Conditions: COPD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 627
Healthy volunteers: no

Brief summary:
Study to Assess the Safety and Tolerability of PT010, PT009 and PT003 in Subjects with Moderate to Very Severe Chronic Obstructive Pulmonary Disease

Detailed description:
A Randomized, Double-Blind, Parallel-Group, 52-Week, Chronic-Dosing, Multi-Center Study to Assess the Safety and Tolerability of PT010, PT009 and PT003 in Subjects with Moderate to Very Severe Chronic Obstructive Pulmonary Disease

Arms:
arm 1: Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) metered dose inhaler (MDI) (PT010, BGF MDI) arm 2: Glycopyrronium and Formoterol Fumarate (GFF) metered dose inhaler (MDI) (PT003, GFF MDI) arm 3: Budesonide and Formoterol Fumarate (BFF) metered dose inhaler (MDI) (PT009, BFF MDI)

Interventions: intervention 1: BGF MDI 320/14.4/9.6 μg intervention 2: GFF MDI 14.4/9.6 μg intervention 3: BFF MDI 320/9.6 μg
Intervention descriptions: intervention 1: Budesonide, Glycopyrronium, and Formoterol Fumarate intervention 2: Glycopyrronium and Formoterol Fumarate intervention 3: Budesonide and Formoterol Fumarate

Protocol document:
Prot_000.pdf: 
 
 
Revised Clinical Study Protocol 
Study Code 
PT010008 
NCT #  
NCT03313570 
Date 
18 March 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 A Randomized, Double-Blind, Parallel-Group, 52-Week, Chronic-Dosing, Multi-Center 
Study to Assess the Safety and Tolerability of PT010, PT009 and PT003 in Subjects with 
Moderate to Very Severe Chronic Obstructive Pulmonary Disease  
 
 
 
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 
13 July 2015 
Version 2, Amendment 1 
18 March 2016 
 
 
 


Clinical Trial Protocol: PT010008-01
Study Title:
A Randomized, Double-Blind, Parallel-Group, 52-Week, Chronic-
Dosing, Multi-Center Study to Assess the Safety and Tolerability of 
PT010, PT009 and PT003 in Subjects with Moderate to Very Severe 
Chronic Obstructive Pulmonary Disease
Study Number:
PT010008-01
Study Phase:
III
Product Name:
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation 
Aerosol, PT010
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol, PT003
Budesonide and Formoterol Fumarate Inhalation Aerosol, PT009
EudraCT Number:
2014-005672-29
Indication:
COPD
Investigators:
Multicenter
Sponsor:
Pearl Therapeutics, Inc.
200 Cardinal Way, 2nd Floor
Redwood City, CA 94063
1-650-305-2600
Sponsor Contact:
Paul M. Dorinsky MD 
Version Number
Date:  
Original Protocol
Version 1.0
13 July 2015
Amended Protocol
Version 2.0
18 March 2016
Confidentiality Statement
Property of Pearl Therapeutics
This document is confidential and may not be used, divulged, published or otherwise 
disclosed without consent of Pearl Therapeutics Inc.


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
SUMMARY OF CHANGES TO ORIGINAL PROTOCOL VERSION 1.0, 
DATED 
The amended study protocol, PT010008-01(Version 2.0), includes the following edits: 
Newly added text is shown in bold font and deleted text is shown as strikethrough font. 
No.
Description of Change
Rationale
1
Section 3: Study Endpoints:  
All assessments are relative to baseline 
assessments performed during the Study 
PT010006 Screening Period (between Visit 
1 and Visit 34) 
To clarify Screening Period is 
considered between Visit 1 and Visit 4 
and not between Visit 1 and Visit 3 in 
this section and throughout the 
document for consistency 
2
Section 4.1 Overall Study Design and Plan
Baseline and demographic characteristics 
collected in Study PT010006 will be used 
for subjects participating in this study. 
Baseline assessments (BMD, lenticular 
opacity, fundoscopic examination, 
intraocular pressure, pupil dilation, and 
visual acuity assessments) will be 
performed prior to randomization in 
Study PT010006. If the first two BMD 
scans differ by more than 5% (as 
determined by the local facility) for 
either site (i.e. first two hip or first two 
lumbar sites) a third scan should be 
obtained. The screening period may be 
extended up to a maximum of 21 days if 
additional time is needed to complete the 
assessments during Study PT010006 
Screening Period (between Visit 1 and 
Visit 4). A separate informed consent will 
be obtained for subjects participating in 
Study PT010008 prior to any study 
PT010008 procedures.start of Study 
PT010006.
Subjects participating in Study PT010008 
who complete visit 10a of Study PT010006 
will transition to the remaining 28 weeks of 
To clarify how the scan information will 
be analyzed, to allow adequate time to 
complete assessments during the 
screening period, and to ensure 
consistency across study section and 
sites
Removed a sentence about reference to 
revisions to SAP or DMC as this is not 
relevant to this section
Confidential and Proprietary
Page 2 of 112


