute value in Airway Volume 
(iVaw) relative to the lobar volume at Day 1 and Day 15. 
!
Specific Image based airway resistance (siRaw): Absolute value in Airway Resistance 
relative to the lobar volume at Day 1 and Day 15. 
The primary efficacy analyses involve a paired comparison to baseline (Day 1), for each 
treatment separately, of the Day 15 siVaw average across lobes and the siRaw average across 
lobes parameters.
Two breathing levels are used to generate FRI parameters at period baseline Visits 2 and 4 -
TLC and FRC - while only TLC is used at Visits 3 and 5. Only data generated from the scans 
taken at TLC will be used for statistical analyses. Data generated at FRC will be listed and 
summarized for selected parameters.
For FRI parameters, data is generated within each of five lung lobes: right upper lobe, right 
middle lobe, right lower lobe, left upper lobe and left lower lobe. Each lobe comprises several 
segments (branches) that are further subdivided into typically 5-10 visible airway generations. 
Generation-level data (within segment within lobe) will be provided by FLUIDDA for iVaw 
and Mass of deposited particles. Lobe-level data can be produced by summing over all data 
points within a lobe for a patient. Lobe-level data will be provided for the other FRI 
parameters. Across-lobe summaries will consist of an average of available lobe-level data.
Because the number of generations visible on a CT scan can vary over time, a subject’s airway 
generations will be “trimmed” so that the generations are the same over a subject’s visits. For
iVaw, trimming will be done by segment, so that for each segment, the generations for a
subject’s four visits (Visits 2-5) are identical. For all other FRI parameters where trimming 
occurs, trimming will be done within period, such that for each segment the generations for 
Visits 2 and 3 are identical, and the generations for Visits 4 and 5 are identical. For the 
analysis of iVaw itself, an “untrimmed” analysis in addition to a trimmed analysis will be 
undertaken (as noted later), while only the trimmed iVaw values will be used for the 
derivation of other FRI parameters.
As described in the Data Transfer Agreement, FRI parameters siVaw and siRaw are derived 
from iVaw and iRaw by dividing iVaw by the image-based lobe volume (iVlobe) for siVaw, 
and by multiplying iRaw by iVlobe for siRaw, respectively. iVaw and siRaw are derived for 
each lobular region, where: RUL (right upper lobe), RML (right middle lobe), RLL (right 
lower lobe), LUL (left upper lobe), LLL (left lower lobe). For example:
!
siVaw LLL = iVaw LLL / iVlobe LLL,
!
siRaw LUL = iRaw LUL * iVlobe LUL.
siVaw and siRaw are also derived for the larger, LL (lung, lower lobes), UL (lung, upper 
lobes), DISTAL (all 5 lobes), CENTRAL, and TOTAL lung regions by summing parameters 
using the formulae below:


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Note, for airflow and resistance parameters, a result from the CENTRAL region of the lung is 
also provided, and this combined with the DISTAL total gives an overall TOTAL. For 
deriving resistance totals, parallel sums of iRaw should be used as described above, by 
summing the inverse of iRaw values and then inverting again (i.e., a harmonic mean).
siVaw
!
iVaw LL = iVaw RLL + iVaw LLL
!
iVaw UL = iVaw RUL + iVaw RML + iVaw LUL
!
iVaw DISTAL = iVaw LL + iVaw UL
!
iVaw TOTAL = iVaw CENTRAL + iVaw DISTAL
!
siVaw LL = iVaw LL / iVlobe LL
!
siVaw UL = iVaw UL / iVlobe UL
!
siVaw CENTRAL= iVaw CENTRAL / iVlobe TOTAL
!
siVaw DISTAL= iVaw DISTAL / iVlobe TOTAL
!
siVaw TOTAL = iVaw TOTAL / iVlobe TOTAL
siRaw
!
iRaw LL = 1 / ( 1/iRaw RLL + 1/iRaw LLL )
!
iRaw UL = 1 / ( 1/iRaw RUL + 1/iRaw RML + 1/iRaw LUL )
!
iRaw DISTAL = 1 / ( 1/iRaw RLL + 1/iRaw LLL +  1/iRaw RUL + 1/iRaw RML + 1/iRaw LUL )
!
iRaw TOTAL =  1 / (  1/iRaw CENTRAL + 1/iRaw RLL +  1/iRaw LLL + … + 1/iRaw LUL )
!
siRaw LL = iRaw LL * iVlobe LL
!
siRaw UL = iRaw UL * iVlobe UL
!
siRaw CENTRAL = iRaw CENTRAL * iVlobe TOTAL
!
siRaw DISTAL = iRaw DISTAL * iVlobe TOTAL
!
siRaw TOTAL = iRaw TOTAL * iVlobe TOTAL
iVlobe
!
iVlobe LL = iVlobe RLL + iVlobe LLL
!
iVlobe UL = iVlobe RUL + iVlobe RML + iVlobe LUL
!
iVlobe TOTAL = iVlobe RLL + iVlobe LLL + iVlobe RUL + iVlobe RML + iVlobe LUL
3.1.4
Secondary Efficacy Endpoints
3.1.4.1
FRI Parameters
!
Airway volume (iVaw): Absolute value at Day 1 and Day 15 
In the CT scans, the airways can be segmented up to the point where no distinction can 
be made between the intraluminal and alveolar air. This is where the airway diameter 
is around 1 – 2 mm, typically around the 5th to 10th bifurcation, depending mainly on 
the disease state of the individual patient. From the resulting model, the central and 
distal airway volumes can be assessed at individual airways or in different regions. 


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The distal airway volume is defined as the segmented airway volume starting from the 
third bifurcation that is from the 5 lung lobes without the central region. It is this distal 
region that will be used in the analyses in this study.
Note that iVaw is provided at the generation-level within segment within lobe. Lobe-
level data can be derived by summing over all data points (generations) within a lobe 
for a subject. The total for a given generation across lobes can be derived by summing 
over all data points (segments) within a generation for a subject.
!
As mentioned previously, the visible airway generations that comprise the lobes can 
vary over time. The iVaw measurements can thus be performed in two ways: 1) for 
each segment use all the generations visible at the particular study visit scan 
(“untrimmed”), or 2) for each segment use only generations of airways that are visible 
in the scans of all four visits (Visits 2-5) (“trimmed”). Both iVaw measures will be 
analysed. 
!
Airway resistance (iRaw): Absolute value at Day 1 and Day 15 
The airway resistance (iRaw) is determined using Computational Fluid Dynamics 
(CFD). During the CFD calculations, the outflow to each lobe is adjusted iteratively 
for each subject to match the internal flow rate distributions obtained from the 
segmentation of the CT scans. Hence, iRaw accounts for the patient-specific internal 
airflow distribution which might be greatly altered by the lung disease. Hence, the 
airflow distribution in the CFD calculation reflects the airflow distribution as derived 
from the expansion of the lung lobes from FRC to TLC. The iRaw is defined as the 
total pressure drop over an airway, divided by the flow rate through that airway.
For iRaw, the airways are trimmed until they are the same length for Visits 2 and 3, 
and for Visits 4 and 5, respectively, for a subject. We thus only assess the generations 
of airways that are visible in the scans of both Visits 2 and 3, and both Visits 4 and 5, 
respectively.
3.1.4.2
Spirometry Parameters
!
Forced expiratory volume in one second (FEV1) at Day 1 and Day 15. Change from 
baseline to Day 15 in post-dose FEV1.
FEV1 is the volume of air exhaled under forced conditions in the first second. Post-
dose results will be used. Change from baseline is calculated relative to the subject-
average baseline.
3.1.4.3
Body Plethysmography Parameters
!
Functional residual capacity (FRC) at Day 1 and Day 15. Change from baseline to Day 
15 in post-dose FRC.


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!
FRC is the volume remaining in the lungs at the end-expiratory position. Change from 
baseline is calculated relative to the subject-average baseline.
3.1.5
Other Efficacy Endpoints
3.1.5.1
FRI Parameters
The following parameters will be analysed formally using scans at TLC with the exception of 
the mass of deposited particles, Internal Airflow Distribution and Air Trapping, which will be 
summarized descriptively only because they are dependent on FRC, which is collected only 
on Day 1. 
!
Image-based Lobe volumes (iVlobe): Absolute value at Day 1 and Day 15 
By identifying and grouping the voxels that represent the air in the lungs the lung 
volume (L) can be determined from the scans. During segmentation, identifying the 
fissure planes on the CT images and using these surfaces as cutting objects can 
separate lung lobes. This means that not only the total lung volume is determined, but 
also the volume of each lobe individually.
o
For each treatment, only scans at the TLC level are taken after the treatment. 
That means that analyses can be performed only on TLC lobar volumes but not 
for FRC. For the FRC level, only descriptive summary of baseline values will 
be presented.
!
Percent predicted image-based lobe volume [based upon age, sex and height] (PP 
iVlobe) This will also be derived and analysed similarly to iVlobe using scans at the 
TLC level and summarized at baseline using scans at the FRC level. 
!
Air trapping (AT): Descriptive summary of baseline results 
Air trapping is defined as all the intrapulmonary voxels with Hounsfield Units between 
-1024 and -850 using the expiratory scans at FRC. This parameter is given as 
percentage of iVlobe.
Air Trapping is only valid on FRC scans, so because there are no FRC scans after 
treatment, no analyses can be done, only descriptive summary of baselines values are 
provided. The air trapping will also be derived for the upper lobes, lower lobes and 
total by summing data from relevant individual lobes.
!
Internal lobar airflow distribution (IAD): Descriptive summary of baseline results
By segmenting the lobes at FRC and TLC for each patient, the patient-specific airflow 
distribution can be established by assessing lobar volume expansion.