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
treatment by completing Visit 10b
(Week 24). Post-baseline lenticular 
opacity, fundoscopic examination, 
intraocular pressure, and visual acuity 
assessments will be performed prior to at
Visit 11 (Week 28), and at Visit 14 (Week 
52) and Treatment
Discontinuation/Withdrawal Visit. A
post-baseline BMD assessment will be
performed prior to Visit 14 (Week 52)
and Treatment
Discontinuation/Withdrawal Visit.
Subjects will return to the clinic at Visit 12
(Week 36), and Visit 13 (Week 44) to
return used medication and obtain new
study drug. Subjects will return to the
clinic at Visit 14 (Week 52) to complete
final study visit procedures
Removed the following sentence: Further 
details will be provided in the DMC 
charter and in the Statistical Analysis Plan 
(SAP
3
 Section 5.2. Exclusion Criteria 
Subjects who meet any of the following 
criteria will be excluded from the study
(please see the exception noted below the
ophthalmologic criteria Section 5.2.2).
Section 5.2.1 Bone Mineral Density 
Criteria applied to either hip or lumbar
region
1. Severe osteoarthritis osteoporosis
2. T-score <-2.5 at baseline
3. Added: Subjects unable to achieve an
acceptable scan (e.g. due to the
patient’s inability to be stable during
the procedure, due to limitation of
scanning equipment to accommodate
a subject ( ~300lbs or ~136kgs) or
other characteristics).
Added reference to exclusion criteria 
exception note (at end of Section 5.2.2) 
for allowance of subjects who meet none 
of the BMD exclusion criteria but one or 
more of ophthalmologic exclusion 
criteria to continue in the study based on 
the specified conditions 
Bone Mineral Density exclusion criteria  
clarified to indicate that it applied to 
either the lumbar or the hip region and 
the following criteria were revised:  
1. severe osteoarthritis term is
corrected to reflect appropriate term
"osteoporosis"
2. T-Score revised from a value of
"2.5" to  minus 2.5 "-2.5" to reflect
the excluded value and clarified
eligibility when >1 scan was
Confidential and Proprietary
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
required
3. Added exclusion criteria to account 
for limitations of the scanning 
equipment  
4
Section 5.2.2 Exclusion Criteria
Ophthalmologic Criteria applied to either 
eye  
1. IOP >21mmHg  (lowest of the 3 
readings)
2. Note: Subjects with IOP >21mmHg 
may be treated and re-tested during the 
screening period. If the re-test 
measurements for IOP < 21mmHg 
this subject may be eligible
NOTE: Subjects who meet none of the 
bone mineral density exclusion 
criteria but who meet one or more
ophthalmologic exclusion criteria may 
be permitted to continue in the study. 
Such subjects would undergo all study 
planned assessments except they would 
undergo no further ophthalmologic 
exams (all tests included in Section 7.2) 
during the randomized treatment 
period. Additionally such subjects would 
be permitted to continue in the study 
provided that the following 2 conditions 
are satisfied:
•
,23LVPP+JHLWKHUZLWKRU
without treatment 
•
In the opinion of the 
optometrist/ophthalmologist, the 
subject does not have a condition 
(e.g., advanced glaucoma) that the 
eye health of the subject could be 
jeopardized by continued 
participation in the study 
Ophthalmologic exclusion criteria:            
clarified to indicate that this criteria 
applies to either eye and the following 
are revised: 
1. The lowest of the 3 IOP readings 
should be considered to evaluate the 
exclusion of IOP >21mmHg  
2. Note is revised to indicate what re-
test value of the IOP could qualify 
subject’s eligibility 
Added exclusion criteria exception note 
(at end of Section 5.2.2) for allowance 
of subjects who meet none of the BMD 
exclusion criteria but one or more of 
ophthalmologic exclusion criteria to 
continue in the study based on the 
specified conditions 
5
Section 5.4.2 Prohibited COPD
To continue alignment with Study 
PT010006 at the start of this 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
Medications
1. Table (Table 5-1). ICS was deleted 
2. Theophylline details were revised to 
indicate 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 in Study PT010006
3. Note below this table
Subjects who are steroid dependent and 
maintained on an equivalent of up to 5 
PJRUDOSUHGQLVRQHSHUGD\RUPJ
oral prednisone every other day are 
permitted to enroll in the study 
provided they have been on a dose of 
oral steroids that remains consistent 
and does not exceed this threshold 
for the last two weeks prior to 
randomization (Visit 4) in Study 
PT010006
supplemental study
6
Section 5.4.3 Other Prohibited 
Medications 
Inserted Table 5.3 Non-COPD 
Medications Allowed Under Certain 
Conditions
Table 5.3 added to align with Study
PT010006 at the start of this 
supplemental study 
7
Section 5.4.3 Other Prohibited Medications 
Table 5.4   
1. Wording before Table 5.4 revised
Subjects requiring medications presented 
in Table 5.4 are prohibited from 
participating in this study. Subjects who 
recently discontinued use of these 
medications may be considered for study 
enrollment provided they have met the 
minimum Washout Period prior to Visit 
1 in Study PT010006.
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 
To continue alignment with Study 
PT010006 at the start of this 
supplemental study  
1. Wording prior to Table 5.4 revised 
to allow Investigator judgement  
2. Table 5.4 added exception of 
carvedilol To align with exclusion 
criteria for CHF Class I and II 
treatment as these subjects are 
permitted to participate in the study
3. Table 5.4 footnote revised  and 
description added to align with 
Study PT010006 
4. Table 5.4 footnote revised  and 
description added to align with 
Study PT010006 and allow 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
discontinued the investigator should 
evaluate the appropriateness of 
continuing the subject in the study
2. Table 5.4 revised to add exception of 
carvedilol for non-specific beta 
blocking agent
3. Table 5.4 Footnote added: 
Anticonvulsants for seizure or other 
indications allowed  provided the 
patient was treated with this class of 
medications during  Study PT010006
4. Table 5.4 Footnote revised:  
Antipsychotic agents and tricyclic 
antidepressants used for previously 
diagnosed underlying medical conditions
are allowed after consultation with the 
Peral Medical Monitor if, in the opinion of 
the Investigator, there are no concerns 
regarding patient safety, and if the 
patient has been on a stable dose for at 
least 6 weeks.
Investigator opinion in the treatment 
of the study subject 
8
Section 7.1 Bone Mineral Density 
Assessments 
Bone mineral density will be evaluated by 
taking two sets of DEXA scans (lumbar 
spine and hip regions) prior to 
randomization (Study PT010006 Visit 4
) within 14 days prior to baseline 
(Screening Visits 1 to 4 in Study 
PT010006) and within 14 days prior to and 
Visit 14 (Week 52) in this study. After the 
first scan, of the lumbar spine and hip 
region, the subject will get up from the 
table, and be repositioned, and another 
scan taken to take another set of scans at 
these skeletal sites. If these first two scans 
differ by more than 5% (as determined by 
the local facility) for either site (i.e. first 
two hip or first two lumbar sites)  a third 
scan should be obtained. The screening 
period may be extended up to a 
To clarify how the scan information 
will be analyzed, allow adequate time to 
complete assessments during the 
screening period and to ensure 
consistency across study sites
Confidential and Proprietary
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
maximum of 21 days if additional time is 
needed to complete the assessments. The 
results of these scans will be provided by 
the central testing facility to the 
investigative site to allow appropriate 
management of the subject
If a subject’s T score is < 2.5 For any 
clinically relevant reduction in T-score,
the investigator should consider 
appropriate treatment options based on 
local guidelines for the subject and/or refer 
them to their local medical doctor or a 
specialist for treatment. If subsequently 
treated with bisphosphonates, the subject 
should be excluded from further BMD 
measures in this study If a subject’s T-
score (hip or lumbar spine) is <-2.5 at 
screening they are excluded. 
Both the lumbar spine L2-L4 and total hip 
bone density will be measured. The 2 scans 
of each skeletal site will be centrally 
analyzed and averaged to obtain the final 
result to be used for data analysis. The 
results of these scans will be relayed by the 
local facility to the investigator to allow 
appropriate management of the subject
Full details can be found in the BMD 
manual
9
Section 7.2 Ophthalmologic Assessments
1. The baseline ophthalmologic 
assessment must be performed prior to 
randomization between Visits 1 and 4 
(Screening) of Study PT010006. Two 
post-baseline ophthalmologic 
assessments will be performed at Visit 
11 (Week 28), and within 14 days 
prior to Visit 14 (Week 52) only per 
exclusion criteria exception noted in 
Section 5.2.2. These post-baseline 
ophthalmologic assessments should be 
scheduled to occur within two weeks 
For #1, Added consistency with respect 
to baseline assessment being conducted 
prior to randomization and within 14 
days and concept for Visit 14 removed 
to correct an error for this study. For the 
two post-baseline ophthalmic 
assessments added clarification to refer 
to the exclusion criteria exception noted 
in Section 5.2.2
For #2 and # 3, Included pupil dilation 
and clarified that a certified LOCSIII 
trained ophthalmologist /optometrist 
could conduct assessments 
Confidential and Proprietary
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
prior to the scheduled clinic visit. Due 
to diurnal variability of IOP, all 
ophthalmic examinations following the 
first ophthalmic examination 
(screening baseline) should be 
scheduled to occur within two hours of 
the time of day when the baseline 
ophthalmic examination was 
performed. The same ophthalmologist 
should perform the ophthalmic 
examinations for a given subject at all 
visits if possible, to ensure consistency.  
2. At participating centers, all subjects 
will be referred to a pre certified 
LOCSIII trained 
ophthalmologist/optometrist for 
evaluation of pupil dilation, lenticular 
opacities, fundoscopic examination, 
intraocular pressure (IOP), manifest 
refraction and visual acuity. This data 
will also be categorized as 
normal/abnormal.  
3. The Lens Opacities Classification 
System (LOCS) III grading system will 
be used to assess lenticular opacities in 
this study. The following assessments 
will be performed using a decimalized 
scale ranging from 0.1 (indicating a
completely clear or colorless lens) to 
either 5.9 (indicating complete 
opacification on the cortex or posterior 
capsule for C or P scales) or 6.9 
(indicating advanced opacification and 
brunescence of the nucleus for NO or 
NC scales). Each assessment will be 
recorded to the nearest 0.1 as 
determined by the certified
ophthalmologist/optometrist. 
4. Moved the “NOTE: The 
ophthalmologist/optometrist must not 
refer to prior LOCS III grades and 
LOGMAR visual acuities from 
For #4 The Note moved with the LOCS 
III assessment to add relevance 
For #5 Eligibility criteria clarified with 
respect to the reading to be considered.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
previous ophthalmic examination at the 
time of a new examination” with the 
LOCS III assessment 
5. The lowest reading will be 
considered to determine eligibility
10
Added: Section 7.3.5: EXACT
The exacerbations of chronic pulmonary 
disease tool (EXACT) questionnaire will 
be captured via the subject eDiary (see 
Appendix 4)  
To align and include as a eDiary 
assessment
11
Section 7.6.1: Medical/Surgical History 
and Physical Examination.
Weight, assessed in ordinary indoor 
clothing with shoes removed will be 
recorded at Visit 1 (Screening) (PT010006 
Screening) and Visit 10a only. Height will 
be recorded at Visit 
1 (Screening) (PT010006 Screening)
only. 
To reference back and align screening
procedures with Study PT010006 
12
Synopsis and Section 7.7.13 Clinical 
Endpoint Committee 
Updated to change the adjudication 
committee name to Clinical Endpoint 
Committee and define their 
responsibilities
To clarify that there is one committee 
for adjudication which is also known as 
Clinical Endpoint Committee and there 
are three Clinical Endpoint Adjudication 
Charters.
13
Synopsis and Section 7.7.14 Data 
Monitoring Committee
The responsibility was updated to 
include assessment of all safety data  
To provide clarity that the DMC 
provides assessment of all safety data 
not just SAEs. 
14
Table 8.1 Revised to move a footnote 
under footnote “a” from footnote “g” and 
revise section referenced to the correct 
section in this Note:
a.
Scheduling visits: All visits will be scheduled relative to Visit 
10a (Week 24) of the lead-in study (PT010006).
Note: Refer to Section 8.68 for procedures that may be required at a 
premature discontinuation visit. Treatment 
Discontinuation/Withdrawal Visits will be captured as unscheduled 
Table 8.1: Revised the placement of the 
note to provide relevance and corrected 
section to reference to Section 8.8 
appropriately 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
visits
Added Section 8.1 Baseline Assessments.  
1. The Baseline PT010008 Assessments 
will be conducted concurrently with 
PT010006 Screening.  All study 
assessments are to be completed 
prior to Randomization (Visit 4) in 
PT010006. 
•
Obtain informed consent prior to 
conducting any Study PT010008 
baseline assessments.
•
Register subject in IWRS for Study 
PT010008 at the same time 
registering in Study PT010006.  
•
Conduct BMD assessments (Refer to 
Section 7.1) 
•
Conduct ocular assessments (Refer 
to Section 7.2) 
2. Randomization 
•
Review Study PT010008 
inclusion/exclusion criteria and 
confirm subject’s eligibility to 
continue.
•
Obtain subject randomization 
number and treatment assignment 
information from IWRS.   
Note :  Randomization in PT01008 
occurs simultaneously with 
randomization in Study PT010006 for 
those patients who qualify for Study 
PT010008. 
•
A reminder phone contact should be 
made prior to Visit 10b. 
Section 8.1:To add the details of the: 
1. Baseline procedures for this 
supplemental study to connect to the 
Study PT010006 where these 
subjects were screened
2. Randomization procedures in 
alignment with the schedule of 
events Table 8.1 
15
Section 8.3 Visit 10b
1. There are 10 scheduled visits in Study 
PT010006; the tenth visit is The last 
visit of the Study PT010006 and the 
1. and bullet 3: To clarify BMD/ocular 
study as PT010008 and align with 
schedule of events
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
first post-baseline visit of the 
supplemental Study (PT010008).  In 
order to differentiate, assessments 
conducted at the completion of the 
supplemental study PT010008, all 
baseline bone mineral density (Section 
7.1) and ocular (Section 7.2)
assessments will be captured during 
Screening (Visits 1 to 4) of Study 
PT010006.  Visit 10b will 
be completed following completion of 
all Visit 10a study procedures. A
reminder phone contact should be made 
prior to Visit 10b  
2. Review BMD/Ocular sub study
inclusion/exclusion criteria
3. Register subject in IWRS to confirm 
participation in the BMD/Ocular sub
studyPT010008 and receive assigned 
treatment
4. Subject will administer dose of study 
drug at home in the evening 
Note: During the sub study subjects 
will continue on the same treatment 
that they were assigned in Study 
PT010006 
5. Schedule ophthalmologic assessment to 
occur within two weeks prior to Visit 
11 (Week 28) 
2. and bullet 4: Clarified "Note" to 
remove "sub" study 
5. Removed ”within two weeks” for 
consistency throughout as not 
required
16
Section 8.4 Visits 11 (Week 28)
•
Confirm scheduled ocular assessments 
have been conducted (Visit 11 should 
be rescheduled if ocular assessments 
not conducted prior to this visit)  
Please refer to the exclusion criteria 
exception noted in Section 5.2.2 to 
see if the ocular assessment applies to 
this visit. 
Added reference to the exclusion criteria 
exception noted in Section 5.2.2 to 
conduct ocular assessment for this visit 
only if applicable 
17
Section 8.7 Visit 14 (Week 52; Final Visit)
•
Confirm ocular assessments were 
conducted prior to this visit (Visit 14 
Added reference to the exclusion criteria 
exception noted in Section 5.2.2 to 
conduct ocular assessment for this visit 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
should be rescheduled if ocular 
assessments not conducted prior to 
this visit) Please refer to the 
exclusion criteria exception noted 
in Section 5.2.2 to see if the ocular 
assessment applies to this visit
only if applicable
18
Section 9.1: Introduction revised sentence 
as follows: 
This is a supplemental study to 
Study PT010006 PT010008 and will be 
conducted in a subset of US sites 
participating in Study PT010006, and will 
evaluate the following treatments
Revised to clarify language and 
reference to appropriate studies 
(PT010006 and PT010008) 
19
Section 9.4.1.1 Percent change from 
baseline in BMD of the lumbar spine 
measured using DEXA scans of L2-L4 
T- and Z- scores will be presented as 
shifts from baseline to each time point; 
details will be provided in the SAP.
Section 9.4.1.2 Percent change from 
baseline in total hip BMD of the hip 
measured using DEXA scans 
The change from baseline in BMD of the 
lumbar spine hip at Week 52 (and 
similarly at EoT) will be analyzed using 
an Analysis of Covariance (ANCOVA) 
model with treatment group and gender as 
categorical covariates and similarly to the 
change from baseline in BMD score, age, 
and age by gender interaction as 
continuous covariates of the lumbar 
spine.
T  and Z  scores will be  presented as shifts 
from baseline to each time point; details 
will be provided in the SAP. Shift tables 
reported row percentages calculated using 
non missing row totals. 
Revised to place details in appropriate 
sections
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
Study PT010006 will not be enrolled in this supplemental study.  The entire study period is 
scheduled to take approximately 58 weeks for most subjects. 
An additional separate informed consent will be obtained for subjects participating in Study 
PT010006 who volunteer to participate in Study PT010008.  This study will evaluate the effects 
of BGF MDI, BFF MDI, and GFF MDI on BMD measurements and ocular assessments. 
Baseline and demographic characteristics collected in Study PT010006 will be used for subjects 
participating in this study. Baseline BMD (Dual Energy X-ray Absorptiometry [DEXA] Scans) 
measurements and ocular assessments (Lens Opacities Classification System [LOCS] III, 
fundoscopic examination, intraocular pressure, and visual acuity) will be performed during Study 
PT010006 Screening Period (between Visit 1 and Visit 4).  
Subjects participating in PT010008 who complete visit 10a of Study PT010006 will transition to 
the remaining 28 weeks of treatment by completing Visit 10b (Week 24) of Study PT010008. 
Post-baseline lenticular opacity, fundoscopic examination, intraocular pressure, and visual acuity 
assessments will be performed at Visit 11 (Week 28), at Visit 14 (Week 52), and/or at a 
Premature Discontinuation/Early Withdrawal Visit. A post-baseline BMD measurement will be 
performed at Visit 14 (Week 52) or at a Premature Discontinuation/Early Withdrawal Visit 
occurring after Visit 10b. Subjects will return to the clinic at Visit 12 (Week 36) and Visit 13 
(Week 44) to return used and obtain new supplies of study drug. Subjects will return to the clinic 
at Visit 14 (Week 52) to complete final study visit procedures. 
A follow up telephone call will be performed at least 14 days after last study drug. 
Study Population:
This study will include a subset of approximately 500 randomized subjects participating in Study 
PT010006 who were randomized to blinded study treatment (BGF MDI, GFF MDI, and BFF 
MDI). Subjects will continue to receive the same treatment they were randomized to receive in 
PT010006. 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
Product, Dose, and Mode of Administration:
Investigational materials will be provided by Pearl Therapeutics (Pearl), as shown below: 
Product Name & Dose
Product Strength
Dosage Form/
Fill Count
Administration
Study Medications
BGF MDI (PT010)
320/14.4/9.6 μg ex-actuator
160/7.2/4.8 μg per actuation
MDI/
120 inhalations
Taken as 
2 inhalations BID
GFF MDI (PT003)
14.4/9.6 μg ex-actuator
7.2/4.8 μg per actuation
MDI/
120 inhalations
Taken as 
2 inhalations BID
BFF MDI (PT009) 
320/9.6 μg ex-actuator
160/4.8 μg per actuation
MDI/
120 inhalations
Taken as 
2 inhalations BID
Open-Label Products
Albuterol Sulfate inhalation 
aerosol 90 ȝJa
ex-actuator 
US source: Ventolin® HFA
HFA inhalation aerosol will be the US-
supplied product.”  Albuterol sulfate 
inhalation aerosol.  Each inhalation 
contains 108 ȝJFRUUHVSRQGLQJWR μg 
albuterol base from the mouthpiece
MDI/
60 or 200 actuations
Taken as directed
Supplies are open-
label 
BID=twice daily; BGF MDI=Budesonide, Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; 
GFF MDI=Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; BFF MDI=Budesonide and Formoterol Fumarate 
Inhalation Aerosol; HFA=Hydrofluroalkane; MDI=Metered Dose Inhaler.
a Rescue medication during the study.
All study drugs will be administered by oral inhalation.
Duration of Treatment: 
It is planned that each subject will receive study treatment for 52 weeks with the initial 24 weeks 
of exposure coincident with Study PT010006.  It is anticipated that the entire study will take 
approximately 58 weeks for each individual subject from the time of Screening in Study 
PT010006. 
Bone Mineral Density Endpoints:
The primary BMD endpoint is: 
•
Percent change from baseline in BMD of the lumbar spine measured using DEXA scans of 
L2-L4 at Week 52
Other BMD endpoints include: 
x
Percent change from baseline in total hip BMD measured using DEXA scans at Week 52 and 
at End of Treatment (EoT)
x
Percent change from baseline in BMD of the lumbar spine measured using DEXA scans of 
L2-L4 at EoT 
Ocular Endpoints: 
The primary ocular endpoint is: 
•
Change from baseline in the LOCS III Posterior subcapsular (P) Score at Week 52 
Other ocular endpoints include:
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
•
Change from baseline in each scale of the LOCS III scores at Week 28, Week 52 (Nuclear 
Opalescence (NO), Nuclear Color (NC), and Cortical Cataract (C) only), and EoT 
•
3URSRUWLRQRIVXEMHFWVZLWK/2&6,,,JUDGHLQFUHDVHVRI&ODVV&ODVVRU
&ODVVXQLWVLQHDFKRIWKHVFDOHVDW:HHN:HHNDQG(R7
•
Change from baseline in intraocular pressure (IOP) at Week 28, Week 52, and EoT 
•
3URSRUWLRQRIVXEMHFWVZLWK,23PP+JDW:HHNDW:HHNDQG(R7
•
3URSRUWLRQRIVXEMHFWVFKDQJHIURPEDVHOLQHLQ,23RIPP+JDW:HHNDW:HHNDQG
EoT
•
Change from baseline in Logarithm of the Minimum Angle of Resolution (LogMAR) visual 
acuity using Early Treatment Diabetic Retinopathy Study (ETDRS) charts at Week 28, Week 
52, and EoT 
•
Change from baseline in horizontal cup-to-disc ratio at Week 28, Week 52, and EoT 
•
Incidence of ocular TEAEs including cataract and glaucoma 
Safety Endpoints: 
•
Adverse events (AEs)
•
12-lead electrocardiograms (ECG)
•
Clinical laboratory testing
•
Vital sign measurements
Efficacy Endpoints:
•
Change from baseline in average daily rescue Ventolin HFA (albuterol sulfate) use
•
Percentage of days with no rescue Ventolin HFA use 
•
Rate of moderate or severe COPD exacerbations
•
Rate of COPD exacerbations of any severity
•
Change from baseline in: the EXACT total score, the 11-item EXACT Respiratory 
Symptoms (E-RS) Total Score (RS-Total Score),  as well as 3 subscale scores symptom (RS-
Breathlessness, RS-Cough and Sputum, and RS-Chest Symptoms) over 52 weeks and over 
each 4-week interval of the 52-week Treatment Period
Statistical Methods:  
Primary Analysis for BMD Endpoint: 
Analyses of BMD endpoints will be conducted on those randomized subjects who have both 
baseline and post-baseline BMD results.
The change from baseline in BMD of the lumbar spine at Week 52 will be analyzed using an 
Analysis of Covariance (ANCOVA) model with treatment group and gender as categorical 
covariates and baseline BMD, age, and the interaction between gender and age as continuous 
covariates.
Primary Analysis for LOCS III Endpoint:  
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
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Clinical Trial Protocol:  PT010008-01
Version 2.0,
Change from baseline in LOCS III (P) scores at Week 52 will be analyzed using an ANCOVA. 
The model will include treatment group as a fixed effect, and baseline LOCS III (P) score, 
smoking pack years, and age as continuous covariates. The model will account for inter-eye 
correlation by including subject and eye (within subject) as random effects.
Two-sided 95% confidence intervals will be computed for pairwise differences of BGF minus 
GFF and BFF minus GFF, and non-inferiority will be declared if the upper confidence bound is 
less than 0.5. 
Sample Size:  
Assuming a 15% rate of discontinuation through Week 52, a subset of 500 randomized subjects 
from the PT010006 study will provide 425 subjects with baseline and on-treatment BMD and 
LOCS III. This sample size will provide approximately 97% power to demonstrate non-
inferiority of BGF MDI to GFF MDI in percent change from baseline in BMD for Lumbar Spine 
L2-L4 at Week 52 based on the lower limit of -2%, true difference of -0.3%, and SD of 4% and 
approximately 91% power for the non-inferiority comparison of BFF MDI to GFF MDI under 
identical assumptions.  It will provide over 99% power to demonstrate non-inferiority of BGF 
MDI to GFF MDI (or BFF MDI to GFF MDI) in change from baseline in LOCS III Score (P) at 
Week 52 based on a margin of 0.5 or more (1-sided, alpha=0.025) assuming no true difference in 
the means.
Data Monitoring and Clinical Endpoint Committees:  
Data Monitoring Committee:
An external Data Monitoring Committee (DMC) that was initiated in Study PT010006 will 
continue to provide systematic and unbiased assessment of safety for Study PT010008.  
Members of the DMC will review data at predetermined intervals.  If significant safety issues 
arise in between scheduled meetings, ad hoc meetings will be scheduled to review the data. 
Based on the safety implications of the data, the DMC may recommend modification or 
termination of the study.
Clinical Endpoint Committee: 
An external clinical endpoint committee (CEC) that was initiated in Study PT010006 will 
continue to provide systematic and unbiased assessment of pre-defined, Investigator reported 
adverse events for Study PT010008.  The committee will consist of experts who will provide a 
centralized review functioning independently of Pearl. Three Clinical Endpoint Adjudication 
Charters will outline the clinical endpoints for adjudication.
•
Cardiovascular- and Cerebro-vascular (CCV) Clinical Endpoint Adjudication Charter 
•
Cause-Specific Mortality Clinical Endpoint Adjudication Charter 
•
Pneumonia Clinical Endpoint Adjudication Charter 
Date of Original Approved Protocol:  
Date of Amendment 1.0 (Version 2.0): 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
TABLE OF CONTENTS
SUMMARY OF CHANGES TO ORIGINAL PROTOCOL VERSION 1.0, DATED 
 .........................................................................................................................2 
SYNOPSIS ...............................................................................................................................13 
TABLE OF CONTENTS .........................................................................................................18 
LIST OF TABLES ...................................................................................................................23 
LIST OF FIGURES .................................................................................................................23 
LIST OF APPENDICES ..........................................................................................................23 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................24 
TRADEMARK INFORMATION ...........................................................................................26 
1 
INTRODUCTION ...........................................................................................................27 
1.1 
Study Rationale ......................................................................................................28 
2 
STUDY OBJECTIVES ....................................................................................................29 
2.1 
Primary Objective ..................................................................................................29 
2.2 
Secondary Objectives.............................................................................................29 
3 
STUDY ENDPOINTS .....................................................................................................30 
3.1 
Bone Mineral Density Endpoints ...........................................................................30 
3.1.1 
Primary Bone Mineral Density Endpoint ....................................................30 
3.1.2 
Other BMD Endpoints .................................................................................30 
3.2 
Ocular Endpoints ...................................................................................................30 
3.2.1 
Primary Ocular Endpoint .............................................................................30 
3.2.2 
Other Ocular Endpoints ...............................................................................30 
3.3 
Safety Endpoints ....................................................................................................31 
3.4 
Efficacy Endpoints .................................................................................................31 
4 
INVESTIGATIONAL PLAN ..........................................................................................32 
4.1 
Overall Study Design and Plan ..............................................................................32 
5 
STUDY POPULATION SELECTION AND WITHDRAWAL CRITERIA .................35 
5.1 
Inclusion Criteria ...................................................................................................35 
5.2 
Exclusion Criteria ..................................................................................................35 
5.2.1 
Bone Mineral Density Criteria applied to either hip or lumbar region ........35 
5.2.2 
Ophthalmologic Criteria applied to either eye .............................................35 
5.3 
Subject Identification .............................................................................................36 
5.4 
Prior, Concomitant, and Prohibited Medications ...................................................36 
5.4.1 
Allowed Concomitant Medications to Treat a COPD Exacerbation ...........36 
5.4.2 
Prohibited COPD Medications ....................................................................36 
5.4.3 
Other Prohibited Medications ......................................................................37 
5.5 
Other Restrictions, Illicit Drugs, or Drugs of Abuse .............................................38 
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Version 2.0,
5.5.1 
Illicit Drugs ..................................................................................................38 
5.5.2 
Dietary Restrictions .....................................................................................38 
5.6 
Smoking Status ......................................................................................................39 
5.7 
Reasons and Procedures for Early Discontinuation from the Study ......................39 
5.7.1 
Reasons for Discontinuation ........................................................................39 
6 
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES ....................................................................................................41 
6.1 
Subject Information ...............................................................................................41 
6.2 
Product Descriptions ..............................................................................................41 
6.3 
Primary Packaging and Labeling Information .......................................................42 
6.4 
Secondary Packaging and Labeling Information (Box) .........................................43 
6.5 
Emergency Unblinding of Treatment Assignment ................................................43 
6.6 
Storage Requirements ............................................................................................44 
6.7 
Instructions for Preparation of Treatments for Administration and Dispensing....44 
6.7.1 
BGF MDI, GFF MDI, BFF MDI .................................................................44 
6.7.2 
Ventolin HFA® ............................................................................................44 
6.8 
Drug Accountability/Return of Clinical Supplies ..................................................45 
7 
STUDY PROCEDURES .................................................................................................46 
7.1 
Bone Mineral Density Assessments.......................................................................46 
7.2 
Ophthalmologic Assessments ................................................................................46 
7.3 
Subject Electronic Diary (eDiary) Data Collection ...............................................47 
7.3.1 
Rescue Medication Usage ............................................................................48 
7.3.2 
Medication Compliance ...............................................................................48 
7.3.3 
Recording of Dose Indicator Reading..........................................................48 
7.3.4 
Major/minor Symptom Worsening Assessment and Alert System .............49 
7.4 
COPD Exacerbations .............................................................................................49 
7.4.1 
Severity of COPD Exacerbation ..................................................................50 
7.4.2 
Duration of COPD exacerbation ..................................................................50 
7.4.3 
Approach for Capturing COPD Exacerbations ............................................51 
7.4.4 
Other Information ........................................................................................51 
7.4.5 
Investigator-Judged COPD Exacerbations ..................................................51 
7.5 
Subject Questionnaire ............................................................................................51 
7.6 
Safety Assessments ................................................................................................52 
7.6.1 
Medical/Surgical History and Physical Examination ..................................52 
7.6.2 
Vital Sign Measurements .............................................................................52 
7.6.3 
12-Lead Electrocardiogram .........................................................................52 
7.6.4 
Clinical Laboratory Tests .............................................................................53 
7.6.4.1 
Hematology ........................................................................................54 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
7.6.4.2 
Clinical Chemistry .............................................................................54 
7.6.4.3 
Urinalysis ...........................................................................................55 
7.6.4.4 
Pregnancy Test ...................................................................................55 
7.7 
Adverse Events ......................................................................................................56 
7.7.1 
Performing Adverse Events Assessments ....................................................56 
7.7.2 
Adverse Event Definitions ...........................................................................56 
7.7.3 
Severity ........................................................................................................57 
7.7.4 
Relationship .................................................................................................57 
7.7.5 
Chronic Obstructive Pulmonary Disease Exacerbations .............................58 
7.7.6 
Adverse Events of Special Interest ..............................................................58 
7.7.6.1 
LABA and LAMA Effects .................................................................58 
7.7.6.2 
Local Steroid Effects..........................................................................58 
7.7.6.3 
Pneumonia..........................................................................................58 
7.7.6.4 
Paradoxical Bronchospasm ................................................................59 
7.7.7 
Major Adverse Cardiovascular Events (MACE) .........................................59 
7.7.8 
Clinical Laboratory Adverse Events ............................................................59 
7.7.9 
Serious Adverse Events ...............................................................................60 
7.7.9.1 
Reporting of Serious Adverse Events ................................................61 
7.7.9.2 
Supplemental Investigations of SAEs ................................................61 
7.7.9.3 
Post-Study Follow-Up of Adverse Events .........................................61 
7.7.9.4 
Notification of Post-Study Serious Adverse Events ..........................61 
7.7.9.5 
Investigational Research Board/Independent Ethics Committee 
Notification of Serious Adverse Events .............................................61 
7.7.9.6 
Health Authority Safety Reports ........................................................62 
7.7.10 
Overdose ......................................................................................................62 
7.7.11 
Pregnancy .....................................................................................................62 
7.7.12 
Use of Steroids during the Study .................................................................62 
7.7.13 
Clinical Endpoint Committee ......................................................................63 
7.7.13.1 
Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint 
Adjudication Charter ..........................................................................63 
7.7.13.2 
Cause-Specific Mortality Clinical Endpoint Adjudication Charter ...63 
7.7.13.3 
Pneumonia Clinical Endpoint Adjudication Charter .........................63 
7.7.14 
Data Monitoring Committee ........................................................................63 
7.8 
Termination of the Study .......................................................................................64 
8 
STUDY ACTIVITIES .....................................................................................................65 
8.1 
Baseline Assessments ............................................................................................67 
8.2 
Randomization .......................................................................................................67 
8.3 
Visit 10b .................................................................................................................67 
8.4 
Visits 11 (Week 28) ...............................................................................................68 
8.5 
Visit 12 (Week 36) .................................................................................................69 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
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Clinical Trial Protocol:  PT010008-01
Version 2.0,
8.6 
Visit 13 (Week 44) .................................................................................................70 
8.7 
Visit 14 (Week 52; Final Visit) ..............................................................................72 
8.8 
Unscheduled Visit and Treatment Discontinuation/Withdrawal Visit ..................73 
8.9 
Follow-up Telephone Call .....................................................................................73 
8.10 
Vital Status Confirmation at Week 52 ...................................................................73 
8.11 
Completion of Study ..............................................................................................74 
9 
PLANNED STATISTICAL METHODS ........................................................................75 
9.1 
Introduction ............................................................................................................75 
9.2 
Protocol Variables ..................................................................................................75 
9.2.1 
Study Endpoints ...........................................................................................75 
9.2.2 
Primary Bone Mineral Density Endpoint ....................................................75 
9.2.3 
Other Bone Mineral Density Endpoints .......................................................75 
9.2.4 
Primary Ocular Endpoint .............................................................................76 
9.2.5 
Other Ocular Endpoints ...............................................................................76 
9.2.6 
Safety Endpoints ..........................................................................................76 
9.2.7 
Efficacy Endpoints .......................................................................................76 
9.3 
Study Populations ..................................................................................................77 
9.4 
Safety Analyses ......................................................................................................77 
9.4.1 
Analysis of BMD Endpoints ........................................................................78 
9.4.1.1 
Percent change from baseline in BMD of the lumbar spine measured 
using DEXA scans of L2-L4 ..............................................................78 
9.4.1.2 
Percent change from baseline in total hip BMD of the hip measured 
using DEXA scans .............................................................................78 
9.4.2 
Analysis of Ocular Endpoints ......................................................................78 
9.4.2.1 
Change from baseline in each of the LOCS III (NO, NC, C, and P) 
scores..................................................................................................78 
9.4.2.2 
Proportion of subjects with LOCS I,,JUDGHLQFUHDVHVRI&ODVV
&ODVVRU&ODVVXQLWVLQHDFKRIWKHVFDOHV ......78 
9.4.2.3 
Change from baseline in intraocular pressure (IOP) ..........................79 
9.4.2.4 
3URSRUWLRQRIVXEMHFWVZLWK,23PP+JDQGWKHSURSRUWLRQRI
subjects with chanJHIURPEDVHOLQHLQ,23RIPP+J ..................79 
9.4.2.5 
Change from baseline in LogMAR visual acuity using ETDRS charts79 
9.4.2.6 
Change from baseline in horizontal cup-to-disc ratio ........................79 
9.4.2.7 
Incidence of ocular TEAEs including cataract, glaucoma .................79 
9.4.3 
Adverse Events ............................................................................................79 
9.4.4 
Cardio- and Cerebrovascular Events Determined by Adjudication 
Committee ....................................................................................................79 
9.4.5 
Pneumonia Events Determined by Adjudication Committee ......................80 
9.4.6 
Clinical Laboratory Measurements ..............................................................80 
9.4.7 
Vital Signs ....................................................................................................80 
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Version 2.0,
9.4.8 
Electrocardiograms ......................................................................................81 
9.4.9 
Exposure ......................................................................................................81 
9.5 
Analyses of Efficacy Endpoints .............................................................................81 
9.5.1 
Rescue Ventolin HFA Use ...........................................................................81 
9.5.2 
Percentage of Days with No Rescue Ventolin HFA Use over the Treatment 
Period ...........................................................................................................81 
9.5.3 
Chronic Obstructive Pulmonary Disease Exacerbations .............................81 
9.5.4 
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) ...................82 
9.5.5 
Control of Type I Error ................................................................................83 
9.6 
Randomization .......................................................................................................83 
9.7 
Experimental Design ..............................................................................................83 
9.8 
Sample Size ............................................................................................................83 
9.9 
Data Validation and Transformation .....................................................................83 
9.10 
Analysis Plan .........................................................................................................83 
9.11 
Handling of Missing Data ......................................................................................83 
9.12 
Statistical Software ................................................................................................83 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................84 
10.1 
Regulatory Authority Approval .............................................................................84 
10.2 
Ethical Conduct of the Study and Institutional Review Board or Independent 
Ethics Committee Approval ...................................................................................84 
10.3 
Subject Information and Consent...........................................................................84 
10.4 
Laboratory Accreditation .......................................................................................85 
10.5 
Confidentiality .......................................................................................................85 
10.5.1 
Confidentiality of Data ................................................................................85 
10.5.2 
Confidentiality of Subject/Patient Records ..................................................85 
10.6 
Quality Control and Assurance ..............................................................................85 
10.7 
Data Management ..................................................................................................85 
10.8 
Study Monitoring ...................................................................................................86 
10.9 
Retention of Data ...................................................................................................87 
10.10 Financial Disclosure...............................................................................................87 
10.11 Investigator's Final Report .....................................................................................87 
10.12 Publication Policy ..................................................................................................87 
11 REFERENCE LIST .........................................................................................................89 
12 APPENDICES ....................................................................................................................90 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
LIST OF TABLES
Table 5-1. 
Prohibited COPD Medications ..................................................................36 
Table 5-2. 
Other Respiratory/Nasal Medications ........................................................37 
Table 5.3. 
Non-COPD Medications Allowed Under Certain Conditions ...................37 
Table 6-1. 
Product Descriptions ..................................................................................41 
Table 6-2. 
Description of Boxes..................................................................................43 
Table 7-1. 
Clinical Laboratory Tests ...........................................................................55 
Table 8-1. 
Schedule of Events .....................................................................................66 
LIST OF FIGURES
Figure 1. 
Study Design ..............................................................................................34 
LIST OF APPENDICES
Appendix 1 
Dose Indicator Reading..............................................................................90 
Appendix 2 
Subject Instructions for Use of  BGF MDI, GFF MDI, and BFF MDI .....91 
Appendix 3 
Instructions for Use of Ventolin HFA Inhalation Aerosol Device ..........100 
Appendix 4 
Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT) 
– Patient-Reported Outcomes ..................................................................107 
Appendix 5 
Sponsor Signature ....................................................................................111 
Appendix 6 
Investigator’s Signature ...........................................................................112 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
Adverse event
AESI
Adverse event of special interest
ANOVA
Analysis of Covariance
BD
Budesonide
BFF
Budesonide and formoterol fumarate
BGF
Budesonide, glycopyrronium, and formoterol fumarate
BID
bis in die, twice daily
BMD
Bone Mineral Density
CCV
Cardio- and cerebro-vascular 
CFR
Code of Federal Regulations
CONSORT
Consolidated Standards Of Reporting Trials
COPD
Chronic obstructive pulmonary disease 
DEXA
Dual Energy X-ray Absorptiometry
DMC
Data Monitoring Committee
ECG
Electrocardiogram 
eCRF
Electronic case report form
EoT
End of Treatment
ETDRS
Early Treatment Diabetic Retinopathy Study
FDA
Food and Drug Administration
FF
Formoterol fumarate
GCP
Good Clinical Practice
GFF
Glycopyrronium and formoterol fumarate
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HFA
Hydrofluoroalkane
IEC
Independent Ethics Committee
IOP
Intraocular Pressure
IRB
Institutional Review Board
LOCS III
Lens Opacities Classification System III
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
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Clinical Trial Protocol:  PT010008-01
Version 2.0,
LogMAR
Logarithm of the Minimum Angle of Resolution
MACE
Major adverse cardiovascular events
MDI
Metered dose inhaler
PRO
Patient-reported outcome
PSC
Posterior Subcapsular Cataract
SAE
Serious adverse event
SD
Standard deviation
TBH
Turbuhaler
TC
Telephone call
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
TRADEMARK INFORMATION 
Trademarks Not Owned By Pearl Therapeutics, Inc.
Oxis
Spiriva 
Symbicort 
Ventolin
Turbuhaler 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
1
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable disease
characterized by persistent airflow limitation that is usually progressive and associated with an 
enhanced chronic inflammatory response in the airways and the lung to noxious particles or 
gases.  Exacerbations and co-morbidities contribute to the overall severity in individual patients.  
Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality worldwide
and results in significant economic and social burden that is both substantial and increasing.  
Pharmacologic therapy in COPD is used to reduce symptoms, reduce the frequency and severity 
of exacerbations, and improve health status and exercise tolerance [Global Initiative for Chronic 
Obstructive Lung Disease (GOLD, 2014); Japanese Respiratory Society (JRS, 2013).
Bronchodilator medications are central to the symptomatic management of COPD.  The principal 
EURQFKRGLODWRUWUHDWPHQWVDUHȕ2-agonists, anticholinergics, and methylxanthines used as 
monotherapy or in combination.  Treatment with long-acting bronchodilators is more convenient 
and more effective at producing maintained symptom relief than treatment with short-acting 
bronchodilators. 
Regular treatment with inhaled corticosteroids (ICS) improves symptoms, lung function, and 
quality of life and reduces the frequency of exacerbations in subjects with COPD with a forced 
expiratory volume in 1 second (FEV1) value of <60% of predicted.  Withdrawal from treatment 
of ICS may lead to exacerbations in some patients.  When combined with a long-acting 
ȕ2-agonist (LABA), an ICS is more effective than the individual components in improving lung 
function, quality of life, and reducing exacerbations in subjects with moderate to very severe 
COPD [GOLD, 2014].   
Pearl Therapeutics, Inc. (hereinafter referred to as Pearl) is developing the fixed-dose ICS/ long-
acting anti-muscarinic agent (LAMA)/LABA triple combination product, Budesonide, 
Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol (PT010), hereafter referred to as 
budesonide, glycopyrronium, and formoterol fumarate metered dose inhaler (BGF MDI), for the 
treatment of patients with COPD.  Budesonide and Formoterol Fumarate Inhalation Aerosol 
(PT009, hereinafter referred to as budesonide and formoterol fumarate (BFF) MDI is also being 
developed as a twice daily (BID) fixed dose ICS/LABA treatment for patients with COPD.
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol (PT003) hereinafter referred to as 
glycopyrronium and formoterol fumarate (GFF) MDI is being developed as a BID maintenance 
bronchodilator treatment in patients with COPD.
Budesonide is a well-established corticosteroid approved worldwide in monotherapy and 
combination therapies for treatment of asthma and allergic rhinitis.  It is available in both 
intranasal and orally inhaled formulations.  Inhaled budesonide in combination with formoterol 
fumarate dihydrate, i.e., Symbicort is approved for use in patients with COPD.  
Glycopyrronium is a LAMA which exerts its bronchodilatory effect via muscarinic receptors 
located on smooth muscle cells within the trachea and bronchi.  Glycopyrronium is approved in 
many countries in multiple formulations for different indications, including for the treatment of 
COPD.  
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0,
Formoterol fumarate is a selective LABA approved worldwide for use in asthma and COPD.  In 
addition, formoterol fumarate is also approved worldwide in combination with budesonide (e.g., 
Symbicort® MDI, Symbicort® Turbuhaler® (TBH [AstraZeneca, LP]) for use in patients with 
asthma and COPD.  When inhaled, formoterol fumarate acts locally in the lung as a 
EURQFKRGLODWRU)RUPRWHUROIXPDUDWHVWLPXODWHVȕ2-adrenoreceptors in the airways, inducing 
airway smooth muscle relaxation and reducing or preventing bronchoconstriction. 
1.1 
Study Rationale 
Patients with COPD are frequently treated with ICS; the impact of ICS use on potential fracture 
risk is not consistent across published literature [Lehouck, 2011; Weldon, 2009; Christensson,
2008]. Studies in adults with COPD have produced a wide range of results in support of the 
direct effect of ICS on bone mineral density (BMD) and fracture risk.
It has also been reported that corticosteroid treatment can lead to multiple ocular effects, 
including cataracts, increased intraocular pressure (IOP) and glaucoma. Furthermore, as the 
majority of the COPD population is elderly, these observed ocular changes are more likely to be 
predominant in an elderly population. For example, in the TORCH safety sub-study, the 
background prevalence of cataracts was high in COPD patients (68.5-75.3% at Screening) 
[Calverley, 2007].  
As a result of the increased occurrence of cataracts, IOP, and glaucoma and the increased risk of 
bone disorders in patients with COPD, definitive ocular and bone mineral density assessments 
are included in this 1-year safety study.
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Clinical Trial Protocol:  PT010008-01
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2
STUDY OBJECTIVES
2.1
Primary Objective 
x
To evaluate the effect of BGF MDI, GFF MDI, and BFF MDI on bone mineral density 
(BMD) over 52 weeks 
•
To evaluate the effect of BGF MDI, GFF MDI, and BFF MDI on ocular assessments over 52 
weeks
2.2
Secondary Objectives
x
To assess the safety and tolerability of BGF MDI, GFF MDI, and BFF MDI 
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Clinical Trial Protocol:  PT010008-01
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3
STUDY ENDPOINTS
All assessments are relative to baseline assessments performed during the Study PT010006 
Screening Period (between Visit 1 and Visit 4).   
3.1
Bone Mineral Density Endpoints
3.1.1
Primary Bone Mineral Density Endpoint 
•
Percent change from baseline in BMD of the lumbar spine measured using DEXA scans of 
L2-L4 at Week 52
3.1.2
Other BMD Endpoints
x
Percent change from baseline in total hip BMD measured using DEXA scans at Week 52 and 
at End of Treatment (EoT)
x
Percent change from baseline in BMD of the lumbar spine measured using DEXA scans of 
L2-L4 at EoT 
3.2
Ocular Endpoints
3.2.1
Primary Ocular Endpoint
•
Change from baseline in the LOCS III (P) Score at Week 52
3.2.2
Other Ocular Endpoints
•
Change from baseline in each scale of the LOCS III scores at Week 28, Week 52 (NO, NC, 
and C only), and EoT 
•
3URSRUWLRQRIVXEMHFWVZLWK/2&6,,,JUDGHLQFUHDVHVRI&ODVV&ODVVRU
&ODVVXQLWVLQHDFKRIWKHVFDOHVDW:HHN:HHNDQG(R7
•
Change from baseline in intraocular pressure (IOP) at Week 28, Week 52, and EoT 
•
3URSRUWLRQRIVXEMHFWVZLWK,23PP+JDW:HHNDW:HHNDQG(R7
•
3URSRUWLRQRIVXEMHFWVFKDQJHIURPEDVHOLQHLQ,23RIPP+JDW:HHNDW:HHNDQG
EoT
•
Change from baseline in LogMAR visual acuity using ETDRS charts at Week 28, Week 52, 
and EoT 
•
Change from baseline in horizontal cup-to-disc ratio at Week 28, Week 52, and EoT
•
Incidence of ocular TEAEs including cataract and glaucoma
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Clinical Trial Protocol:  PT010008-01
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3.3
Safety Endpoints
•
Adverse events (AEs)
•
12-lead electrocardiograms (ECGs)
•
Clinical laboratory testing
•
Vital sign measurements
3.4
Efficacy Endpoints
•
Change from baseline in average daily rescue Ventolin HFA (albuterol sulfate) use
•
Percentage of days with no rescue Ventolin HFA use 
•
Rate of moderate or severe COPD exacerbations
•
Rate of COPD exacerbations of any severity
•
Change from baseline in: the EXACT total score, the 11-item EXACT Respiratory 
Symptoms (E-RS) Total Score (RS-Total Score),  as well as 3 subscale scores symptom (RS-
Breathlessness, RS-Cough and Sputum, and RS-Chest Symptoms) over 52 weeks and over 
each 4-week interval of the 52-week Treatment Period
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Clinical Trial Protocol:  PT010008-01
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4
INVESTIGATIONAL PLAN
4.1 
Overall Study Design and Plan 
This is a randomized, double-blind, parallel-group, 52-week, chronic-dosing, multi-center 
supplemental study to assess the effects of PT010, PT009, and PT003 on bone mineral density 
(BMD), ocular assessments, and safety and tolerability in subjects with moderate to very severe 
COPD.  This 52-week study will be conducted in a sub-set of subjects participating in Study 
PT010006. Approximately 70 sites are planned to participate in the study, contributing 
approximately 8 subjects per site.  Across these sites, it is planned that approximately 
500 subjects randomized to double-blind treatment only will be included in Study PT010008 
to provide approximately (425) subjects who will complete the study at Visit 14 (Week 52). 
Subjects will receive the same treatment (BGF MDI, GFF MDI, or BFF MDI) they were 
randomized to in Study PT010006. Subjects randomized to open-label Symbicort TBH will not 
be enrolled in this study, however, since baseline BMD and ocular assessments will be 
performed prior to randomization all subjects who will eventually be randomized to Symbicort 
TBH will have a baseline assessment. The entire study period is scheduled to take approximately 
58 weeks for most subjects. 
This safety study will evaluate the effects of BGF MDI, BFF MDI, and GFF MDI on bone 
mineral density (BMD) measurement (Johnell, 2002) and lenticular opacity (Chylack, 1993) and 
ocular pressure assessments. 
Baseline and demographic characteristics collected in Study PT010006 will be used for subjects 
participating in this study. Baseline assessments (BMD, lenticular opacity, fundoscopic 
examination, intraocular pressure, pupil dilatation, and visual acuity assessments) will be 
performed prior to randomization in Study PT010006.  If the first two BMD scans differ by more 
than 5% (as determined by the local facility) for either site (i.e. first two hip or first two lumbar 
sites) a third scan should be obtained. The screening period may be extended up to a maximum 
of 21 days if additional time is needed to complete the assessments. A separate informed consent 
will be obtained for subjects participating in Study PT010008 prior to any study PT010008 
procedures.   
Subjects participating in Study PT010008 who complete visit 10a of Study PT010006 will 
transition to the remaining 28 weeks of treatment by completing Visit 10b (Week 24). Post-
baseline lenticular opacity, fundoscopic examination, intraocular pressure, and visual acuity 
assessments will be performed prior to Visit 11 (Week 28), Visit 14 (Week 52) and Treatment 
Discontinuation/Withdrawal Visit. A post-baseline BMD assessment will be performed prior to
Visit 14 (Week 52) and Treatment Discontinuation/Withdrawal Visit. Subjects will return to the 
clinic at Visit 12 (Week 36), and Visit 13 (Week 44) to return used medication and obtain new 
study drug. Subjects will return to the clinic at Visit 14 (Week 52) to complete final study visit 
procedures. 
All subjects will continue to receive sponsor-provided Ventolin® HFA (albuterol sulfate 
inhalation aerosol) for rescue use throughout the study. 
After Visit 14 (Week 52), a follow-up telephone call will be performed at least 14 days after the 
last study drug dose. For subjects who withdraw consent, schedule a follow-up telephone call at 
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Clinical Trial Protocol:  PT010008-01
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least 14 days after the last study drug dosing, if the final visit is performed >14 days post last 
study drug dosing, a follow-up TC will not be required.   
If a subject chooses not to continue with study assessments, at a minimum the subject will 
complete the Treatment Discontinuation/Withdrawal Visit (refer to Table 8-1). For subjects 
discontinuing treatment at any time during the study including the time during which they are 
participating in Study PT010006, lenticular opacity, fundoscopic examination, intraocular 
pressure, pupil dilation and visual acuity assessments should be performed as soon as possible.  
For subjects discontinuing treatment after Visit 10b (Week 24), BMD assessments should also be 
obtained as soon as possible (Note: Subject who discontinues prior to Visit 10b will not complete 
BMD assessments).  These subjects will return to appropriate maintenance COPD medications, 
per the investigators discretion. A follow-up telephone call will be performed at least 14 days 
after the last study drug dose. In the event the Treatment Discontinuation/Withdrawal Visit is 
performed >14 days post last study drug dosing, a follow-up TC will not be required. These 
subjects will be followed for vital status at 52 weeks post-randomization in accordance with the 
informed consent. 
An overall study design is summarized and displayed in Figure 1. 
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Clinical Trial Protocol:  PT010008-01
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Figure 1. 
Study Design 
 