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Internal Airflow Distribution requires both FRC and TLC scans, so because there are 
no FRC scans after treatment, no analyses can be done. Only descriptive summary of 
baselines values will be produced.
!
Low attenuation or emphysema score (LAS): Absolute value at Day 1 and Day 15 
Low attenuation score is defined as all the intrapulmonary voxels with Hounsfield 
Units between -1024 and -950 using the inspiratory scans at TLC. This parameter is 
given as percentage of iVlobe.
!
Blood vessel density or fibrosis score (iVbv): Absolute value at Day 1 and Day 15 
Blood vessel density can be determined through segmentation and three-dimensional 
reconstruction of the blood vessels. The segmentation is based on a Hounsfield unit 
(HU) threshold between -600 and 600 and is performed on the TLC scan. The blood 
vessel density can be considered a surrogate for perfusion. This parameter is given as 
percentage of iVlobe.
!
Airway wall thickness (iVaww): Absolute value at Day 1 and Day 15 
The airway wall volume (also called airway wall thickness) consists of all visible 
tissue in the CT scan that encompasses the airway wall. The airway wall volume can 
typically be described to the same generation level as the volume description of the 
airway lumen; this is where the airway diameter is around 1 - 2 mm. Visible airway 
generations can be different over repeated scans. For airway wall thickness, the 
airways are trimmed until they are the same length for Visits 2 and 3, and for Visits 4 
and 5, respectively, for a subject. We thus only assess the generations of airways that 
are visible in the scans of both Visits 2 and 3, and both Visits 4 and 5, respectively.
!
Mass of deposited particles per defined airway section: Descriptive summary of 
baseline results
Regional aerosol deposition is determined by simulating the flow in the patient 
specific geometries using patient specific boundary conditions by means of CFD. 
While solving the flow equations, simultaneously particles are released in the flow and 
the force mass balance of the individual particles is determined through additional 
discrete phase computations. When a calculated particle trajectory intersects with the 
airway wall, the particle is trapped in that location. This allows determining the 
regional concentration of inhaled aerosols and consequently the effective lung dose of 
inhaled medication. These are measured in the full airway tree. 
Mass of deposited particles is a useful way to see the particle deposition in each region 
of the lung. Data from the baseline TLC scan will be summarized. Distal and 
peripheral data will be summed. Upper lobe and lower lobe totals will also be derived. 
However, for the analysis of mass of deposited particles by generation number, any 
distal or peripheral data corresponding to a given generation number will be employed. 


Statistical Analysis Plan 
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A given generation within a segment within a lobe will be either distal or peripheral. 
Thus, no summing is needed of distal and peripheral values for the by-generation 
analyses.
FRI parameters - Low attenuation or emphysema score (LAS), Air Trapping (AT), and Blood 
vessel density or fibrosis score (iVbv), will be provided by FLUIDDA, while Internal Airflow 
Distribution (IAD) and some of iVaww - will need to be calculated. Further detail can be 
found in the Data Transfer Agreement.
Internal Airflow Distribution (IAD)
!
IAD LLL = 100 * (iVlobe LLL TLC - iVlobe LLL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
!
IAD LUL = 100 * (iVlobe LUL TLC - iVlobe LUL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL 
FRC)
!
IAD RML = 100 * (iVlobe RML TLC - iVlobe RML FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL 
FRC)
!
IAD RUL = 100 * (iVlobe RUL TLC - iVlobe RUL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL 
FRC)
!
IAD RLL = 100 * (iVlobe RLL TLC - iVlobe RLL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL 
FRC)
!
IAD LL = IAD RLL + IAD LLL
!
IAD UL = IAD RUL + IAD RML + IAD LUL
Airway wall thickness (iVaww)
!
iVaww LL = iVaww RLL + iVaww LLL
!
iVaww UL = iVaww RUL + iVaww RML + iVaww LUL
!
iVaww DISTAL = iVaww RLL + iVaww LLL + iVaww RUL + iVaww RML + iVaww LUL
!
iVaww TOTAL = iVaww CENTRAL + iVaww DISTAL
For FRI parameters the values for each lobe, the lower lobe total, upper lobe total, and overall 
total will be listed.
3.1.5.2
Spirometry Parameters
The following parameters will be assessed at baseline (Day 1) and Day 15. The change from 
baseline at Day 15 post-dose will be calculated relative to the subject-average baseline.
!
Forced vital capacity (FVC): the determination of the vital capacity from a maximally 
forced expiratory effort
!
Tiffeneau index (FEV1/FVC ratio): the proportion of a person's vital capacity that they 
are able to expire in the first second of forced expiration
!
Forced expiratory flow 25%-75% (FEF25-75): forced expiratory flow at 25–75% of 
forced vital capacity