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Clinical Trial Protocol:  PT010008-01
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5
STUDY POPULATION SELECTION AND WITHDRAWAL 
CRITERIA
5.1 
Inclusion Criteria 
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Give their signed written informed consent to participate. 
2. Subjects must have agreed to participate in Study PT010006. 
5.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study (please see 
the exception noted below the ophthalmologic criteria Section 5.2.2).
5.2.1
Bone Mineral Density Criteria applied to either hip or lumbar region
1. Severe osteoporosis  
2. T-score < -2.5 at baseline  
3. Subjects unable to achieve an acceptable scan (e.g. due to the patient’s inability to be 
stable during the procedure, due to limitation of scanning equipment ( ~300 lbs or ~136 
kgs) or other characteristics) 
5.2.2
Ophthalmologic Criteria applied to either eye  
4. Inability to dilate pupil >6 mm 
5. IOP >21mmHg  (lowest of the 3 readings) 
Note: Subjects with IOP >21mmHg may be treated and re-tested during the screening period. 
If the re-test measurements for IOP <21mmHg this subject may be eligible  
6. Subjects who have an implanted artificial intraocular lens, i.e., subjects who have 
undergone, or are scheduled to undergo, cataract removal surgery. 
 
NOTE: Subjects who meet none of the bone mineral density exclusion criteria but who meet 
one or more ophthalmologic exclusion criteria may be permitted to continue in the study. 
Such subjects would undergo all study planned assessments except they would undergo no 
further ophthalmologic exams (all tests included in Section 7.2) during the randomized 
treatment period. Additionally such subjects would be permitted to continue in the study 
provided that the following 2 conditions are satisfied: 
•
,23LVPP+JHLWKHUZLWKRUZLWKRXWtreatment 
•
In the opinion of the optometrist/ophthalmologist, the subject does not have a condition 
(e.g., advanced glaucoma) that the eye health of the subject could be jeopardized by 
continued participation in the study 
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Clinical Trial Protocol:  PT010008-01
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5.3
Subject Identification 
All subjects who participate in this study will maintain the unique screening identification 
number and unique subject randomization number assigned to them for participation in Study 
PT0100006. 
5.4 Prior, Concomitant, and Prohibited Medications  
Any additions, deletions, or changes in the dose of these medications while in the study 
should be entered on the CRF.  Any current ongoing medications, including OTC drugs and 
herbal supplements, will be allowed provided they are not prohibited by the protocol (refer 
to Section 5.4) and are approved by the investigator.  Subjects should also be instructed to 
contact the investigator if they develop any illnesses.  
All concomitant medications taken during the study will be recorded on the Concomitant 
Medications CRF page with indication, total daily dose, and dates of drug administration. 
5.4.1
Allowed Concomitant Medications to Treat a COPD Exacerbation
Medications to treat an exacerbation should not be used for more than 14 days. Recent data 
have suggested that treatment with systemic steroids for shorter periods of time results in 
similar outcomes with less systemic steroid exposure. Therefore, it is recommended that 
subjects are treated with a 5 day course of steroids and no longer than 14 days.
5.4.2 Prohibited COPD Medications 
The following medications used for the treatment of COPD are not permitted during this 
study.  These medications must have been discontinued during the Screening Period of Study 
PT010006 and are prohibited during this supplemental study (Table 5-1). 
Table 5-1.
Prohibited COPD Medications 
Class of medication
LAMAs
Short-acting muscarinic antagonists (SAMA)
LABAs (inhaled)
Fixed-combinations of LABA/LAMA
Fixed-combinations of LABA/ICS
Fixed-combinations of SABAs and SAMAs 
SABAsa
2UDOȕ-agonists
Theophylline (total daily dose >400 mg/day)b
Abbreviations:  ICS=inhaled corticosteroid; LABA=long-DFWLQJȕ2-agonist; LAMA=long-acting muscarinic antagonist; SABA=short-
DFWLQJȕ2-agonist; SAMA=short-acting muscarinic antagonist
a
Other than sponsor-provided open-label Ventolin HFA.  
 