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!
Inspiratory capacity (IC): the amount of air that can be inhaled after the end of a 
normal expiration. The average of the available Day 15 post-dose assessments will be 
used. 
3.1.5.3
Body Plethysmography Parameters
The following parameters will be assessed at baseline (Day 1) and Day 15. The change from 
baseline at Day 15 will be calculated relative to the subject-average baseline.
!
Residual volume (RV): the volume of air remaining in the lungs after a maximal 
exhalation
!
Total Lung Capacity (TLC): the volume in the lungs at maximal inflation
!
Airway resistance (Raw): the resistance of the respiratory tract to airflow during 
inspiration and expiration
!
Specific airway resistance (sRaw): airway resistance corrected for differences in lung 
volume. 
!
Specific airway conductance (sGaw): derived as the mathematical inverse of airway 
resistance corrected for differences in lung volume.
3.2
Safety Endpoints 
The safety assessments include Adverse Events (AEs) and Serious Adverse Events (SAEs) 
during the study period.
AEs experienced by the subjects will be collected throughout the entire study and will be 
coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).
Only treatment emergent adverse events from the time of randomization onwards will be 
summarized. AEs will be assigned to the treatment period in which they first occurred. AEs 
reported as starting during a Washout Period or follow-up period will be assigned to the last 
treatment received. If an AE has a missing or partial onset date, then unless the stop date of 
the AE indicates otherwise, this will be considered an on-treatment event. 
Clinically relevant findings from laboratory, ECG and vital sign parameters will be reported 
as adverse events. As such these assessments will not be further tabulated.
3.3
Handling of missing data
The lung comprises 5 lobes which are each divided into further segments. The airway 
continues to divide into smaller airways and each branching point defines a new generation of 
the airway. Data for FRI parameters will be provided for each subject for each lobe of the 
lung, and, for some parameters, for each generation within each segment within each lobe of 


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the lung. Descriptive statistics and analyses may require that a subject’s data are summarized 
by lobe, across lobes, by generation, or across generations.
There may be missing data for certain lobes, if for example the subject is missing that lobe, or 
no airways lead to the lobe (giving a volume of zero and infinite airway resistance). Similarly, 
there may be missing segments for a lobe, or generations within a segment, as not all airway 
generations are observable in each CT scan. Some generations may not be present, or their 
diameter may be too small to be evaluable. It is assumed that in such cases the contribution of 
this generation to the total airway volume of the segment or to the total for that generation 
across lobes is negligible.
A segment’s value will be calculated by summing its available generation values. For the 
calculation of the lobe’s values, if there is a missing segment, the calculation will consist of 
the sum of the other present segments. Data from all individually evaluable lobes will be used 
in the analysis to allow for the estimation of effects at the subject-level for each lobe, and 
across all lobes.
Similarly, data from individually evaluable generations will be summed in the generational 
analysis to allow for estimation for each generation, and across generations. Sensitivity 
analyses are described in section 4.2.4 for by-generation analyses imputing small values for 
patients with no evaluable data at later generations.
If, for a subject, a particular lobe has missing data, then summed totals of lobes will not be 
computed for that subject (for regions to which the missing lobe would belong).
Where scans are not evaluable for a single assessment or period, this data is assumed to be 
missing at random. Where Day 15 assessments are missing, data from unscheduled post-
baseline assessments will be used in their place, if available. No further imputation for entirely 
missing assessments is planned.
Combined or indistinguishable lobes
If fissures between lobes cannot be distinguished, then only a combined estimate across 
multiple lobes may be produced. Such results from combined lobes will not be used in the 
derivation of averages (Baseline, Day 15, or across lobes) or in analyses that require the use of 
individual-lobe values (e.g. repeated measures analyses for which lobe is the repeated 
measure, and any within-lobe analyses). This will be consistent for both periods – i.e. if for a 
subject, certain lobes are combined for one period, then they must be combined for the other 
period too. 
Such combined lobe results may however enable totals and sub-totals to be calculated for a 
subject, if the lobes which are combined coincide with those required for relevant regions (for 
which a summed total of the affected lobes would be needed). 


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For subjects with lobes that cannot be distinguished, data for that subject’s lobe will be 
considered unevaluable and will not contribute to the lobe analysis. This rule will be applied
for both periods. 
4.
ANALYSIS METHODS
The primary objective of this study is to assess the effect of treatment with Glycopyrronium 
(GP) MDI administered twice daily (BID) and Formoterol Fumarate (FF) MDI administered 
BID on specific image-based airway volumes and resistance in subjects with moderate to 
severe chronic obstructive pulmonary disease (COPD) following chronic dosing after 
approximately two weeks treatment.
Additional analyses will compare the distribution of regional effects between the two 
treatments for the different FRI endpoints. The magnitude of differences in effects between 
treatments overall, locally (by lobe), and in terms of central vs. peripheral effects (i.e. by 
generation) will be estimated. As such, treatment effects will also be estimated between 
treatments overall (“across lobes”), locally (by lobe), and by generation (where available), and 
it will be investigated whether there is any evidence for differential patterns in the effects of 
each treatment.
4.1
General principles
4.1.1
Treatment Effect Assessment
For the efficacy analyses, GP MDI and FF MDI will be assessed for Day 15 effects. P-values 
for differences from baseline, and between treatments, as well as for tests of treatment 
interaction, will be reported as two-sided. For the co-primary endpoints, the other FRI 
parameters, as well as spirometry and plethysmography parameters, the Day 15 summary 
statistics for each treatment period will be reported and analysed.
The Intent-to-Treat (ITT) Population will be considered the primary analysis population for 
efficacy. Supportive analyses will be conducted for the modified Intent-to-Treat (mITT) 
Population, if the mITT Population is significantly different from the ITT Population.
Continuous efficacy variables will be summarized with descriptive statistics n (the number of 
non-missing values, mean, standard deviation, median, minimum and maximum). Where data 
have been logarithmically transformed for analysis, the summary statistics on the back-
transformed data will include the geometric mean and the coefficient of variation (calculated 
as 100x√[exp(s2)-1], where s is the standard deviation of the data on the log scale. Categorical 
variables will be summarized with frequency counts and percentages, by treatment.
4.1.2
Hypothesis Testing
For the efficacy analyses, the individual effects of each of GP MDI and FF MDI respectively, 
will be assessed. The effect is defined as the difference between the value at Day 15 and the 
value at Day 1. Effect is thus the change from baseline to Day 15, for a GP MDI treatment, 
and the change from baseline to Day 15, for a FF MDI treatment.


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Denote the FRI value on Day 1 by FRI1 and FRI on Day 15 by FRI15.The difference between 
FRI15 and FRI1 for each patient will be calculated as FRIDIFF = FRI15 - FRI1 for the within-
treatment comparison between Day 1 and Day 15. The hypotheses for the respective “per-
treatment” comparisons are: 
Ho: FRIDIFF = 0, for GP MDI (no effect of treatment)
H1: FRIDIFF ≠ 0, for GP MDI
Ho: FRIDIFF = 0, for FF MDI (no effect of treatment)
H1: FRIDIFF ≠ 0, for FF MDI.
The hypothesis that FRIDIFF = 0 will be tested using a paired t-test and a two-sided p-value ≤ 
0.05 will be regarded statistically significant. 
Additional analyses will compare the distribution of regional effects between the two 
treatments for the different FRI endpoints. These treatment comparisons will not be 
considered to be formal hypothesis testing, but as estimation and investigation of regional 
treatment effects.
4.1.3
Control of Type I error
For the primary efficacy endpoints, Hochberg's step-up procedure will be used as a 
multiplicity adjustment to control the type I error within each product at 5%. Specifically, 
Hochberg’s procedure will be applied once for the siVaw and siRaw endpoints, for GP MDI, 
and then applied separately again for the same endpoints for FF MDI. No correction will be 
performed for the secondary or other endpoints or for between treatment comparisons. P-
values outside of the Hochberg procedures will be interpreted at the two-sided 5% level.
4.1.4
Software
All statistical analysis will be conducted using SAS version 9.2 or higher, or other validated 
software as appropriate.
4.2
Analysis methods
4.2.1
Disposition, demographics and baseline characteristics
Descriptive summaries of disposition, demographics and baseline characteristics will be 
produced. Disposition tables will summarize the number of patients who received each 
treatment, the number who completed 1 or 2 treatment periods and the number of early 
discontinuations. The number of patients in each analysis set will be summarized along with 
any reasons for exclusion.
Demographics and baseline characteristics at screening will be summarized descriptively, 
including COPD disease duration, symptom severity scores. Baseline pre and post 
bronchodilator spirometry parameters (and their percent predicted values) and reversibility to 
Ventolin HFA will be summarized using descriptive statistics based upon the baseline 
assessments within each treatment period. Percent predicted residual volume (RV) and percent 