 
 
b
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 in Study PT010006.
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Clinical Trial Protocol:  PT010008-01
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Note:  
•
During the Treatment Period (Visit 10b to Visit 14), subjects may be treated with 
systemic corticosteroids if required
•
Subjects who are steroid dependent and maintained on an equivalent of up to 5 mg oral 
SUHGQLVRQHSHUGD\RUPJRUDOSUHGQLsone every other day are permitted to enroll in 
the study provided they have been on a dose of oral steroids that remains consistent and 
does not exceed this threshold for the last two weeks prior to randomization (Visit 4) in 
Study PT010006 
The following respiratory medications are not permitted during this study (Table 5-2).
Table 5-2.
Other Respiratory/Nasal Medications 
Class of Medication
Leukotriene antagonists (e.g., zafirlukast, montelukast and zilueton)
Cromoglycate
Nedocromil
Ketotifena
a Ketotifen eye drops are allowed
5.4.3
Other Prohibited Medications
Table 5.3 lists certain non-COPD medications that can be used under the stated conditions 
during this study. Each concomitant drug must be individually assessed against all exclusion 
criteria.  If in doubt, the Investigator should contact Pearl’s Medical Monitor before 
randomizing a subject or allowing a new medication to be started:
Table 5.3.
Non-COPD Medications Allowed Under Certain Conditions
Medications Allowed Under Certain 
Conditions
Condition 
SSRIs or SNRIs 
Treatment regimen has been stable for at 
least 4 weeks prior to Visit 1 and not altered 
during the Screening Period, and does not 
exceed the maximum recommended dose
Intranasal corticosteroids, intranasal 
antihistamines, or combination thereof 
Administered at constant dose and dosing 
regimen for at least 7 days prior to Screening 
(Visit 1) and during the Screening Period 
Abbreviations:  COPD=chronic obstructive pulmonary disease; SNRI=serotonin–norepinephrine reuptake 
inhibitors; SSRI=selective serotonin reuptake inhibitors
Subjects requiring medications presented in Table 5-4 are prohibited from participating in 
this study. Subjects who recently discontinued use of these medications may be considered
for study enrollment providing they have met the minimum Washout Period prior to Visit 1. 
These medications are prohibited throughout the course of the study, and, should a subject 
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Clinical Trial Protocol:  PT010008-01
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require use of any of the listed medications, the investigator should evaluate the 
appropriateness of continuing the subject in the study. 
Table 5.4.
Prohibited Medications
5.5 Other Restrictions, Illicit Drugs, or Drugs of Abuse 
5.5.1
Illicit Drugs
Illicit drugs or drugs of abuse will not be allowed from Visit 10b to Visit 14 or to whenever 
the subject withdraws from 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 at the discretion of the investigator.  Medical marijuana is not an 
exclusionary drug if used for medical purposes, and there is no change in the dose or 
frequency of consumption. 
5.5.2
Dietary Restrictions
Subjects must not ingest xanthine and/or xanthine analogue (caffeine)-containing foods and 
beverages for at least 6 hours prior to each study visit and for the duration of each study visit.  
Examples of such products include coffee, tea, chocolate, and cola.  Decaffeinated beverages 
are acceptable.
Prohibited Medications
Any drug with potential to significantly prolong the QT interval 
Other investigational drugs
Non-selective beta-blocking agents (exception Carvedilol )
Cardiac antiarrhythmics Class Ia, III )
Anticonvulsants for seizure disorder a
Anticonvulsants for other indications a
Tricyclic antidepressantsb
Monoamine oxidase inhibitors
Anti-tumor QHFURVLVIDFWRUĮ71)ĮDQWLERGLHVHJLQIOL[LPDEDQGDQ\RWKHUPHPEHUVRIWKLVFODVVRIGUXJV
Monoclonal antibodies
Antipsychotic drugs b
Systemic calcineurin inhibitors, systemic antifungal agents, protease inhibitors and cimetidine
Systemic anticholinergicsc
Illicit drugs or drugs of abuse
Chinese complementary and alternative bronchodilatory medicines (CAM), i.e., herbal therapies 
(e.g., Astragalus membranaceus [huáng qí], Panax ginseng [ginseng products] and Cordyceps sinensis. A. 
membranaceus [ghost moth caterpillar fungus])d
Note: Benzodiazepines are not exclusionary.
a Anticonvulsants for seizure or other indications allowed provided the patient was treated with this class of medications 
during  Study PT010006
b Antipsychotic agents and tricyclic antidepressants used for previously diagnosed underlying medical conditions are allowed 
if, in the opinion of the Investigator, there are no concerns regarding patient safety, and if the patient has been on a stable 
dose for at least 6 weeks.
c Systemic anticholinergics are allowed provided the patient was treated with this class of medications during  Study 
PT010006
d,Requires case-by-case review by the Investigator to determine appropriate wash-out period, if needed.
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5.6 Smoking Status 
Changes in a subject’s smoking status (e.g., stopping or re-starting smoking) may have an 
impact on the efficacy outcome measures.  At all visits the subject will be asked about any 
recent change in their smoking status (i.e., whether a subject’s status has changed from 
smoker to non-smoker or vice versa).  Smoking status changes during the 28-week Treatment 
Period 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: Use of electronic cigarettes will be viewed and managed in the same manner as 
traditional smoking.
5.7 
Reasons and Procedures for Early Discontinuation from the 
Study 
5.7.1
Reasons for Discontinuation
Subjects may be withdrawn from the study at any time at their own request, upon request of 
the Investigator, or by Pearl at any time or for any reason. A subject who withdraws consent 
will always be asked about the reason(s) and the presence of any adverse events (AE).   All 
subjects who discontinue for any reason, or their family or healthcare providers, will be 
contacted 52 weeks post-Randomization to determine vital status, and if appropriate, cause of 
death (Section 8.8).    The subject may voluntarily discontinue treatment at any time without 
prejudice to further treatment.  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:
•
Calculated QTcF intervals >500 msec, and have increased by 60 msec or more over test 
day baseline value
•
Following dosing, a heart rate increase of >40 bpm from the pre-dose value obtained on 
that specific test day and the measured value is also >120 bpm 
•
Following dosing, a systolic blood pressure increase of >40 mmHg from the 
pre-dose value obtained on that specific test day and the measured value is also 
>160 mmHg
•
'HFUHDVHLQFUHDWLQLQHFOHDUDQFHWRDYDOXH mL/minute using CKD-EPI formula or a 
clinically relevant change from baseline as determined by the Investigator
•
Hepatic impairment defined as abnormal liver function test of AST, ALT or total 
ELOLUXELQWLPHVXSSHUOLPLWRIQRUPDORQUHSHDWWHVWLQJ
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Clinical Trial Protocol:  PT010008-01
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If a subject requires the following prohibited medications, they should be withdrawn from the 
study:
•
Initiation of maintenance therapy with any prohibited medications as listed in Section 
5.4.2
•
Initiation of maintenance therapy with a LABA (e.g., salmeterol, formoterol, indacaterol, 
vilanterol, olodaterol) administered alone or in combination with an ICS or a LAMA 
(e.g., tiotropium, aclidinium, glycopyrronium, umeclidinium) 
•
Change inhaled maintenance therapy during the course of the study 
 