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predicted functional residual capacity (FRC) will also be summarized. Predicted values for 
FEV1 will be calculated using The Third National Health and Nutrition Examination Survey 
(NHANES III) (Hankinson 1999) reference equations. Predicted values for RV and FRC will 
be calculated using Quanjer (1993).
4.2.2
Concomitant medications
Concomitant medications will be assigned a preferred term and an ATC (Anatomic 
Therapeutic Class) term using the latest version of the World Health Organization Drug 
Dictionary (WHO-DD) available. Medications will be summarized according to whether they 
are COPD related or non-COPD related. Summaries will be presented for those medications 
started prior to the beginning of study treatment, those started during a treatment period and 
those started during the washout period.
4.2.3
Exposure
The number of days of exposure to each treatment will be defined as ((End date of treatment –
Date of first dose of treatment) + 1).
Exposure to IP will be summarized by treatment using the safety analysis set. 
4.2.4
Analysis of FRI data
Primary endpoint analyses (siVaw, siRaw)
Within-Treatment Comparison of Day 1 and Day 15
The primary efficacy analyses will consist of a within-treatment comparison of Day 1 and Day 
15 using a paired t-test for each primary endpoint and for each treatment. A paired t-test will 
compare the Day 15 siVaw in the GP MDI treatment period to the corresponding Day 1 value 
for that period; the same will be done for siRaw. Paired t-tests will be similarly applied for FF 
MDI. 
Linear Mixed Effect Models
As secondary analyses, the Day 15 value for each parameter in each period will be analyzed 
using a linear mixed effect model. It is anticipated that the data will be logarithmically 
transformed prior to analysis. A multi-level model will be used to incorporate the repeated 
measurements from the lobes for each subject. 
The model will include fixed effects for period, treatment, lobe, and treatment-by-lobe 
interaction. The model will not include treatment sequence unless that term is determined to 
be important (p<0.10). Lobe will be included as a random effect, within each subject. 
Heterogeneity across lobes (within subject) will be modelled using an unstructured variance-
covariance matrix, with independence assumed between subjects. 
If this model fit fails to converge, a compound symmetry covariance structure will be 
considered to model correlation across lobes from the same patient. 


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Estimates will be produced of the difference between treatments, for each lobe and across all 
lobes. Where logarithmic transformations have been made, estimates will be exponentiated 
and treatment effects presented as ratios. Estimates and standard errors will be reported along 
with 2-sided 95% confidence intervals and p-values. The Kenward-Roger approximation for 
degrees of freedom and correction of downward bias in the standard error of fixed effect 
parameters will be used. The p-values for the treatment effect and the treatment-by-lobe 
interaction will be reported across-lobe.
Line-plots will be produced displaying Day1 and Day 15 absolute values by treatment and 
sequence at the individual subject level using the mean of data from available single lobes for 
each subject. 
Secondary and other efficacy endpoint analyses for FRI
Similar analyses to the primary endpoint analysis will be conducted for secondary and other 
efficacy endpoints, except for Mass of deposited particles, Internal Airflow Distribution 
(IAD), and Air Trapping (AT), whose analyses are described under generation-level analyses, 
Mass of Deposited Particles, and IAD and AT analyses respectively.
Sensitivity Analyses
If the mITT population differs from the ITT population, the mITT population will be used to 
conduct sensitivity analyses of the mixed models for the co-primary endpoints. The mITT 
population will only include patients with data from both periods without important protocol 
deviations. Similar mixed models will be used.
For the primary endpoints only, a further model will be produced which includes covariates 
for baseline. The model will include fixed effects for period, treatment, lobe, and treatment-
by-lobe interaction, subject-average baseline by lobe and period-dependent baseline by lobe. 
Both versions of baseline are continuous covariates. The use of both subject-average and 
period-dependent baselines allows for different coefficients for the between and within subject 
covariate regressions (Kenward and Roger 2010). Period-dependent baselines will be 
summarized for the primary endpoints. The p-values for the treatment effect and the 
treatment-by-lobe interaction will be reported across-lobes.
IAD and AT Analyses
For Internal Airflow Distribution (IAD) and Air Trapping (AT) endpoints, no statistical 
analyses will be undertaken. Descriptive summary statistics will be produced for these 
endpoints in each lobe of the subject’s lungs at baseline (Day 1). 
Mass of Deposited Particles
Mass of deposited particles is a useful way to see the particle deposition in each lobe of the 
lung. Summaries will be provided for the deposition in each lobe of the patient’s lungs at 


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baseline TLC, as well as for the upper lobe and lower lobe totals. Distal and peripheral data 
will be summed. Only descriptive summaries will be produced.
Generation-level Analyses
Two endpoints, iVaw and Mass of deposited particles, will have data produced by generation-
level and not lobe-level data. The number of generations per subject may differ, and a typical 
airway model includes 5-10 generations, depending mainly on the disease state of the subject. 
For each segment, the generations available for each subject-visit will be reviewed and agreed 
upon in a blinded manner prior to unblinding of the database. [For further details regarding the 
numbering of the generations, please refer to the data transfer specifications.]
Mixed models of iVaw by generation will be conducted using the total across all segments for
a given generation number so that each subject has at most one data point per generation. 
Several analyses (1, 2, 3, and 4 below) will be conducted to apply different methods to handle 
the fact that each subject potentially has a different number of generations with evaluable data.
If the model fit fails to converge, a compound symmetry covariance structure will be 
considered to model correlation across generations from the same patient. 
In an analysis called “repeated measures through generation H and beyond” (Analysis 1), for 
each subject-visit, the number of generations available for each segment within each lobe will 
be determined and numbered separately, from 1, 2, 3, etc. The maximum generation number 
will then be determined across the lobe-specific segments, for each subject-visit. Using only 
the maximum generation numbers from Visits 3 and 5, the smallest value will be determined 
across all subjects, and will be denoted as H. H is the highest generation number common to 
all subjects (amongst Visits 3 and 5). Where a subject has generations higher than H, the 
parameter values will be aggregated (summed) across those generations and added to the 
value for generation H, and treated as generation “≥H”. 
In an analysis called “repeated measures through generation H” (Analysis 2), parameter 
values from generations beyond generation H will not be employed, and the final generation 
included in the analysis will be generation H and will be called generation “H”.
Let K denote the largest generation number observed for at least half of the subjects (again, 
using only Visits 3 and 5). Let m-iVaw denote the smallest iVaw that is observed for any 
subject for any visit for any generation. For a log-transformed analysis, impute any 
unobservable generation for a subject with the value of m-iVaw. The analysis of such data 
will be called “repeated measures through generation K: transformed” (Analysis 3). 
For an untransformed analysis, impute any missing generation for a subject with the value of 
zero for iVaw. The analysis of such data will be called “repeated measures through 
generation K: untransformed” (Analysis 4). Analysis 4 will only be conducted if the data 
distribution allows.


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Note the values of “H” and “K”, once determined prior to data unblinding, will be used in 
table titles, rather than “H” and “K” themselves. 
For each repeated-measures iVaw analysis (Analyses 1, 2, 3, and 4), a repeated measures 
model will include fixed effects for period, treatment, generation and treatment-by-generation 
interaction. The model will not include treatment sequence unless that term is determined to 
be important (p<0.10). Generation will be included as a random effect, within each subject. 
Heterogeneity across generations (within subject) will be modelled using a Toeplitz variance-
covariance matrix, with independence assumed between subjects. The p-values for the 
treatment effect and the treatment-by-generation interaction will be reported across-
generations. Analyses 1, 2, and 3 will have logarithmic transformation. Analysis 4 will not. 
Analyses 1-4 will be conducted separately for trimmed and untrimmed data.
A graphical display of model-based estimates for iVaw by generation for each treatment will 
be implemented. The estimated geometric mean Untrimmed Airway Volume (iVaw) will be 
plotted along with 95% confidence interval bars by generation number (on the horizontal 
axis). The estimated geometric mean Trimmed Airway Volume (iVaw) will also be plotted, in 
a separate display.
For mass of deposited particles, no statistical analyses will be undertaken. Descriptive 
summary statistics will be produced showing the deposition in each generation of the subject’s 
lungs at baseline (Day 1). 
4.2.5
Spirometry / Body Plethysmography data
For spirometry and body plethysmography parameters, data are acquired at the subject-level 
and not by lobe. Paired t-tests will be used for within-treatment comparisons of Day 1 and 
Day 15. Associated estimates of the change from period-dependent baseline to Day 15 will be 
reported for each treatment, with a 95% confidence interval and p-value.
For comparisons between treatments, the change from baseline to Day 15 for each endpoint 
will be analysed using a linear mixed effect model including subject-average baseline as a 
continuous covariate and treatment and period as fixed effects. The model will not include 
treatment sequence unless that term is determined to be important (p<0.10). Subject will be 
modelled as a random effect. The ITT population will be used. It is expected that 
plethysmography endpoints may require logarithmic transformation, but that spirometry 
endpoints will not. Estimates of the difference between treatments, with 95% confidence 
interval and p-value, will be reported.
See Appendix 8.1 for a consolidated list of efficacy analyses and their essential differences for 
the FRI parameters, spirometry, and plethysmography.
4.2.6
Assumptions Checks and Removal of Outliers in Sensitivity Analyses
It is expected that logarithmic transformations will be required for most FRI and 
plethysmography endpoints, with the exception of the percent predicted lobe volume. Data 
will be transformed via the natural logarithm prior to analysis and the adjusted mean estimates 