 
NOTE:  Subjects who suffer an exacerbation (regardless of severity) 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.  The definition and severity of 
exacerbations are discussed in Section 7.2.2.1. 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 (see Section 7.2.3.4).
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Clinical Trial Protocol:  PT010008-01
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6.3 
Primary Packaging and Labeling Information 
Investigational materials will be packaged by the Sponsor.  Ventolin HFA will be supplied as
open-label MDIs.
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 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. Labels will be printed with black ink and may include the following text: Labels will 
be printed with black ink and may include the following text: 
Lot # (Packaging Lot Trace ID)
Space for entry of screening #
Component ID # 
Space for entry of randomization # 
Fill Count & Dosage Form 
Visit # (Space for Entry of Interval ID)
Storage Conditions
Protocol # 
Country regulatory requirements 
Sponsor address Translation Key 
ID = identification; # = number
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Clinical Trial Protocol:  PT010008-01
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6.4 Secondary Packaging and Labeling Information (Box) 
Blinded investigational drug and open-label supplies (Ventolin HFA) will be packaged in 
individual boxes as outlined in Table 6-2. Box configuration is subject to change as a result 
of packaging constraints. 
Table 6-2.
Description of Boxes
Drug Supplies
Individual Box Contents
Blinded
Ventolin (albuterol sulfate) HFA
1 MDI
1 MDI
HFA=Hydrofluoroalkane; MDI=metered dose inhaler
Each box will be labeled with a 2-part label printed with black ink and may include the 
following text:
Packaging Lot ID #
Space for entry of screening #
Component ID # 
Space for entry of randomization # 
Kit Contents (1 MDI) 
Space for entry of Interval ID
Re-evaluation/Expiration date (if applicable)
Dosing Instructions (if applicable)
Storage Conditions 
Compound ID - Protocol #
Country regulatory requirements 
Sponsor address (if applicable) 
Translation Key (if applicable)
ID = identification; # = number
6.5 Emergency Unblinding of Treatment Assignment  
The IWRS should be used in order to unblind subjects and to unmask drug identity.  When 
the Investigator contacts the system to unblind a subject, he/she must provide the requested 
subject identifying information and confirm the necessity to unblind the subject.  Pearl will 
not provide a disclosure envelope with the clinical supplies. 
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 Medical Monitor or 
appropriate study personnel before unblinding the subject’s treatment assignment.  If this is 
impractical, the Investigator must notify Pearl as soon as possible, but without revealing the 
treatment assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study.  The date and reason for the unblinding must be 
recorded in the appropriate data collection tool.
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6.6
Storage Requirements
Blinded Supplies should be kept in a secured location.  BGF MDI, GFF MDI, and BFF MDI 
should be stored below 25° C (77° F) in a dry place.  Excursions permitted up to 30° C (86° 
F).
Ventolin® HFA supplies: Store between 15°C and 25°C (59°F and 77°F).  Store the inhaler 
with the mouthpiece down.  For best results, the inhaler should be at room temperature 
before use.  Do not use or store near heat or open flame.  Exposure to temperatures above 
120°F (49°C) may cause bursting. Never throw into a fire or incinerator. 
The clinical supplies storage area at the site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range specified in 
accordance with the product label.  Documentation of temperature monitoring should be 
maintained.
6.7 Instructions for Preparation of Treatments for Administration and 
Dispensing 
6.7.1
BGF MDI, GFF MDI, BFF MDI
Individual BGF MDI, GFF MDI, and BFF 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 ID number.  Confirm that the identifier given 
by IWRS and the component ID number written on the label are the same.  The visit 
treatment box is labeled with a 2-part label.  Write the subject number and treatment visit 
number on each of the 2-part labels.  The ‘tear-off’ part of the label is to be placed onto the 
IWRS confirmation report. 
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.
The MDI must be primed in a separate room, away 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 at room temperature by the subject, to avoid temperature extremes, and the 
products should not be stored in direct sunlight.  Refer to Appendix 2 for instructions on 
administration and cleaning of BGF MDI, GFF MDI, and BFF MDI.   
6.7.2
Ventolin HFA®  
Refer to Appendix 3 for the manufacturer’s instructions on the administration and cleaning of 
Ventolin HFA.
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6.8 
Drug Accountability/Return of Clinical Supplies 
Under no circumstances will the Investigator(s) allow the study drug to be used other than as 
directed by this protocol. 
Investigational clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secure location to which only the 
Investigator and designated assistants have access.  Storage conditions for the clinical 
supplies should be observed, monitored and documented.  Clinical supplies are to be 
dispensed only in accordance with the protocol.  The Investigator or designee is responsible 
for keeping accurate records of the clinical supplies received from Pearl, the amount 
dispensed to and returned by the subject, and the amount remaining at the conclusion of the 
study. Study medication should be handled in accordance with Good Pharmacy Practices 
(i.e., gloves should always be worn by study personnel if directly handling tablets or capsules 
that are returned).  The Clinical Monitor should be contacted with any questions concerning 
investigational products where special or protective handling is indicated.  At the end of the 
study, all clinical supplies including partial and empty containers must be returned as 
directed by Pearl.
Sites should check with the Pearl representative for appropriate documentation that needs to 
be completed for drug accountability. 
The Investigator or designated assistant should not open individual clinical supply containers 
until all pre-dose assessments have been completed and the subject is eligible to be 
randomized/continue with the study.  Any deviation from this must be discussed with the 
Clinical Monitor.
For each subject, all used study drug materials will be collected.  Used subject supplies will 
be kept at room temperature in a secure and locked cabinet until returned to Pearl or 
designee.   
Note: Used study drug will be stored separately from unused study drug. 
All product complaints (including device malfunctions) must be reported to Pearl using the 
Product Complaints Form provided in each site’s regulatory binder.  Pearl will contact the 
site to evaluate the nature of the complaint and determine what further action is needed. 
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7
STUDY PROCEDURES
A schedule of events is provided in Table 8-1.   
7.1 
Bone Mineral Density Assessments 
Bone mineral density will be evaluated by taking two sets of DEXA scans (lumbar spine and 
hip regions) prior to randomization (Study PT010006 Visit 4) and Visit 14 (Week 52) in this 
study. After the first scan, of the lumbar spine and hip region, the subject will get up from the 
table, and be repositioned, to take another set of scans at these skeletal sites. If these first two 
scans differ by more than 5% (as determined by the local facility) for either site (i.e. first two 
hip or first two lumbar sites) a third scan should be obtained. The screening period may be 
extended up to a maximum of 21 days if additional time is needed to complete the 
assessments. The results of these scans will be provided by the central testing facility to the 
investigative site to allow appropriate management of the subject. 
For any clinically relevant reduction in T-score, the investigator should consider appropriate 
treatment options based on local guidelines for the subject and/or refer them to their local 
medical doctor or a specialist for treatment. If a subject’s T-score (hip or lumbar spine) is <-
2.5 at screening they are excluded.
Both the lumbar spine L2-L4 and total hip bone density will be measured. The scans of each 
skeletal site will be centrally analyzed to obtain the final result to be used for data analysis.
For >1 scan the median will be considered for eligibility. 
Full details can be found in the BMD manual 
7.2 
Ophthalmologic Assessments
The baseline ophthalmologic assessment must be performed prior to Randomization between 
Visits 1 and 4 (Screening) of Study PT010006. Two post-baseline ophthalmologic 
assessments will be performed at Visit 11 (Week 28), and Visit 14 (Week 52) only per 
exclusion criteria exception noted in Section 5.2.2. These post-baseline ophthalmologic 
assessments should be scheduled to occur within two weeks prior to the scheduled clinic 
visit. Due to diurnal variability of IOP, all ophthalmic examinations following the first 
ophthalmic examination (baseline) should be scheduled to occur within two hours of the time 
of day when the baseline ophthalmic examination was performed. The same ophthalmologist
should perform the ophthalmic examinations for a given subject at all visits if possible, to 
ensure consistency.  
At participating centers, all subjects will be referred to a certified as LOCSIII trained 
ophthalmologist/optometrist for evaluation of pupil dilation, lenticular opacities, fundoscopic 
examination, intraocular pressure (IOP), manifest refraction and visual acuity. This data will 
also be categorized as normal/abnormal. 
The Lens Opacities Classification System (LOCS) III grading system will be used to assess 
lenticular opacities in this study. The following assessments will be performed using a 
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decimalized scale ranging from 0.1 (indicating a completely clear or colorless lens) to either 
5.9 (indicating complete opacification on the cortex or posterior capsule for C or P scales) or 
6.9 (indicating advanced opacification and brunescence of the nucleus for NO or NC scales). 
Each assessment will be recorded to the nearest 0.1 as determined by the certified 
ophthalmologist/optometrist.
Since the posterior subcapsular region is thought to be the area most characteristically 
affected by corticosteroid use, the LOCS III (P) score is the primary analysis.
• Nuclear Opalescence (NO scale 0.1 to 6.9) is the average of the opalescence of the
two regions of the nucleus 
• Nuclear Color (NC scale 0.1 to 6.9) is the grade of color of the posterior 
   subcapsular reflex (a proxy for nuclear color)  
• Cortical Cataract (C scale 0.1 to 5.9) is the aggregate area of visible opacification (in the 
lightly and darkly shadowed) portions of the cortical opacities
• The severity of Posterior Subcapsular Cataract (PSC) will be expressed as a P grade derived
   from the LOCS III P scale (0.1 to 5.9). With a maximally dilated pupil the LOCS III P  
grade will be defined as the total area of aggregated component PSCs related to the LOCS  
   III P standards, regardless of where they are located on the posterior capsule. The method  
for making this assessment will be dealt with in the LOCS III training recordings.
NOTE: The ophthalmologist/optometrist must not refer to prior LOCS III grades and 
LOGMAR visual acuities from previous ophthalmic examination at the time of a new 
examination
Fundoscopic examination will include the evaluation of horizontal cup-to-disc ratio for each 
eye.
Intraocular Pressure: Intraocular pressure (IOP) will be measured using Goldman 
Applanation Tonometry. Three measures of IOP will be completed for each eye during each 
ophthalmic examination and all three measures will be recorded. The lowest reading will be 
considered to evaluate eligibility criteria
Visual acuity and manifest refraction: 
Visual acuity (best-corrected distance vision) and manifest refraction (sphere, cylinder and 
axis) will be assessed during each ophthalmic examination. LogMAR (Logarithm of the 
Minimum Angle of Resolution) visual acuity using Early Treatment Diabetic Retinopathy 
Study (ETDRS) charts will be utilized. Both the visual acuity and manifest refraction values 
will be captured in the source document. 
7.3
Subject Electronic Diary (eDiary) Data Collection
Subjects will continue to use their electronic subject diary (eDiary) provided during 
participation in Study PT010006 to continue to record time of study medication 
administration, use of rescue albuterol (Ventolin HFA), and dose indicator reading (if 
assigned to BGF MDI, GFF MDI or BFF MDI only). 
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Electronic Diary Compliance Requirement:  Subject participation may be terminated at 
any time during the study for the following reasons:
•
Chronic failure, in the judgment of the Investigator, to comply with diary compliance, 
despite documentation at the site of repeated efforts to reinforce compliance.  As defined 
for this study, compliance requires >70% subject completion of diary assessments.  Pearl 
may also instruct a site to discontinue a subject based on consistent noncompliance   
In-clinic dosing times and dose indicator readings will be documented by the site staff and 
will not be entered by the subject into their eDiary.
The eDiary data report will be available to site personnel through the vendor's server. The 
eDiary data report should be reviewed by the study personnel at each visit. The review 
should verify that morning and evening diary entries have been recorded by the subject for 
compliance requirements.  The subject should be reinstructed, as appropriate, on the 
importance of recording twice daily entries if missing entries are observed.
7.3.1
Rescue Medication Usage
The subject will record the total number of “puffs” of rescue medication (i.e., albuterol 
sulfate or locally available equivalent product) used on a daily basis in the eDiary.  The 
number of “puffs” of rescue product will be recorded as the number of actuations on the 
canister.  For example, when rescue product is required and 2 actuations are inhaled, this 
should be recorded as 2 “puffs.”  In the event the subject requires 4 actuations, this should be 
recorded as 4 “puffs”.  Subjects requiring more than 8 puffs per day on 3 consecutive days 
with worsening symptoms should contact the site.   
7.3.2
Medication Compliance 
Time of dosing with study medication will be recorded in the subject’s eDiary for each day 
of treatment (except the in-clinic dosing time).  Study medication compliance will be 
checked at all visits, and any issues identified will be documented in the appropriate study 
files.
7.3.3
Recording of Dose Indicator Reading
The BGF MDI, GFF MDI and BFF MDI will be fitted with a dose indicator to track in life 
use of the MDI.
Subjects will be instructed to record the dose indicator reading from the MDI in their 
eDiary.
Prior to dosing at Visit 11 to Visit 14, 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.
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Note: The dose indicator reading recorded by the site staff will be dose indicator reading 
observed prior to subject dosing.  For new MDIs the recorded count will be the count
following the priming of the MDI but before the subject dose. 
At each visit, the site staff will compare the dose indicator reading from the prior evening 
entered in the subject eDiary with the dose indicator reading recorded by the site staff.  For 
major discrepancies (i.e., >20 puff difference) the site staff will review the major discrepancy 
with the subject and document reason for the major discrepancy.  If appropriate, site staff 
will retrain the subject on the proper recording of dose indicator reading and/or proper use of 
the MDI.
7.3.4
Major/minor Symptom Worsening Assessment and Alert System
All major and minor symptoms of a worsening event will be captured at once each morning 
for the purposes of a symptom worsening alert. The purpose of this alert is to notify both the 
subject and the site of a potential symptom worsening event that warrants contact between 
the subject and site for further evaluation. 
All questions will have a 24-hour recall period.  Questions pertaining to the severity of 
symptoms versus their usual state will have 3 response options (e.g., How breathless have 
you been in the last 24 hours? Less breathlessness than usual, Usual level of breathlessness, 
More breathless than usual) whereas questions related to the presence or absence of a
symptom will have a dichotomous response (e.g., Have you had a sore throat in the last 24 
hours? No, Yes, I had a sore throat). 
An alert will be triggered if 2 or more major symptoms (dyspnea, sputum volume, and 
sputum color) worsen for 2 consecutive days or if 1 major symptom and 1 minor symptom 
(sore throat, cold, fever without other cause, cough, and wheeze) worsen for at least 
2 consecutive days. When either of these criteria is met, the subject will be alerted via the 
eDiary to contact the site as soon as possible for further evaluation. Likewise, the study site 
will be alerted to contact the subject within approximately 24 to 72 hours if he/she has not 
yet contacted the study site for further evaluation.
7.3.5: EXACT
The exacerbations of chronic pulmonary disease tool (EXACT) questionnaire will be 
captured via the subject eDiary (see Appendix 4)
7.4 
COPD Exacerbations 
A COPD exacerbation will be defined as a change in the subject’s usual COPD symptoms 
that lasts 2 or more days, is beyond normal day-to-day variation, is acute in onset, and may 
warrant a change in regular medication.  The change in symptoms must include at least one 
major COPD symptom and at least one other major or minor symptom from the list below:
x
Major COPD symptoms: dyspnea, sputum volume, and sputum color  
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x
Minor COPD symptoms: cough, wheeze, sore throat, cold symptoms (rhinorrhea or nasal 
congestion), and fever without other cause   
If symptoms are acute or have progressed rapidly and require treatment less than two days 
from onset of symptoms, the investigator will have to justify the decision for defining the 
event as an exacerbation and record it in the eCRF. 
If a subject’s symptoms and the overall clinical findings support the diagnosis of a COPD 
exacerbation, but the subject has not experienced a worsening of at least one major COPD 
symptom and at least one other major or minor symptom, the investigator will have to justify 
the decision for defining the event as an exacerbation and record it in the eCRF. 
7.4.1 
Severity of COPD Exacerbation
COPD exacerbations will be classified as mild, moderate or severe based on the following 
criteria:
Exacerbations will be considered moderate if they result in: 
x
Use of systemic corticosteroids and/or antibiotics for at least 3 days; a single depot 
injectable dose of corticosteroids will be considered equivalent to a 3-day course of 
systemic corticosteroids
Exacerbations will be considered severe if they result in: 
x
An inpatient COPD-related hospitalization (documentation stating that the subject was 
KRVSLWDOL]HGIRUWKH&23'H[DFHUEDWLRQRUDUHFRUGRIWKHVXEMHFWEHLQJDGPLWWHGIRU
hours to  an observation area, the emergency department, or other equivalent healthcare 
facility depending on the country and healthcare system) 
x
COPD-related death
Exacerbations will be considered mild if they do not meet the requirements to be classified as 
moderate or severe but otherwise fulfill the definition of COPD exacerbation.  
7.4.2
Duration of COPD exacerbation
For moderate or severe exacerbations, the duration is defined by the length of prescribed 
treatment, whereas for mild exacerbations, the duration is defined by the length of symptoms. 
For moderate or severe COPD exacerbations, the start date will be defined as the start date of 
prescribed treatment with a systemic corticosteroid or systemic antibiotic and the stop date 
will be defined as the last day of prescribed treatment with a systemic corticosteroid or 
systemic antibiotic.  In order to ensure that the same event is not counted twice, concurrent 
moderate or severe COPD exacerbations with start and stop dates equal to or less than 7 days 
apart will be considered the same event and assigned the maximum severity between the 
two.
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For mild COPD exacerbations, start date will be defined as the onset of worsened symptoms 
as recorded by the subject in the eDiary, and the stop date will be defined as the last day of 
worsened symptoms.  In order to ensure that the same event is not counted twice, mild COPD 
exacerbations with start and stop dates equal to or less than 7 days apart will be considered 
the same event.   
7.4.3
Approach for Capturing COPD Exacerbations
All moderate or severe COPD exacerbations must be captured using the COPD Exacerbation 
eCRF.  Mild COPD exacerbations will be captured based on symptoms as recorded by the 
subject in the eDiary.  COPD exacerbations of any severity will be considered expected study 
endpoints and will not be reported as adverse events (AEs) unless considered a serious AE 
(SAE).
7.4.4
Other Information
Pearl Therapeutics will be using an electronic diary (eDiary) to capture daily symptom 
reporting.  If symptoms meet a specific threshold (i.e., one major COPD symptom and at 
least one other major or minor symptom for 2 consecutive days), the eDiary generates alerts 
to the subject and the clinical site.  This alert is intended to generate a contact between the 
subject and the clinical investigator.  The clinical investigator makes the decision to escalate 
or initiate treatment (steroids and/or antibiotics and/or hospitalizations).
Circumstances will occur where symptoms are not captured in the eDiary (e.g., technical 
difficulties, rapid deterioration, or sudden death).  In these cases, the investigator or designee 
will enter the information into the eCRF to capture the symptoms related to a COPD 
exacerbation.
7.4.5
Investigator-Judged COPD Exacerbations
For events which do not meet the outlined symptom criteria and/or when symptoms have a 
shorter duration, the investigator can justify the decision for considering the event an 
exacerbation.  Exacerbations could be defined by an investigator when symptoms of COPD 
warranted urgent treatment due to rapid onset or rapidly progressive symptoms.  Such a 
situation does not allow enRXJKWLPHWRVWULFWO\IXOILOOWKHFULWHULDIRUV\PSWRPGXUDWLRQ
consecutive days).  In these cases, the investigator may define such an event as a COPD 
exacerbation.  As clinical presentations may vary among patients with COPD, exacerbations 
defined by an investigator can be supported by respiratory symptoms that may not strictly 
fulfill all symptom requirements defined above.  Since the investigator will need to document 
the symptoms that justify his or her decision to begin treatment defining a COPD 
exacerbation event, all exacerbations in the study will have documented symptoms justifying 
their clinical relevance.  
7.5
Subject Questionnaire
The exacerbations of chronic pulmonary disease tool (EXACT) questionnaire will be 
captured via the subject eDiary (see Appendix 4).
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7.6
Safety Assessments
The safety assessments include physical examination findings, vital signs, ECGs, and clinical 
laboratory tests in addition to recording of AEs and SAEs.  
7.6.1
Medical/Surgical History and Physical Examination
Medical history, including specific cardiovascular history details, will be collected at Visit 1 
(Screening) in Study PT010006. A complete physical examination will be performed at the 
conclusion of Study PT010006 (Visit 10a) and will not be obtained during Visit 10b. A 
complete physical examination will also be conducted at the Final Visit (Visit 14) or at the 
Treatment Discontinuation/Withdrawal Visit, if applicable. A complete physical examination 
will include evaluation of the following: general appearance, skin, head, eyes, ears, nose, 
throat, neck (including thyroid), lymph nodes, chest, heart, abdomen, extremities, and 
nervous system. Weight, assessed in ordinary indoor clothing with shoes removed will be 
recorded in Study PT010006 at Visit 1 and Visit 10a only. Height will be recorded at Visit 1 
(PT010006 Screening) only.
7.6.2
Vital Sign Measurements
Vital signs, including heart rate (HR) and systolic and diastolic blood pressure (DBP), and 
temperature will be assessed as outlined below; assessments may be obtained while the 
subject is resting for 5 minutes in either the supine or seated position. 
Vital signs will be obtained at the conclusion of the lead-in study PT010006 (Visit 10a) and 
will not be obtained during Visit 10b. 
At Visits 11 through 13:  
•
Pre-dose vital signs will be obtained once within 60 minutes prior to study drug dosing 
•
Post-dose vital signs will be obtained at 30 minutes post study drug dosing 
A single set of vital signs will also be obtained at a Visit 14 (Week 52) or at the Treatment 
Discontinuation/Withdrawal Visit, if applicable.
Temperature will be obtained pre-dose at all visits and will not be repeated at subsequent 
time points unless clinically indicated. A single set of vital signs will be obtained at the 
Treatment Discontinuation/Withdrawal Visit, if applicable. 
7.6.3
12-Lead Electrocardiogram 
ECGs will be obtained at the conclusion of Study PT010006 (Visit 10a) and will not be 
obtained during Visit 10b. 
At Visit 12 (Week 36) only, an ECG will be obtained within 60 minutes prior to study drug 
dosing. 
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7.6.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured prior to dosing at the final visit of Study PT010006 (Visit 
10a), and will not be obtained during Visit 10b.   
Hematology assessments will be obtained prior to dosing at Visit 12 (Week 36). Hematology 
assessments will also be obtained and Visit 14 (Week 52) or at the Treatment 
Discontinuation/Withdrawal Visit, if applicable.
7.6.4.2
Clinical Chemistry
Albumin, alkaline phosphatase, blood urea nitrogen (BUN), total bilirubin, calcium, total 
cholesterol, magnesium, phosphate, sodium, potassium, chloride, creatinine, ˠ-GT, blood 
glucose, total protein, bicarbonate, triglycerides, AST and ALT will be measured prior to 
dosing at the final visit of Study PT010006 (Visit 10a), and will not be obtained during Visit 
10b.
Clinical chemistry assessments will be obtained at Visit 12 (Week 36). Hematology 
assessments will also be obtained and Visit 14 (Week 52) or at the Treatment 
Discontinuation/Withdrawal Visit, if applicable.
Refer to Table 7-1 for a list of study-associated laboratory tests.  The central laboratory will 
supply procedures for the preparation and collection of these samples. 
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Table 7-1.
Clinical Laboratory Tests
Hematology
Hemoglobin 
Mean corpuscular 
hemoglobin 
Hematocrit 
Mean corpuscular hemoglobin 
concentration 
White blood cell count with differential 
Mean corpuscular volume 
Red blood cell count 
Eosinophils
Platelet count 
Clinical Blood Chemistry
Liver Enzyme and Other Liver Function Tests
Other Clinical Blood
Chemistry
Alanine aminotransferase 
Albumin
Aspartate aminotransferase 
Blood Urea Nitrogen (BUN)
Alkaline phosphatase 
Calciuma
Bilirubin, total 
Chloridea
Gamma-glutamyl transferase 
Cholesterol 
Bicarbonate
Creatininea
Glucosea
Magnesium 
Potassiuma
Phosphate
Protein, total 
Sodiuma
Urinalysis
Macroscopic examination including specific gravity, pH, protein, glucose, ketones, blood, and 
urobilinogen.
Other Tests:
Pregnancy test (women of childbearing potential only):  serum hCG at Visit 10a of Study PT010006  and  at Visit 14
(Week 52) the Treatment Discontinuation/Withdrawal Visit of this study.
Creatinine clearance will be estimated by the CKD-EPI formula [Levey, 2009].
Abbreviations: CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; hCG=human chorionic 
gonadotropin
a
Parameters included in the Basic Metabolic Panel.
7.6.4.3
Urinalysis
Urinalysis will be measured at the final visit of Study PT010006 (Visit 10a), and will not be 
obtained during Visit 10b.  
Urinalysis will be obtained prior to dosing at Visit 12 (Week 36).  Urinalysis will be obtained 
at Visit 14 (Week 52) or at the Treatment Discontinuation/Withdrawal Visit, if applicable.
7.6.4.4
Pregnancy Test
A serum pregnancy test will be performed at the Central Laboratory in pre-menopausal 
women who are not surgically sterile at the final visit of Study PT010006 (Visit 10a), and 
will not be obtained during Visit 10b.   
A serum pregnancy test will also be obtained at Visit 14 (Week 52) or at the Treatment 
Discontinuation/Withdrawal Visit, if applicable. 
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A urine pregnancy test will be performed at Visit 12 (Week 36).   
If any of these tests are positive, the subject must be discontinued from the study.  The 
pregnancy test should be performed prior to ECG or blood collection for laboratory 
assessments.
7.7
Adverse Events
7.7.1
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 and on the AE Reporting Form. If the AE is 
“alarming,” the Investigator must report the AE immediately to Pearl.  In addition, certain 
AEs (as described in Section 7.4.9) are classified as "serious" and must be reported no later 
than 24 hours after the Investigator recognizes/classifies the event as an SAE to Pearl or its 
designee.
In the case of SAEs, after discussing the details of the AE, the Investigator and the Medical 
Monitor may discontinue the subject prematurely. 
7.7.2
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 (e.g., 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 (e.g., 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 leads to the procedure are an AE (e.g., 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.) 
7.7.3
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. 
7.7.4
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 drugs, or concurrent treatments. 
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. 
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Not Related: A reaction for which sufficient data exist to indicate that the etiology is 
unrelated to the study drug. 
7.7.5
Chronic Obstructive Pulmonary Disease Exacerbations
All moderate or severe COPD exacerbations must be captured using the COPD Exacerbation 
eCRF.  Mild COPD exacerbations will be captured based on symptoms as recorded by the 
subject in the eDiary.  COPD exacerbations of any severity will be considered expected study 
endpoints and will not be reported as adverse events (AEs) unless considered a serious AE 