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and confidence intervals from the linear models will be exponentiated back for presentation. 
As such the treatment effect for these endpoints will be presented as a ratio.
Hypotheses may be tested by means of the Wilcoxon signed rank test, in addition to the paired 
t-test, if the distribution of the data warrants it.
Under certain circumstances, (eg, 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. Depending on the plots of the 
standardized residuals versus fitted values of the mixed-effect models, other data 
transformations may be considered. If necessary, this may include the fifth root, adapted for 
positive and negative values: fifth root (x) = sign (x) * ( abs (x) ) ^ (1/5).
For resistance measures, outliers can occur that are real values but affect the model estimates 
extremely. In these cases, values that are larger than the third quantile + 3 times the 
interquartile range may be removed. Infinite values for resistance are possible and these will 
be listed, but will be removed from the data before statistical analysis. 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 the analysis.
4.2.7
Exploratory analyses
To gain insights into the mode of action of the product, additional exploratory analyses may 
be executed using (robust) linear regression or mixed models, and these may be reported 
outside of the CSR. These may entail post-hoc tests on the previously generated mixed-effect 
model. A regression of airway volume (iVaw), or change from baseline in airway volume, on 
Mass of deposited particles may be considered, to assess any correlation.
Pearson or Spearman’s rank correlations between variables may be produced (depending upon 
behaviour of distributions). If appropriate, exploratory analyses of mixed-effect regressions or 
linear regression between parameters may be conducted to investigate associations between 
parameters, but these will be reported outside of the CSR.
The results of the PT003019 study can be combined with the results of the PT003018 
(EudraCT: 2015- 001743-36) for further examination. However, this would be the subject of a 
separate SAP.
4.2.8
Safety data
Adverse events will be summarized by the number and percentage of subjects experiencing an 
event. Tables will show the overall incidence of AEs, and the incidence for each treatment. 
Treatment emergent adverse events from the time of randomization onwards will be 
summarized. AEs reported as starting during a Washout Period or follow-up period will be 
assigned to the last treatment received.


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AEs will be presented according to MedDRA preferred term and system organ class. 
Summaries will be produced by severity, seriousness, AEs leading to discontinuation, and by 
causality assessment to study drug. No hypothesis tests will be performed. 
Clinically relevant findings from laboratory, ECG and vital sign parameters will be reported 
as adverse events. As such, these assessments will not be further tabulated.
5.
INTERIM ANALYSES (NOT APPLICABLE)
No interim analyses are planned in this study.
6.
CHANGES OF ANALYSIS FROM PROTOCOL 
Similar to the effect described in section 9.3.1 of the protocol, a paired comparison to baseline 
will be implemented. However, for FRI parameters, regional (lobe and generation) models to 
compare treatments will use Day 15 values.
For spirometry and plethysmography, models to compare treatments will use the change to 
Day 15 (either as change from baseline, or ratio to baseline).
Given that the ITT, mITT and Safety Populations are expected to only differ slightly, 
demographics and other characteristics will only be summarized for the ITT population. The 
mITT population will purely be used for sensitivity analyses of the primary endpoints should 
the ITT and mITT populations differ.
Statistical analyses will be done primarily with SAS (not R).
7.
REFERENCES
De Backer L, Vos W, De Backer J, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD: a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012 Aug 1;40(2):298–305.
Kenward MG, Roger JH. The use of baseline covariates in crossover studies. Biostatistics 
2010, 11, 1, 1–17
Hankinson JL, Odencrantz, JR, et al. Spirometric reference values from a sample of the 
general U.S. population. Am J Respir Crit Care Med 1999; 159: 179-187
Quanjer, Ph., Tammeling, et al. Lung volumes and forced ventilatory flows. European 
Respiratory Journal - Eur Resp J. 1993; 6. Suppl. 16 5-40.