(SAE). 
Exacerbation(s) of COPD is expected to occur as a progression of disease despite 
standardized drug treatment, or treatment(s) with combination therapies. As a result, the 
Sponsor has classified this event as a protocol specified criteria expected event. Any 
individual case safety reports received related to exacerbation of COPD will not be submitted 
on an expedited basis as a Suspected Unexpected Serious Adverse Reaction (SUSAR) unless 
otherwise required as per the Sponsor’s medical assessment.
7.7.6
Adverse Events of Special Interest
Certain AEs have been identified as adverse events of special interest (AESIs) due to the 
class of drugs being studied.  Additional adverse events of special interest, including 
increased IOP, glaucoma, other ocular AE’s and fractures will be defined in the SAP. Some 
events are described below but this is not a comprehensive list of all AESIs.
7.7.6.1
LABA and LAMA Effects
Known effects of LAMAs and LABAs include cardiovascular effects, ocular disorders, 
urinary retention, gastrointestinal disorders, and anticholinergic effects for LAMAs and 
cardiovascular and tremor effects for LABAs. 
7.7.6.2
Local Steroid Effects 
Local steroid effects include oral candidiasis, hoarseness candidiasis, oropharyngeal 
candidiasis, dysphonia, and throat irritation.  
7.7.6.3
Pneumonia
In order to adequately assess and characterize the risk of pneumonia in patients in a non-
biased manner, an external, independent pneumonia adjudication committee (PAC) will 
review all adverse events reported as pneumonia to ensure appropriate pre-defined and 
clinically consistent pneumonia criteria are met.
To standardize the diagnosis of pneumonia a clinically consistent definition of pneumonia 
will be implemented, which will require the following: 
1. Clinical diagnosis of pneumonia by the investigator 
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2. Documentation of chest imaging obtained within 14 days of the diagnosis of pneumonia 
that is compatible with the diagnosis of pneumonia 
3. Treatment with antibiotics (and/or if appropriate antiviral and/or antifungal agents)
4. At least 2 of the following clinical signs, symptoms, or laboratory findings: 
•
Increased cough  
•
Increased sputum purulence or production  
•
Adventitious breath sounds on auscultation  
•
Dyspnea or tachypnea 
•
Fever
•
Elevated white blood cell counts 
•
Hypoxemia 
The PAC will be empowered to request any additional information, including copies of chest 
X-rays or CT scans if needed, to confirm the pneumonia diagnosis.   
Radiographs will be evaluated locally and the results (infiltrate compatible with pneumonia 
(yes/no) will be entered in the eCRF.  If the investigator becomes aware that a diagnosis of 
pneumonia was made without a chest image having been performed, he or she should obtain 
a chest image (frontal and lateral) up to 10 to 14 days after the date of pneumonia diagnosis.  
7.7.6.4
Paradoxical Bronchospasm
Monitoring for paradoxical bronchospasm will occur through spontaneous reporting. 
7.7.7
Major Adverse Cardiovascular Events (MACE)
Due to the prevalence of cardiovascular diseases in patients with COPD, MACE will be 
evaluated according to pre-defined criteria as described in the Charters.  CCV and Mortality 
Adjudication Committees will review and adjudicate serious CCV events as MACE and are 
defined as the following: 
x
Cardiovascular death
x
Non-fatal myocardial infarction (MI)
x
Non-fatal stroke
Charters will be established to govern these processes prior to the First Patient First Visit. 
7.7.8
Clinical Laboratory Adverse Events
Many laboratory abnormalities observed during the course of a study will be included under 
a reported AE describing a clinical syndrome (e.g., elevated BUN and creatinine in the 
setting of an AE of renal failure, or decreased hemoglobin in a case of bleeding esophageal 
varices).  Isolated laboratory abnormalities should be reported as AEs if they are considered 
to be clinically significant by the Investigator.
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Criteria for a "clinically significant" laboratory abnormality are:
• A laboratory abnormality that leads to a dose-limiting toxicity (e.g., an abnormality that 
results in study drug dose reduction, suspension, or discontinuation) 
• A laboratory abnormality that results in any therapeutic intervention (i.e., concomitant 
medication or therapy)
• Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (e.g., significant fall in hemoglobin not requiring transfusion) 
For laboratory abnormalities that do not meet the above criteria but are outside of normal 
range (e.g., < or > normal reference range), the Investigator should indicate whether the 
value is clinically significant or not clinically significant for the subject.
7.7.9
Serious Adverse Events
An AE is considered “serious” if, in the view of the Investigator or Sponsor, it results in any 
of the following outcomes: 
• Death
• A life-threatening AE
• In patient 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 
jeopardize the subject or 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 or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of 
drug dependency or drug abuse. 
Hospitalization for a pre-existing condition, including elective procedures, which has not 
worsened, does not constitute an SAE. 
An 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.  
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7.7.9.1
Reporting of 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 Therapeutics no later than 24 hours after the Investigator recognizes/classifies the event 
as an 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 (e.g., 
SAE Report Form).  After the initial report, as necessary, the Investigator must provide any 
additional information on a SAE to Pearl Pharmacovigilance within 2 working days after 
he/she receives that 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 7.4.9.4.
The Investigator is responsible for continuing to report any new or relevant follow-up 
information that he/she learns about the SAE. 
7.7.9.2
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.
7.7.9.3
Post-Study Follow-Up of Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
eCRF.  Pearl retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
7.7.9.4
Notification of Post-Study Serious Adverse Events
Investigators are not obligated to actively follow subjects after the completion of the study.  
However, if the Investigator becomes aware of a post-study SAEs occurring up to 14 days 
following the last dose of study drug must be reported to Pearl, whether or not the event is 
attributable to study drug.  All SAEs must be reported to Pearl no later than 24 hours after the 
Investigator recognizes/classifies the event as an SAE.
7.7.9.5
Investigational Research Board/Independent Ethics Committee Notification of 
Serious Adverse Events
The Investigator is responsible for promptly notifying her/his Investigational Research 
Board/Independent Ethics Committee (IRB/IEC) of all SAEs, including any follow-up 
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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 ICF or other measures based on its review of 
an SAE report. 
7.7.9.6
Health Authority Safety Reports
Pearl or its representatives will submit a safety report to the Food and Drug Administration 
(FDA) and/or any other appropriate regulatory agencies, for any suspected adverse reaction 
that is both serious and unexpected within the appropriate time frame. 
Pearl or its representatives will send copies of each safety report submitted to the FDA and/or 
other regulatory agencies to the Investigators who are actively participating in Pearl-
sponsored clinical studies.  Safety reports must be submitted to the appropriate IRB/IEC as 
soon as possible.  Documentation of the submission to the IRB/IEC must be retained for each 
safety report.
7.7.10
Overdose
An overdose is defined as a dose greater than the high dose level evaluated in this study as 
described in Section 6.2 (Product Descriptions) 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 Investigator’s 
Brochure for BGF MDI, BFF MDI, GFF MDI, and approved product labeling for open-label 
products. 
7.7.11
Pregnancy
To ensure subject safety, each pregnancy in a female subject from Visit 1 (Screening) until 
study completion must be reported to Pearl within 24 hours of learning of its occurrence.  
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.  Pregnancy should be 
recorded on a Paper Pregnancy Report Form and reported by the Investigator to Pearl 
Pharmacovigilance or designee.  Pregnancy follow-up should be recorded on the same form 
and should include an assessment of the possible relationship to the Pearl study drug of any 
pregnancy outcome.  Any SAE experienced during pregnancy must be reported on the SAE 
Report Form. 
7.7.12
Use of Steroids during the Study
At each visit, subjects will be asked whether they have been administered oral, intramuscular, 
or intravenous corticosteroids since last visit.  Use of oral, intramuscular, or intravenous 
corticosteroids for the management of COPD exacerbations or other condition is not a reason 
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for early termination.  Use of corticosteroids should be documented.  Subjects who are being 
treated for a COPD exacerbation with oral corticosteroids or have been treated for a COPD 
exacerbation with oral corticosteroids within 14 days of the scheduled visit will be allowed to 
perform PFTs under close medical supervision.  The Investigator can decide to stop PFTs if 
subject safety is at risk or symptoms make it difficult for the subject to continue.
Subjects treated with oral, intramuscular, or intravenous corticosteroids for other indications 
will follow their visit schedule.  If a subject requires intraocular corticosteroids, this should 
be fully documented and the Investigator should make a determination as to the suitability of 
the subject continuing in the study. 
7.7.13
Clinical Endpoint Committee 
An external clinical endpoint committee (CEC) that was initiated in Study PT010006 will 
continue to provide systematic and unbiased assessment of pre-defined, Investigator reported 
adverse events for Study PT010008.  The committee will consist of experts who will provide 
a centralized review functioning independently of Pearl. Three Clinical Endpoint 
Adjudication Charters will outline the clinical endpoints for adjudication.   
•
Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint Adjudication Charter
•
Cause-Specific Mortality Clinical Endpoint Adjudication Charter
•
Pneumonia Clinical Endpoint Adjudication Charter 
7.7.13.1
Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint Adjudication 
Charter
A Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint Adjudication Charter will 
be referenced for the review and assessment of non-fatal serious CCV events and 
classification of Major Adverse Cardiovascular Event (MACE).  The CEC will review 
potential clinical endpoints to determine if the event meets MACE criteria.  
7.7.13.2
Cause-Specific Mortality Clinical Endpoint Adjudication Charter
A Cause-Specific Mortality Clinical Endpoint Adjudication Charter will be referenced for the 
review and assessment of the cause of deaths. The CEC will review fatal reports to determine 
if the event meets MACE criteria. Cardiovascular deaths will be classified as MACE.    
7.7.13.3
Pneumonia Clinical Endpoint Adjudication Charter
A Pneumonia Clinical Endpoint Adjudication Charter will be referenced for the review and 
assessment of all pneumonia-related events to ensure appropriate pre-defined and clinically 
consistent pneumonia criteria are met. 
7.7.14
Data Monitoring Committee
An external Data Monitoring Committee (DMC) that was initiated in Study PT010006 will 
continue to provide systematic and unbiased assessment of safety for Study PT010008.  
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Members of the DMC will review data at predetermined intervals.  If significant safety issues 
arise in between scheduled meetings, ad hoc meetings will be scheduled to review the data. 
Based on the safety implications of the data, the DMC may recommend modification or 
termination of the study. 
7.8 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’ wellbeing.
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8
STUDY ACTIVITIES
A schedule of events is provided in Table 8-1.
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8.1
Baseline Assessments
The Baseline PT010008 Assessments will be conducted concurrently with PT010006 
Screening.  If the first two BMD scans differ by more than 5% (as determined by the local 
facility) for either site (i.e. first two hip or first two lumbar sites) a third scan should be 
obtained. The screening period may be extended up to a maximum of 21 days if additional 
time is needed to complete the assessments All study assessments are to be completed prior 
to Randomization (Visit 4) in PT010006. 
•
Obtain informed consent prior to conducting any Study PT010008 baseline assessments. 
•
Register subject in IWRS for Study PT010008 at the same time registering in Study 
PT010006.  
•
Conduct BMD assessments (Refer to Section 7.1)
•
Conduct ocular assessments (Refer to Section 7.2)
8.2 
Randomization  
•
Review Study PT010008 inclusion/exclusion criteria and confirm subject’s eligibility to 
continue. 
•
Obtain subject randomization number and treatment assignment information from IWRS.  
Note :  Randomization in PT01008 occurs simultaneously with randomization in Study 
PT010006 for those patients who qualify for Study PT010008. 
•
A reminder phone contact should be made prior to Visit 10b. 
8.3 
Visit 10b  
The last visit of the Study PT010006 and the first post-baseline visit of Study 
(PT010008).  Visit 10b will be following completion of all Visit 10a study procedures.  
•
Review BMD/Ocular inclusion/exclusion criteria
•
Confirm all visit 10a procedures have been completed before proceeding to register 
subjects in IWRS 
•
Register subject in IWRS to confirm participation in the PT010008 and receive assigned 
treatment 
•
Confirm subject’s ability to use MDI correctly (provide training as needed) 
•
Return electronic diary to subjects and provide retraining if appropriate
•
When assigned blinded study drug site personnel will complete priming in the clinic 
before dispensing to the subject for at home use 
•
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
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•
Record/document the dose indicator reading. The dose indicator count recorded by the 
site staff will be dose indicator count observed after priming but prior to subject dosing. 
Refer to Section 7.2.1.3 for more details
•
Subject will administer dose of study drug at home in the evening 
Note: During the study subjects will continue on the same treatment that they were 
assigned in Study PT010006. 
•
Subjects will be instructed to bring their eDiary and all study medication (including used 
study drug, replacement MDI kit and sponsor-provided rescue Ventolin HFA) to the next 
scheduled clinic visit 
•
Schedule ophthalmologic assessment to occur prior to Visit 11 (Week 28)  
•
Schedule visit 11 to occur after ocular assessments are conducted and ensure subject has
adequate supply of study drug including a replacement MDI kit and sponsor-provided 
rescue Ventolin HFA
8.4
Visits 11 (Week 28) 
•
Confirm scheduled ocular assessments have been conducted (Visit 11 should be 
rescheduled if ocular assessments not conducted prior to this visit)  Please refer to the 
exclusion criteria exception noted in Section 5.2.2 to see if the ocular assessment applies 
to this visit.
•
Review and verify subject’s eligibility to continue
•
Collect study drug including sponsor-provided Ventolin HFA
•
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, the visit must be rescheduled) 
•
Confirm the subject took their last dose of randomized study medication as scheduled.  
If the time of dosing was not in accordance with the protocol, then the visit must be 
rescheduled
•
Review subject diary for data collection compliance. Review EXACT for completion as 
part of the eDiary review
•
Review smoking status and prior/concomitant medications
•
Review all prior medications and ensure adherence to COPD regimen 
•
Record COPD exacerbations and AEs (if any) 
•
Obtain vital signs within 60 minutes prior to dosing 
•
Return electronic diary to subjects and provide retraining if appropriate
•
Prior to dosing, site personnel will use IWRS to assign subjects a new kit of study drug 
for in-clinic dosing and to continue dosing at home until the next scheduled visit 
•
For new MDIs, the recorded count will be the count following the priming of the device 
but before the subject doses.  Refer to Section 7.2.1.3 for more details
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•
Administer in-clinic study drug dosing from the new kit assigned at the visit
•
Obtain vital signs 30 minutes post study drug dosing
•
Subjects will be instructed to track study drug dosing in their electronic diary between 
study clinic visits
•
Subject will be instructed to dose while at home from the site-primed MDI only, unless 
all of the following replacement conditions are met:
o
Dose indicator is in the red zone (See Appendix 1 for dose indicator reading 
instructions)  
o
,IWKHGRVHLQGLFDWRUUHJLVWHUVpuffs remaining, and their next scheduled study 
clinic visit is not the following day
o
If these replacement conditions are met, subjects will be instructed to open one of 
their replacement kits, prime the MDI and start using for at home dosing until the 
next scheduled study clinic visit
o
Subjects will be instructed to bring their eDiary and all study medication (including 
used study drug, replacement MDI kit and sponsor-provided rescue Ventolin HFA) 
to the next scheduled clinic visit 
•
Schedule next visit and ensure subject has adequate supply of study drug including two
replacement MDI and sponsor-provided rescue Ventolin HFA 
•
Follow up telephone call one day prior to scheduled visit 
8.5
Visit 12 (Week 36)
•
Confirm subject eligibility to continue
•
Collect study drug including sponsor-provided Ventolin HFA
•
Determine time of last dose of short-acting bronchodilator and other COPD 
medications (if <6 hours, the visit must be rescheduled)
•
Confirm the subject took their last dose of randomized study medication as scheduled.
If the time of dosing was not in accordance with the protocol, then the visit must be 
rescheduled  
•
Review subject diary for data collection compliance. Review EXACT for completion 
as part of the eDiary review
•
Review smoking status and prior/concomitant medications 
•
Review all concomitant medications and ensure adherence to COPD regimen
•
Record COPD exacerbations and adverse events (if any)
•
Obtain vital signs within 60 minutes prior to dosing
•
Obtain 12-lead ECG within 60 minutes prior to study drug dosing
•
Perform urine pregnancy test
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•
Obtain clinical laboratory samples prior to study drug dosing
•
Return electronic diary to subjects and provide retraining if appropriate
•
Prior to dosing, site personnel will use IWRS to assign subjects a new kit of study drug 
for in-clinic dosing and to continue dosing at home until the next scheduled visit 
•
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
•
If assigned to blinded study drug, record/document the dose indicator readings of the 
used device and the replacement device  
•
For new MDIs, the recorded count will be the count following the priming of the device 
but before the subject doses.  Refer to Section 7.2.1.3 for more details
•
Administer in-clinic study drug dosing from the new kit assigned at the visit
•
Obtain vital signs 30 minutes post study drug dosing
•
Subjects will be instructed to track study drug dosing in their electronic diary between 
study clinic visits
•
Subject will be instructed to dose while at home from the site-primed MDI only, unless 
all of the following replacement conditions are met:
o
Dose indicator is in the red zone (See Appendix 1 for dose indicator reading 
instructions)  
o
,IWKHGRVHLQGLFDWRUUHJLVWHUVSXIIVUHPDLQLQJDQGWKHLUQH[WVFKHGXOHGVWXG\
clinic visit is not the following day
o
If these replacement conditions are met, subjects will be instructed to open one of 
their replacement kits, prime the MDI and start using for at home dosing until the 
next scheduled study clinic visit
o
Subjects will be instructed to bring their eDiary and all study medication 
(including used study drug, replacement MDI kit and sponsor-provided rescue 
Ventolin HFA) to the next scheduled clinic visit
•
Schedule next visit and ensure subject has adequate supply of study drug including two
replacement MDI kits and sponsor-provided rescue Ventolin HFA 
•
Follow up telephone call one day prior to scheduled visit 
8.6
Visit 13 (Week 44)
•
Confirm subject eligibility to continue
•
Collect study drug including sponsor-provided Ventolin HFA
•
Determine time of last dose of short-acting bronchodilator and other COPD 
medications (if <6 hours, the visit must be rescheduled)
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•
Confirm the subject took their last dose of randomized study medication as scheduled.  
If the time of dosing was not in accordance with the protocol, then the visit must be 
rescheduled 
•
Review subject diary for data collection compliance. Review EXACT for completion 
as part of the eDiary review
•
Review smoking status and prior/concomitant medications
•
Review all concomitant medications and ensure adherence to COPD regimen
•
Record COPD exacerbations and adverse events (if any)
•
Obtain vital signs within 60 minutes prior to dosing
•
Return electronic diary to subjects and provide retraining if appropriate
•
Prior to dosing, site personnel will use IWRS to assign subjects a new kit of study drug 
for in-clinic dosing and to continue dosing at home until the next scheduled visit 
•
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
•
If assigned to blinded study drug, record/document the dose indicator readings of the 
used device and the replacement device  
•
For new MDIs, the recorded count will be the count following the priming of the device 
but before the subject doses.  Refer to Section 7.2.1.3 for more details
•
Administer in-clinic study drug dosing from the new kit assigned at the visit
•
Obtain vital signs 30 minutes post study drug dosing
•
Subjects will be instructed to track study drug dosing in their electronic diary between 
study clinic visits
•
Subject will be instructed to dose while at home from the site-primed MDI only, unless 
all of the following replacement conditions are met:
o
Dose indicator is in the red zone (See Appendix 1 for dose indicator reading 
instructions)  
o
,IWKHGRVHLQGLFDWRUUHJLVWHUVSXIIVUHPDLQLQJDQGWKHLUQH[WVFKHGXOHGVWXG\
clinic visit is not the following day
o
If these replacement conditions are met, subjects will be instructed to open one of 
their replacement kits, prime the MDI and start using for at home dosing until the 
next scheduled study clinic visit
o
Subjects will be instructed to bring their eDiary and all study medication 
(including used study drug, replacement MDI kit and sponsor-provided rescue 
Ventolin HFA) to the next scheduled clinic visit
• Schedule ophthalmologic assessments and BMD assessments to occur within two weeks 
prior to Visit 14 (Week 52)  
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•
Schedule visit 14 to occur after ocular assessments and BMD assessments are 
conducted and ensure subject has adequate supply of study drug including two
replacement MDI kits and sponsor-provided rescue Ventolin HFA 
•
Follow up telephone call one day prior to scheduled visit 
8.7 
Visit 14 (Week 52; Final Visit) 
•
Confirm ocular assessments were conducted prior to this visit (Visit 14 should be 
rescheduled if ocular assessments not conducted prior to this visit) Please refer to the 
exclusion criteria exception noted in Section 5.2.2 to see if the ocular assessment 
applies to this visit
•
Confirm  BMD assessments were conducted prior to this visit (Visit 14 should be 
rescheduled if BMD assessment not conducted prior to this visit) 
•
Confirm subject eligibility to continue
•
Collect study drug including sponsor-provided Ventolin HFA
•
Determine time of last dose of short-acting bronchodilator and other COPD 
medications (if <6 hours, the visit must be rescheduled)
•
Confirm the subject took their last dose of randomized study medication as scheduled.  
If the time of dosing was not in accordance with the protocol, then the visit must be 
rescheduled 
•
Review subject diary for data collection compliance. Review EXACT for completion 
as part of the eDiary review
•
Review smoking status and prior/concomitant medications
•
Perform physical examination, including weight 
•
Review all concomitant medications and ensure adherence to COPD regimen
•
Record COPD exacerbations and adverse events (if any)
•
Obtain vital signs 
•
Perform serum pregnancy test
•
Obtain 12-lead ECG 
•
Obtain clinical laboratory samples  
•
Collect subject eDiary
•
Inform subject about reporting all SAEs up to 14 days following the last dose of study 
drug 
•
Return subject to pre-study or appropriate maintenance COPD medications 
•
Schedule the follow-up telephone call at least 14 days from Visit 14 
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Clinical Trial Protocol:  PT010008-01
Version 2.0, 
8.8 Unscheduled Visit and Treatment Discontinuation/Withdrawal Visit 
Repeat assessments, if needed, will be captured in unscheduled visits. 
Premature discontinuations visits will be captured as unscheduled visits.  The following 
minimum procedures should be completed at the Premature Discontinuation Visit:
x
Collect all study drugs 
x
Record COPD exacerbations and adverse events (if any)
x
Review concomitant medications
x
Conduct a physical examination, including vital signs 
x
Perform ECG and collect blood samples for hematology and chemistry 
x
Collect a blood sample for pregnancy test for women of child bearing potential 
x
Collect subject eDiary
x
Inform subject about reporting all SAEs up to 14 days following the last dose of study 
drug 
x
Return subject to pre-study or appropriate maintenance COPD medications
x
Capture the subject discontinuation reason 
x
Schedule a follow-up telephone call (TC) 14 days post last study drug dosing.  If the 
discontinuation visit is performed > 14 days post last study drug dosing a follow-up 
TC will not be required 
x
Schedule ocular assessments as early as practical
x
If after Visit 10b (Week 24), schedule BMD measurement  as early as practical
8.9 
Follow-up Telephone Call 
Subjects will be followed-up within 14 days after the last study drug dosing.  The following 
information will be requested: 
•
Review previously on-going COPD exacerbations and AEs (if any)
•
Review concomitant medications
Note:  For subjects who withdraw consent, schedule a follow-up TC at least 14 days after 
the last study drug dosing unless the visit is performed >14 days post last study drug dosing, 
a follow-up TC will not be required.  For treatment discontinuation subjects, a telephone 
follow-up call is not required as long as at least one post treatment study visit is completed.
8.10 Vital Status Confirmation at Week 52 
All subjects who discontinue study treatment after Visit 10b will have their vital status 
confirmed at 52 weeks post-randomization. 
To confirm the vital status and cause of death, if appropriate, the following attempts will be 
made:
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Clinical Trial Protocol:  PT010008-01
Version 2.0, 
•
The first and second attempts may be conducted as telephone follow-up call to the subject 
within 2 weeks after 52 weeks post-randomization
•
The third attempt will be by certified mail to the subject’s address provided at the time of 
informed consent within 3 weeks after 52 weeks post-randomization 
•
The fourth attempt will be made as a telephone follow-up call to the next of 
kin/emergency contact provided at the time of informed consent within 4 weeks 52 weeks 
post-randomization 
•
A fifth attempt will be made through a certified letter to the next of kin/emergency 
contact provided at the time of informed consent within 5 weeks after 52 weeks post-
randomization 
After the fifth attempt, the study site will contact the national death registries (if available in 
that country) to confirm date and cause of death. 
8.11 Completion of 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 
• Adverse events(s)
• Administrative reasons (e.g., 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 (see Section 5.7)
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Clinical Trial Protocol:  PT010008-01
Version 2.0, 
9
PLANNED STATISTICAL METHODS
9.1 
Introduction 
This Study PT010008 will be conducted in a subset of US sites participating in Study 
PT010006, and will evaluate the following treatments: 
•
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•
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•
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Across these sites, it is planned that approximately 500 subjects randomized to double-blind 
treatment only will provide approximately 425 subjects who will complete the study. 
Subjects will receive the same treatment (BGF MDI, GFF MDI, or BFF MDI) they were 
randomized to in Study PT010006. Subjects randomized to open-label Symbicort TBH will 
not be enrolled in this study.  
This study will evaluate the safety of BGF MDI, BFF MDI, and GFF MDI on bone mineral 
density (BMD) measurement and ophthalmologic assessment.  
Baseline and demographic characteristics will be collected in Study PT010006 with the 
exceptions of baseline BMD and lenticular opacity and ocular pressure measurements. 
Baseline BMD and lenticular opacity and ocular pressure measurements will be performed 
prior to Visit 4 (Randomization) of Study PT010006. A separate informed consent will be 
obtained for subjects participating in Study PT010008. 
9.2
Protocol Variables
All efficacy assessments are relative to baseline assessments obtained at Screening (Visits 1 
to 3) in Study PT010006.   
9.2.1
Study Endpoints
9.2.2
Primary Bone Mineral Density Endpoint 
•
Percent change from baseline in BMD of the lumbar spine measured using DEXA scans 
of L2-L4 at Week 52
9.2.3
Other Bone Mineral Density Endpoints
x
Percent change from baseline in BMD of the hip measured using DEXA scans at Week 
52 and at EoT
x
Percent change from baseline in BMD of the lumbar spine measured using DEXA scans 
of L2-L4 at EoT 
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Clinical Trial Protocol:  PT010008-01
Version 2.0, 
9.2.4
Primary Ocular Endpoint
•
Change from baseline in the  LOCS III (P) Score at Week 52
9.2.5
Other Ocular Endpoints
•
Change from baseline in each scale of the LOCS III scores at Week 28, Week 52 (NO, 
NC, and C only), and EoT 
•
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&ODVVXQLWVLQHDFKRIWKHVFDOHVDW:HHN:HHNDQG(R7
•
Change from baseline in intraocular pressure (IOP) at Week 28, Week 52, and EoT 
•
3URSRUWLRQRIVXEMHFWVZLWK,23PP+JDW:HHNDW:HHNDQG(R7
•
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and EoT 
•
Change from baseline in LogMAR visual acuity using ETDRS charts at Week 28, Week 
52, and EoT 
•
Change from baseline in horizontal cup-to-disc ratio at Week 28, Week 52, and EoT 
•
Incidence of ocular TEAEs including cataract and glaucoma
9.2.6
Safety Endpoints
The safety endpoints for this study include: 
•
Adverse events (AEs)
•
12-lead electrocardiograms (ECGs)
•
Clinical laboratory testing
•
Vital sign measurements
9.2.7
Efficacy Endpoints
•
Change from baseline in average daily rescue Ventolin HFA (albuterol sulfate) use.
•
Percentage of days with no rescue Ventolin HFA use 
•
Rate of moderate or severe COPD exacerbations
•
Rate of COPD exacerbations of any severity
•
Change from baseline in: the EXACT total score, the 11-item EXACT Respiratory 
Symptoms (E-RS) Total Score (RS-Total Score),  as well as 3 subscale scores symptom 
(RS-Breathlessness, RS-Cough and Sputum, and RS-Chest Symptoms) over 52 weeks 
and over each 4-week interval of the 52-week Treatment Period
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Clinical Trial Protocol:  PT010008-01
Version 2.0, 
9.3 
 Study Populations 
The following analysis populations are defined in this study: 
•
The Safety Population will consist of all subjects enrolled in PT010008 who receive any 
amount of study medication.  Subjects will be analyzed according to treatment received 
rather than randomized.  If a subject received more than 1 randomized treatment, they 
will be analyzed and included in summaries according to the treatment they received the 
most. Subjects receiving no study treatment will be excluded, as will subjects who have 
no post-dose safety assessments.  (Note that a subject who used a study treatment, but 
took less than 1 full dose of treatment will qualify for this population).  
Note: The statement that a subject had no AEs also constitutes a safety assessment
•
The BMD Analysis Population is defined as all evaluable subjects in the Safety 
Population who have a baseline BMD assessment and at least 1 on-treatment BMD 
assessment. Subjects will be analyzed according to actual treatment received
•
The Ophthalmologic Analysis Population is defined as all evaluable subjects in the 
Safety Population who have a baseline ophthalmologic assessment and at least 1 on-
treatment ophthalmologic assessment. Subjects will be analyzed according to actual 
treatment received 
•
The mITT Population is defined as the subgroup of mITT subjects from Study 
PT010006, who enrolled in PT010008. Subjects will be analyzed according to the active 
treatment they were assigned to at randomization in Study PT010006. (Note that a subject 
who used a study treatment, but took less than one full dose of treatment will qualify for 
this population).  Data from both Study PT010006 and Study PT010008 will be included 
Exclusions from the ophthalmologic and BMD population will be defined in the SAP. 
Analyses will be performed as follows:
Demographics will be summarized for the Safety Population. Demographics will also be 
summarized for the BMD and Ophthalmologic Analysis populations if these are different 
from the Safety Population. Analyses of ophthalmologic endpoints will be performed on the 
Ophthalmologic Analysis Population, and those of BMD endpoints will be performed on the 
BMD Analysis Population. All other safety analyses will be presented for the Safety 
Population. Efficacy will be presented for mITT population. 
9.4
Safety Analyses
Safety data will be summarized both cumulatively over 52 weeks using data observed during 
PT010006 and this supplemental study. Analyses involving change from baseline will use 
baseline values from Study PT010006. 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
9.4.1 Analysis of BMD Endpoints
9.4.1.1
Percent change from baseline in BMD of the lumbar spine measured using 
DEXA scans of L2-L4
The change from baseline in BMD of the lumbar spine at Week 52 (and similarly at EoT) 
will be analyzed using an Analysis of Covariance (ANCOVA) model with treatment group 
and gender as categorical covariates, and baseline BMD score, age, and age by gender 
interaction as continuous covariates. 
T- and Z- scores will be presented as shifts from baseline to each time point; details will be 
provided in the SAP. 
9.4.1.2
Percent change from baseline in total hip BMD of the hip measured using DEXA 
scans  
The change from baseline in BMD of the hip at Week 52 (and similarly at EoT) will be 
analyzed similarly to the change from baseline in BMD of the lumbar spine. 
9.4.2
Analysis of Ocular Endpoints  
9.4.2.1
Change from baseline in each of the LOCS III (NO, NC, C, and P) scores 
Change from baseline in the LOCS III (P) scores at each post-randomization visit will be 
analyzed using an Analysis of Covariance (ANCOVA). The model will include treatment 
group as a fixed effect, and baseline LOCS III (P) score, smoking pack years, and age as 
continuous covariates. The model will account for inter-eye correlation by including subject 
and eye (within subject) as random effects. 
Two-sided 95% confidence intervals will be computed for pairwise differences of BGF 
minus GFF and BFF minus GFF, and non-inferiority will be declared if the upper confidence 
bound is less than 0.5. The analysis of the change from baseline in LOCS III (P) scores at 
Week 52 will be the primary ocular analysis, with analyses at Week 28 and EoT being 
supportive. 
The above analyses will be repeated for the other 3 LOCS III (NO, NC, and C) scores, but 
with the corresponding baseline LOCS III scale score as a covariate.
9.4.2.2
Proportion of subjects with LOCS I,,JUDGHLQFUHDVHVRI&ODVV
&ODVVRU&ODVVXQLWVLQHDFKRIWKHVFDOHV
7KHSURSRUWLRQRIVXEMHFWVZLWK/2&6,,,JUDGHLQFUHDVHVLQHLWKHUH\HRI&ODVV
&ODVVDQG&ODVVXQLWVLQHDFKRIWKHVFDOHs at Week 28, at Week 52, and at 
EoT will be summarized by treatment group. 
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Clinical Trial Protocol:  PT010008-01
Version 2.0, 
9.4.2.3
Change from baseline in intraocular pressure (IOP) 
The change from baseline in IOP at Week 28, Week 52, and EoT will be analyzed using a 
similar model as for the LOCS III (P) score at 52 weeks, but with the baseline IOP as a 
covariate.
9.4.2.4
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7KHSURSRUWLRQRIVXEMHFWVZLWK,23PP+JLQHLWKHUH\HDW:HHN:HHNDQG(R7
will be summarized by treatment group.  Similarly, the proportion of subjects with IOP 
LQFUHDVHVIURPEDVHOLQHRIPP+JLQHLWKHUH\HDW:HHN:HHNDQG(R7ZLOl be 
summarized.  
9.4.2.5
Change from baseline in LogMAR visual acuity using ETDRS charts 
Change from baseline in LogMAR visual activity scores will be summarized for each eye at 
each visit by treatment group using descriptive statistics.
9.4.2.6
Change from baseline in horizontal cup-to-disc ratio 
Change from baseline in horizontal cup-to-disc ratio will be summarized for each eye at each 
visit by treatment group using descriptive statistics.
9.4.2.7
Incidence of ocular TEAEs including cataract, glaucoma
The proportion of subjects with ocular TEAEs in each treatment group will be summarized 
overall, as well as by individual AE. AEs qualifying as ocular AEs include cataract and 
glaucoma.
9.4.3
Adverse Events
The version of the Medical Dictionary for Regulatory Activities (MedDRA) that is current at 
the time of database lock will be used to code verbatim terms for AEs for final analysis of the 
data.  The number and incidence of adverse events, serious adverse events, adverse events of 
special interest by category, confirmed AEs of pneumonia, and study drug discontinuations 
due to adverse events will be summarized by treatment group.  They will be tabulated at the 
level of the Medical Dictionary for Regulatory Activities (MedDRA) preferred term and the 
MedDRA system organ class.  Tabulations will be broken down by severity, by relationship 
to study drug, and AEs leading to treatment discontinuation. No hypothesis tests will be 
performed.
9.4.4
Cardio- and Cerebrovascular Events Determined by Adjudication 
Committee
CCV and Mortality Adjudication Committees will review and adjudicate serious CCV events 
as MACE. MACE events are defined as the following: 
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Clinical Trial Protocol:  PT010008-01
Version 2.0, 
x
Cardiovascular death
x
Non-fatal myocardial infarction (MI)
x
Non-fatal stroke 
The adjudication committees will review and assess these non-fatal serious CCV events 
and all deaths as to whether or not they fulfill criteria (based on adjudication committee 
working practices) for MACE. 
MACE events will be summarized by treatment group.
9.4.5
Pneumonia Events Determined by Adjudication Committee
All AEs/SAEs with preferred terms that could relate to pneumonia will be adjudicated to 
provide a more complete assessment of all physician-reported pneumonias. The assessment 
of pneumonia events will include the overall rates of pneumonia. 
9.4.6
Clinical Laboratory Measurements
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) for the 
baseline assessment (Day 1) and for the pre-dose value and change from baseline at pre-dose 
value of post-baseline visits with scheduled lab assessments of continuous laboratory 
variables, including serum potassium and glucose will be tabulated. 
Shift tables relative to the normal reference ranges will be produced using the categories 
defined by the CTCAE Version 4.03 grades.  For these shift tables, for each treatment, 
the subject’s pre-dose grade will be cross-tabulated by the subject’s maximum post-baseline 
grade during the treatment; also, the subject’s maximum post-baseline grade during treatment 
will be tabulated for all baseline grades combined.
The number and percent of subjects with potentially clinically significant (PCS) lab values 
will be summarized.  Potentially clinically significant values for serum potassium are <3.0 
mmol/L or >6.0 mmol/L, and for blood glucose <2.2 mmol/L or >13.9 mmol/L.  Potentially
clinically significant values for labs will be defined in the SAP.  No hypothesis tests will be 
performed.
9.4.7
Vital Signs
Summary statistics (mean, median, standard deviation and range) for absolute values 
and change from baseline values will be tabulated for each treatment and assessment time. 
For vital signs, baseline values will be defined as the average of the values prior to dosing 
at the randomization visit (Visit 4).  Potentially clinically significant values for vital signs 
will be defined in the SAP and the percentage of subjects with PCS values will be 
summarized.  No hypothesis tests will be performed. 
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Clinical Trial Protocol:  PT010008-01
Version 2.0, 
9.4.8
Electrocardiograms
Summary statistics (mean, median, standard deviation and range) for raw values and 
change from baseline values in heart rate, PR interval, QRS axis, QRS interval, QT interval 
and QTcF interval will be calculated, where baseline is defined as the average of the pre-dose 
measurements taken prior to the start of treatment at the randomization visit (Visit 4).  
The QTcF (Fridericia Corrected QT) is defined as (QT/[RR1/3]). Heart rate (bpm) is 
estimated as 60,000/RR.  These assessments will be tabulated for each treatment and 
assessment time.  Potentially clinically significant values for ECG parameters will be defined 
in the SAP, and the percentage and number of subjects with PCS ECG values will be 
tabulated.  No hypothesis tests will be performed.
9.4.9
Exposure
The duration of exposure to study medication (in days), the person-years of exposure, the 
mean number of doses, and number and percentage of subjects who are compliant will be 
summarized by treatment group.  All exposure summaries will be generated for the safety 
population by actual treatment received.
9.5
Analyses of Efficacy Endpoints
Analyses of efficacy will be performed using the mITT Population. 
9.5.1
Rescue Ventolin HFA Use
The number of puffs of rescue Ventolin HFA taken in the previous 12 hours will be recorded 
in the subject diary in the morning and evening.  For every period of time for which the mean 
number of puffs of rescue will be calculated, missing values will be ignored in both the 
numerator and denominator.  As such, the denominator will be adjusted based on the number 
of days (including half days) with non-missing values.
The mean change from baseline in rescue use will be summarized by treatment group over 52 
weeks and over each post-randomization 4-week interval (Interval 1 to Interval 13).  
9.5.2
Percentage of Days with No Rescue Ventolin HFA Use over the Treatment 
Period
As a supportive analysis, percentage of days with ‘no rescue Ventolin HFA use’ over 52 
weeks will be summarized using descriptive statistics.  A ‘day with no rescue use’ is defined 
using rescue Ventolin HFA usage data from days where rescue Ventolin HFA usage data is 
non-missing as any day where the subject reported no puffs of rescue Ventolin HFA.   
9.5.3
Chronic Obstructive Pulmonary Disease Exacerbations
The rate of moderate or severe COPD exacerbations will be summarized by treatment group.  
Chronic obstructive pulmonary disease exacerbations will be considered separate events 
provided that 7 or more days are between the recorded stop date of the earlier event and start 
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Clinical Trial Protocol:  PT010008-01
Version 2.0, 
date of the latter.  For moderate or severe COPD exacerbations, the start date is be defined as 
the start date of prescribed treatment with a systemic corticosteroid or systemic antibiotic and 
the stop date will be defined as the last day of prescribed treatment with a systemic 
corticosteroid or systemic antibiotic. The rate of COPD exacerbations of any severity will be 
presented in a similar manner.
Duration of COPD Exacerbation 
For moderate or severe exacerbations, the duration is defined by the length of prescribed 
treatment, whereas for mild exacerbations, the duration is defined by the length of symptoms. 
For moderate or severe COPD exacerbations, the start date will be defined as the start date of 
prescribed treatment with a systemic corticosteroid or systemic antibiotic and the stop date 
will be defined as the last day of prescribed treatment with a systemic corticosteroid or 
systemic antibiotic. In order to ensure that the same event is not counted twice, concurrent 
moderate or severe COPD exacerbations with start and stop dates equal to or less than 7 days 
apart will be considered the same event and assigned the maximum severity between the two.  
For mild COPD exacerbations, start date will be defined as the onset of worsened symptoms 
as recorded by the subject in the eDiary, and the stop date will be defined as the last day of 
worsened symptoms.  In order to ensure that the same event is not counted twice, mild COPD 
exacerbations with start and stop dates equal to or less than 7 days apart will be considered 
the same event.  
In addition, in order to not double count exacerbations that are moderate or severe, eDiary 
data from dates within 7 days of a moderate or severe exacerbation will not be included as 
additional mild COPD exacerbations.  This implies that continuing worsened symptoms that 
meet the definition of a mild exacerbation would need to be present at least 2 days prior to 
the 7-day period immediately preceding the start date of a moderate or severe COPD 
exacerbation in order to be considered a separate event.  Similarly, worsened symptoms 
would need to be present for at least 2 days after the 7-day period immediately following a 
moderate or severe COPD exacerbation to be considered a separate event.  
9.5.4
Exacerbations of Chronic Pulmonary Disease Tool (EXACT)
The EXACT is a 14-item PRO daily diary which will be used to measure the effect of 
treatment on exacerbations, and on the severity of respiratory symptoms.  The E-RS is an 
11-item subset which will be used to measure the effect of treatment on the severity of 
respiratory symptoms.  Mean change from baseline in: the daily EXACT Total Score, the 
daily total symptom score (RS-Total Score), as well as 3 subscale scores, RS-Breathlessness, 
RS-Cough and Sputum, and RS-Chest Symptoms, will be calculated over each 4-week 
interval of the 52-week Treatment Period.  The last 7 days of the Screening Period from lead-
in Study PT010006 will be used to calculate the baseline.  The mean change from baseline 
in RS-Total Score, RS-Breathlessness, RS-Cough and Sputum, and RS-Chest Symptoms will 
be summarized by treatment group over 52 weeks and over each post-randomization 4-week 
interval (Interval 1 to Interval 13). 
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Version 2.0, 
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 or 
Independent Ethics Committee Approval 
The study will be conducted in accordance with Good Clinical Practice (GCP).  These 
standards respect the following guidelines: 
• 
Guideline for Good Clinical Practice E6 (R1):  Consolidated Guideline (International 
Conference on Harmonization of Technical Requirements for the Registration of 
Pharmaceuticals for Human Use, May 1996). 
•
US 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/Patient Records
By signing this protocol, the Investigator agrees that Pearl (or representative), IRB/IEC, or 
Regulatory Agency representatives may consult and/or copy study documents in order to 
verify worksheet/case report form data.  By signing the consent form, the subject/patient 
agrees to this process.  If study documents will be photocopied during the process of 
verifying worksheet/case report form information, the subject/patient will be identified by 
unique code only; full names/initials will be masked prior to transmission to Pearl.  In 
addition, the Investigator agrees to treat all subject data used and disclosed in connection 
with this study in accordance with all applicable laws (i.e., Health Insurance Portability and 
Accountability Act), rules and regulations. 
10.6
Quality Control and Assurance
Pearl is responsible for implementing and maintaining quality control and quality assurance 
systems with written SOPs to ensure that Studies 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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Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
10.8 Study Monitoring 
In accordance with applicable regulations, GCP, and Pearl procedures, clinical monitors will 
contact the site prior to subject enrollment to review the protocol and data collection 
procedures with site staff.  In addition, the monitor will periodically contact the site, 
including conducting on-site visits.  The extent, nature, and frequency of on-site visits will be 
based on such considerations as the study objective and/or endpoints, the purpose of the 
study, study design complexity, and enrollment rate. 
During these contacts, the monitor will:
•
Check the progress of the study 
•
Review study data collected
•
Conduct source document verification 
•
Identify any issues and address their resolution 
This will be done in order to verify that the: 
•
Data are authentic, accurate, and complete
•
Safety and rights of subjects are being protected
•
Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements 
The Investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues.
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the Investigator or site staff, as appropriate:
•
Return of all study data to Pearl 
•
Data queries 
•
Accountability, reconciliation, and arrangements for unused investigational 
product(s) 
•
Review of site study records for completeness
After the final review of the study files, the files should be secured for the appropriate time 
period as specified in Section 10.9. The Investigator will also permit inspection of the study 
files by Pearl’s Quality Assurance auditors, and authorized representatives of the FDA or 
other applicable regulatory agencies.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
10.9 Retention of Data 
Documents that individually and collectively permit evaluation of the conduct of the study 
and the quality of the data produced must be maintained for review by Pearl’s quality 
assurance auditors and by all applicable regulatory authorities.  The period of time these 
documents must be maintained is governed by applicable regulations.  Pearl or its designee 
will inform the Investigator when these documents may be destroyed.  Pearl or its designee 
must be notified in writing at least 6 months prior to the intended date of disposal of any 
study record related to this protocol to allow Pearl to make alternate storage arrangements.
10.10 
Financial Disclosure 
The Principal Investigator or sub-Investigators named on the Form FDA 1572 or the locally 
accepted alternate Investigator Statement form, 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. 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 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
review, 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. 
3. 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. 
4. 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, e.g., protocol and amendments, data tabulations.  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.
5. Reporting of Clinical Trial 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 Study, and to facilitate reader understanding of the Study design, 
conduct, analysis and interpretation, and to support their ability to assess the validity of 
its results.
6. 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 (e.g., EUdraCT; https://eudract.ema.europa.eu).  Per AstraZeneca 
policy, Pearl posts clinical study protocols for public viewing when a manuscript is 
published in a medical journal.  Prior to being made public, the protocol is reviewed by 
AstraZeneca Intellectual Property.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
12 APPENDICES
Appendix 1 
Dose Indicator Reading 
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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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
•
The Dose indicator number will continue to change after every 20 puffs. 
•
When the number in the Dose indicator window changes to 20 and the color behind the 
number changes to red, this means that there are only 20 puffs left in your inhaler. See 
Figure 2d.
Figure 2d
Preparing the Inhaler for Use: 
The inhaler comes in a foil pouch that contains a drying packet (desiccant).
•
Take the inhaler out of the foil pouch. 
•
Throw away the pouch and the drying packet.  Do not eat or inhale the contents of the 
drying packet.  
•
Remove the Cap from the Mouthpiece as shown in Figure 3.  
Figure 3
Figure 2b
110 puffs
Figure 2a
120 puffs
Figure 2c
100 puffs
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
Prime the inhaler before you use it for the first time.
Priming the Inhaler:
•
Check inside the Mouthpiece for objects before use. 
•
Hold the Actuator with the Mouthpiece pointing away from you and others as shown in 
Figure 4a. 
•
Shake the inhaler well before each puff. 
•
Push down fully on the center (not ‘off center’) of the Dose indicator on top of the 
Canister (see Figure 1) until the Canister stops moving in the Actuator to release a 
puff from the Mouthpiece as shown in Figure 4b.  Note:  It is normal to hear a soft click 
from the dose indicator as it counts down during use. 
•
Repeat this priming step 3 more times for a total of 4 times, shaking the inhaler each time 
before you press it. 
•
After completing the 4 priming puffs, your inhaler is now primed ready to use for the first 
time.
You must re-prime your inhaler again if you have not used it in more than 7 days.  Take the 
cap off the mouthpiece and shake and spray the inhaler 2 times into the air away from your 
face.
Using the Inhaler:
Your dose of medicine comes from 2 puffs from the inhaler. 
Refer to Figure 5 for Step 1 through Step 8. 
•
Step 1: Remove the Cap from the Mouthpiece. 
•
Step 2: Shake the inhaler well before each puff.
•
Step 3: While holding the inhaler with the Mouthpiece pointing towards you breathe out 
through your mouth to empty as much air from your lungs as possible. 
Figure 4a
Figure 4b
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
•
Step 4:  Close your lips around the Mouthpiece and tilt your head back slightly to make 
sure your tongue is away from the Mouthpiece. 
•
Step 5: Take a deep breath in (inhale) slowly through your mouth while pressing down 
firmly on the center (not ‘off center’) of the Dose indicator until the Canister stops 
moving in the Actuator and a puff has been released. Then, stop pressing the Dose 
indicator.
•
Step 6: When you have finished breathing in, remove the Mouthpiece from your mouth 
and hold your breath for 10 seconds or as long as comfortable.    
•
Step 7:  Then, breathe out normally. 
Take your second puff of medicine by repeating Step 2 through Step 7.  
•
Step 8: Replace the Cap back on the Mouthpiece.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
Figure 5 
How to clean the Inhaler: 
It is very important to keep your inhaler clean so medicine will not build-up and block the 
spray through the Mouthpiece.  See Figure 6.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
Figure 6
The Canister should be gently pulled from the top of the Actuator once a week and the 
Actuator cleaned.  Do not clean the Canister or let it get wet.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
•
Step 1: Pull the Canister out of the Actuator as shown in Figure 7.
Figure 7
•
Step 2:  Set the Canister aside where it will not get wet.
•
Step 3: Take the Cap off the Mouthpiece.
•
Step 4:  Rinse the Actuator through the top with warm running water for 30 seconds.  
Then rinse the actuator again through the Mouthpiece (see Figure 8). 
Figure 8
•
Step 5:  Shake all of the water droplets out of the Actuator. 
•
Step 6: Look in the Actuator and the Mouthpiece to make sure it is clean and clear.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
Repeat Step 4 through Step 6, until the Actuator and the Mouthpiece are clean and clear.
•
Step 7: Let the Actuator dry completely, such as overnight as shown in Figure 9. Do 
Not put the Canister back into the Actuator if it is still wet.
Figure 9
Reassembly of the Inhaler and Instructions for Use after Cleaning:
•
After the Actuator is completely dry, gently press the Canister down in the Actuator as 
shown in Figure 10. It is not necessary to press down on the Canister hard enough to 
cause a puff to be released.
Figure 10
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
•
Re-prime your inhaler 2 times after each cleaning.
•
Hold the Actuator with the Mouthpiece pointing away from you and others as shown in 
Figure 4. 
•
Shake the inhaler well before each puff. 
•
Push down fully on the center (not ‘off center’) of the Dose indicator on top of the 
Canister until the Canister stops moving in the Actuator to release a puff from the
Mouthpiece. 
•
Repeat this re-priming step 1 more time for a total of 2 times.
•
After re-priming your inhaler 2 times, your inhaler is now ready to use. 
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
Appendix 3 
Instructions for Use of Ventolin HFA Inhalation Aerosol 
Device 
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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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
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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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
Figure C
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
Figure D
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.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
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.
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.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
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.
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.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
Figure H
Step 10. Turn the actuator upside down and run warm water through the mouthpiece for 
about 30 seconds. See Figure I.
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.
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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
Figure J
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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Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc. 
Clinical Trial Protocol:  PT010008-01
Version 2.0, 
Appendix 6 
Investigator’s Signature 
Study Title:
A Randomized, Double-Blind, Parallel-Group, 52-Week, Chronic-
Dosing, Multi-Center Study to Assess the Safety and Tolerability of 
PT010, PT009 and PT003 in Subjects with Moderate to Very Severe 
Chronic Obstructive Pulmonary Disease 
Study Number:
PT010008-01
Final Date:
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. (hereafter referred to as Pearl)
•
Not to implement any changes to the protocol without agreement from Pearl and prior 
review and written approval from the Institutional Review Board/Independent Ethics 
Committee, 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 and all applicable 
regulatory requirements
•
That I am thoroughly familiar with the appropriate use of the investigational product(s), 
and other information provided by Pearl including, but not limited to, the following: the 
protocol and the current Investigators 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 with any necessary information regarding ownership interest and financial 
ties; to promptly update this information if any relevant changes occur during the course of 
the study and for 1 year following completion of the study; and agree that Pearl may 
disclose any information it has about such ownership interests and financial ties to 
regulatory authorities
•
I agree to report all information or data in accordance with the protocol and any other 
study conduct procedures provided by Pearl
•
That since the information in this protocol and IB is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or 
conduct of the study is prohibited
•
To accurately transfer all required data from each subject’s source document to the 
electronic case report forms (eCRFs).  The eCRFs will be provided to Pearl in a timely 
manner at the completion of the study, or as otherwise specified by Pearl
•
To allow authorized representatives of Pearl or regulatory authority representatives to 
conduct on-site visits to review, audit, and copy study documents.  I will personally meet 
with these representatives to answer any study-related questions
Signature: 
 
Date: 
 
Name:  
 
 
 
 
 
 
 
 
 
 
 
 
Affiliation:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential and Proprietary
Page 112 of 112

SAP_001.pdf: 
 
Statistical Analysis Plan 
 
Study Code 
PT010008 
NCT#  
NCT03313570 
Date 
17 JULY 2017 
 
 
 
 
 
 
 
 
 
 
  A Randomized, Double-Blind, Parallel-Group, 52-Week, Chronic- 
Dosing, Multi-Center Study to Assess the Safety and Tolerability of PT010, 
PT009, and PT003 in Subjects with Moderate to Very Severe Chronic 
Obstructive Pulmonary Disease 
 
 
 


 
Statistical Analysis Plan 
Protocol No.:  PT010008 
Date:  17 Jul 2017 
(Page 1 of 77)
 
 
STATISTICAL ANALYSIS PLAN FOR 
STUDY PT010008 
 
 
Protocol Number: 
PT010008 
 
 
Investigational Drug 
and Drug Number: 
BGF MDI; PT010 
GFF MDI; PT003 
BFF MDI; PT009
Indication: 
COPD 
Dosage Form/Dose: 
 BGF MDI 320/14.4/9.6 μg ex-actuator BID 
 GFF MDI 14.4/9.6 μg ex-actuator BID 
 BFF MDI 320/9.6 μg ex-actuator BID 
 
PT010008 Protocol Title: A Randomized, Double-Blind, Parallel-Group, 52-Week, Chronic-
Dosing, Multi-Center Study to Assess the Safety and Tolerability of PT010, PT009, and PT003 
in Subjects with Moderate to Very Severe Chronic Obstructive Pulmonary Disease 
 
 
Date of Issue: 
17 Jul 2017 
 
Version: 
Version 1.0 
 
 






 
Statistical Analysis Plan 
Protocol No.:  PT010008 
Date:  17 Jul 2017 
(Page 4 of 77)
 
 
Change Log 
Version No. 
Effective Date 
Reason for the Change / Revision 
Supersedes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Protocol No.:  PT010008 
Date:  17 Jul 2017 
(Page 5 of 77)
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ..................................................................................................................................... 14 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................ 14 
2.1 
STUDY OBJECTIVES ............................................................................................................................ 14 
2.1.1 
Primary Objectives ............................................................................................................. 14 
2.1.2 
Secondary Objectives ......................................................................................................... 14 
2.2 
STUDY ENDPOINTS ............................................................................................................................. 14 
2.2.1 
Bone Mineral Density Endpoints ........................................................................................ 14 
2.2.1.1 
Primary Bone Mineral Density Endpoint: .......................................................... 14 
2.2.1.2 
Other BMD Endpoints: ...................................................................................... 14 
2.2.2 
Ocular Endpoints ................................................................................................................ 15 
2.2.2.1 
Primary Ocular Endpoint ................................................................................... 15 
2.2.2.2 
Other Ocular Endpoints ..................................................................................... 15 
2.2.3 
Safety Endpoints ................................................................................................................. 15 
2.2.4 
Efficacy Endpoints ............................................................................................................. 15 
3. 
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS ............................................................. 16 
3.1.1 
Overall Study Design and Plan ........................................................................................... 16 
3.1.2 
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other Restrictions (if 
applicable) .......................................................................................................................... 18 
3.2 
HYPOTHESIS TESTING ........................................................................................................................ 18 
3.3 
INTERIM ANALYSIS ............................................................................................................................ 19 
3.4 
SAMPLE SIZE ...................................................................................................................................... 19 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE ........................................................................ 19 
5. 
ANALYSIS POPULATIONS ................................................................................................................... 20 
5.1 
POPULATION DEFINITIONS ................................................................................................................. 20 
5.1.1 
Safety Population ................................................................................................................ 20 
5.1.2 
BMD Analysis Population .................................................................................................. 20 
5.1.3 
Ophthalmologic Analysis Population ................................................................................. 20 
5.1.4 
mITT Population ................................................................................................................. 21 
6. 
STATISTICAL ANALYSIS ..................................................................................................................... 21 
6.1 
DATA HANDLING RULES AND DEFINITIONS, INCLUDING HANDLING OF MISSING DATA .................... 21 
6.2 
SUBJECT DISPOSITION AND ANALYSIS POPULATIONS ........................................................................ 22 
6.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS AND EXTENT OF EXPOSURE ................................. 23 
6.3.1 
Demography, Physical Characteristics, Baseline ................................................................ 23 
6.3.2 
COPD History, Screening/Baseline .................................................................................... 24 
6.3.3 
Medical and Surgical History at Screening, Reproductive Status and Pregnancy Testing . 25 
6.3.4 
Prior, Concomitant, and Post-Treatment Medications/Treatments ..................................... 25 
6.3.5 
Extent of Exposure to Study Medication and Compliance ................................................. 26 
6.4 
SAFETY ANALYSES ............................................................................................................................ 27 
6.4.1 
Bone Mineral Density Analyses ......................................................................................... 27 
6.4.1.1 
Percent Change from Baseline in BMD of the Lumbar Spine Measured Using 
DEXA Scans of L2-L4 ....................................................................................... 28 
6.4.1.2 
Percent Change from Baseline in Total Hip BMD of the Hip Measured Using 
DEXA Scans ...................................................................................................... 28 


 
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6.4.2 
Ocular Analyses .................................................................................................................. 29 
6.4.2.1 
Change from Baseline in Each of the LOCS III (P, NO, NC, and C) Scores ..... 29 
6.4.2.2 
Proportion of Subjects with LOCS III Grade Increases of ≥ 0.5 (Class 1), ≥ 1.0 
(Class 2), or ≥ 1.5 (Class 3) Units in Each of the 4 Scales ................................. 30 
6.4.2.3 
Change from Baseline in Intraocular Pressure ................................................... 30 
6.4.2.4 
Proportion of Subjects with IOP ≥ 22 mmHg and the Proportion of Subjects 
with Change from baseline in IOP of ≥ 7 mmHg .............................................. 30 
6.4.2.5 
Change from Baseline in LogMAR Visual Acuity Using ETDRS Charts ......... 30 
6.4.2.6 
Change from Baseline in Horizontal Cup-to-disc Ratio .................................... 30 
6.4.2.7 
Incidence of Ocular TEAEs including Cataract and Glaucoma ......................... 30 
6.4.3 
Adverse Events ................................................................................................................... 30 
6.4.3.1 
Adverse Events of Special Interest .................................................................... 33 
6.4.3.2 
MACE Events Determined by Clinical Endpoint Committee ............................ 35 
6.4.3.3 
Pneumonia Events Determined by Clinical Endpoint Committee ..................... 35 
6.4.3.4 
Cause of Death Determined by Clinical Endpoint Committee .......................... 35 
6.4.4 
Clinical Laboratory Measurements ..................................................................................... 36 
6.4.5 
Vital Signs .......................................................................................................................... 40 
6.4.6 
12-Lead Electrocardiogram Measurements ........................................................................ 42 
6.4.7 
Physical Examination ......................................................................................................... 44 
6.4.8 
Control of Type I Error ....................................................................................................... 44 
6.5 
EFFICACY ANALYSES ......................................................................................................................... 44 
6.5.1 
Rescue Ventolin HFA Use .................................................................................................. 44 
6.5.2 
Percentage of Days with No Rescue Ventolin HFA Use over the Treatment Period ......... 44 
6.5.3 
Chronic Obstructive Pulmonary Disease Exacerbations..................................................... 45 
6.5.4 
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) .......................................... 50 
6.5.5 
Baselines and Baseline Covariates for Analysis: ................................................................ 50 
6.5.6 
Visits and Time Windows for Visit-Based Efficacy Assessments: .................................... 50 
7. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................... 51 
8. 
STATISTICAL SOFTWARE ................................................................................................................... 51 
9. 
REFERENCES .......................................................................................................................................... 52 
APPENDIX 1: DATA HANDLING RULES .................................................................................................... 53 
APPENDIX 2: ANALYSIS DATASET SPECIFICATIONS .......................................................................... 61 
APPENDIX 3: SAS CODE FOR STATISTICAL ANALYSES ..................................................................... 61 
APPENDIX 4: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES AND CENTRAL 
LABORATORY REFERENCE RANGES FOR USE IN FLAGGING ABNORMAL VALUES .... 61 
APPENDIX 5: STANDARD MEDDRA QUERIES (SMQ) ............................................................................ 61 
APPENDIX 6: TABLE OF CONTENTS FOR END-OF-TEXT TLFS ......................................................... 61 
 
 
 


 
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List of Tables 
Table 1 
Terms for the Assessment of Adverse Events of Special Interest.......................... 33 
Table 2 
Lab Parameters ....................................................................................................... 37 
Table 3 
Analysis Study Time Windows for Clinical Lab Assessments .............................. 38 
Table 4 
Potentially Clinically Significant (PCS) Laboratory Parameter Criteria ............... 40 
Table 5 
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood 
Pressure Parameters ............................................................................................... 41 
Table 6 
Potentially Clinically Significant Criteria for Heart Rate Parameters ................... 41 
Table 7 
Analysis Study Time Windows for Vital Signs Assessments ................................ 42 
Table 8 
Analysis Study Time Window for ECG Assessments ........................................... 43 
Table 9 
Criteria for PCS ECG Values ................................................................................. 43 
 
 


 
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List of Figures 
Figure 1 
Study Design .......................................................................................................... 18 
Figure 2  
Overarching Intervals of Moderate-to-Severe (QMS) and Severe (QS) COPD 
Exacerbations ......................................................................................................... 48 
Figure 3  
Overarching Intervals (I) of Mild-Moderate-or-Severe COPD Exacerbation Events 
Based on e-Diary Symptom Data ........................................................................... 48 
Figure 4  
Overarching Intervals (QQ) of Mild-Moderate-or-Severe COPD Exacerbation 
Events Incorporating Both CRF Data and e-Diary Symptom Data ....................... 49 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
anatomic therapeutic class 
BFF MDI 
Budesonide and Formoterol Fumarate Metered Dose Inhaler 
BGF MDI 
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose 
Inhaler 
BID 
bis in die, twice daily 
bpm 
beats per minute 
BMD 
bone mineral density 
BMI 
body mass index 
C 
cortical cataract 
CAT 
Chronic Obstructive Pulmonary Disease Assessment Test 
CCV 
cardio- and cerebrovascular 
CEC 
Clinical Endpoint Committee 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
cm 
centimeter 
COPD 
chronic obstructive pulmonary disease 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
diastolic blood pressure 
DEXA 
dual energy x-ray absorptiometry 
DMC 
data monitoring committee 
DMP 
data management plan 


 
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E-RS 
EXACT Respiratory Symptoms 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic Diary 
e.g. 
exempli gratia; for example 
EoT 
end of treatment 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ex-actuator 
dose delivered from the actuator (i.e., mouthpiece) of the MDI  
EXACT 
Exacerbations of Chronic Pulmonary Disease Tool – Patient Reported 
Outcomes 
EXACT-RS 
Exacerbations of Chronic Pulmonary Disease Tool – Patient Reported 
Outcomes- Respiratory Symptoms 
GFF MDI 
Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler 
GGT 
gamma glutamyl transferase 
hCG 
human chorionic gonadotropin 
HFA 
hydrofluoroalkane 
HLGT 
High Level Group Term 
HLT 
High Level Term 
HR 
heart rate 
ICF 
informed consent form 
ICS 
inhaled corticosteroid 
i.e. 
id est; that is 
IOP 
intraocular pressure 
IWRS 
interactive web response system 
L 
liter 
LOCS III 
Lens Opacities Classification System III 
LogMAR 
logarithm of the minimum angle of resolution 
MACE 
major adverse cardiovascular event 


 
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MCID 
minimal clinically important difference 
MDI 
metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MNAR 
missing not at random 
µg 
microgram 
mITT 
modified intent-to-treat  
mL 
milliliter 
mm 
millimeter 
mmHg 
millimeter of mercury 
msec (ms) 
millisecond 
NC 
nuclear color 
NO 
nuclear opalescence 
OTC 
over-the-counter 
P 
Posterior subcapsular 
PCS 
potentially clinically significant 
PT 
preferred term 
PT003 
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol 
PT009 
Budesonide and Formoterol Fumarate Inhalation Aerosol 
PT010 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation 
Aerosol 
QA 
quality assurance 
QC 
quality control 
QTcF 
QT corrected using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 


 
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SD 
standard deviation 
SMQ 
Standard MedDRA Query 
SOC 
system organ class 
SOP 
standard operating procedure 
TC 
telephone call 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO-DD 
World Health Organization Drug Dictionary 


 
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Trademark Information 
Trademarks Not Owned By Pearl 
SAS 
Ventolin 
 


 
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Date:  17 Jul 2017 
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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and 
analysis of data to be performed at the end of Pearl Therapeutics, Inc. (Pearl) Study PT010008. 
The SAP should be read in conjunction with the study protocol and the electronic Case Report 
Forms (eCRFs) for the study. This version of the SAP has been developed using the PT010008-
01 Amended Protocol (Version 2.0 dated 18 March 2016) and the PT010008 CRFs (Revision 0.0 
dated 06 August 2015). 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objectives 
 To evaluate the effect of BGF MDI, GFF MDI, and BFF MDI on bone mineral density 
(BMD) over 52 weeks. 
 To evaluate the effect of BGF MDI, GFF MDI, and BFF MDI on ocular assessments over 52 
weeks. 
2.1.2 
Secondary Objectives 
 To assess the safety and tolerability of BGF MDI, GFF MDI, and BFF MDI over 52 weeks. 
2.2 
Study Endpoints 
All assessments are relative to baseline assessments performed during the Study PT010006 
Screening Period (between Visit 1 and Visit 4). 
2.2.1 
Bone Mineral Density Endpoints 
2.2.1.1 
Primary Bone Mineral Density Endpoint: 
 Percent change from baseline in BMD of the lumbar spine measured using Dual Energy X-
ray Absorptiometry (DEXA) scans of L2-L4 at Week 52. 
 
2.2.1.2 
Other BMD Endpoints: 
 Percent change from baseline in total hip BMD measured using DEXA scans at Week 52 and 
at End of Treatment (EoT). 
 Percent change from baseline in BMD of the lumbar spine measured using DEXA scans of 
L2-L4 at EoT. 


 
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2.2.2 
Ocular Endpoints 
2.2.2.1 
Primary Ocular Endpoint 
 Change from baseline in the Lens Opacities Classification System III (LOCS III) (P) Score 
(Severity of Posterior Subcapsular Cataract) at Week 52. 
2.2.2.2 
Other Ocular Endpoints 
 Change from baseline in each scale of the LOCS III scores at Week 28, Week 52 (Nuclear 
Opalescence [NO], Nuclear Color [NC], and Cortical Cataract [C] only), and EoT (the last 
available time point). 
 Proportion of subjects with LOCS III grade increases of ≥ 0.5 (Class 1), ≥ 1.0 (Class 2), or ≥ 
1.5 (Class 3) units in each of the 4 scales at Week 28, Week 52, and EoT. 
 Change from baseline in intraocular pressure (IOP) at Week 28, Week 52, and EoT. 
 Proportion of subjects with IOP ≥ 22 mmHg at Week 28, at Week 52, and EoT. 
 Proportion of subjects with change from baseline in IOP of ≥ 7 mmHg at Week 28, at Week 
52, and EoT. 
 Change from baseline in the Logarithm of the Minimum Angle of Resolution (LogMAR) 
visual acuity using Early Treatment Diabetic Retinopathy Study (ETDRS) charts at Week 28, 
Week 52, and EoT. 
 Change from baseline in horizontal cup-to-disc ratio at Week 28, Week 52, and EoT. 
 Incidence of ocular treatment emergent adverse events (TEAEs) including cataract and 
glaucoma. 
2.2.3 
Safety Endpoints 
The safety endpoints include: 
 Adverse events (AEs). 
 12-lead electrocardiograms (ECGs). 
 Clinical laboratory testing. 
 Vital signs measurements. 
 
2.2.4 
Efficacy Endpoints 
 Change from baseline in average daily rescue Ventolin (albuterol sulfate) hydrofluoroalkane 
(HFA) use. 
 Percentage of days with no rescue Ventolin HFA use. 
 Rate of moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations. 


 
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 Rate of COPD exacerbations of any severity. 
 Rate of Severe COPD exacerbations 
 Change from baseline in: the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) 
total score, the 11-item EXACT Respiratory Symptoms (E-RS) Total Score (RS-Total 
Score), as well as 3 subscale symptom scores (RS-Breathlessness, RS-Cough and Sputum, 
and RS-Chest Symptoms) over 52 weeks and over each 4-week interval of the 52-week 
Treatment Period. 
 
3. 
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS 
3.1.1 
Overall Study Design and Plan 
This is a multi-center, randomized, double-blind, parallel-group, chronic-dosing (52 weeks), 
supplemental study to assess the effects of PT010, PT009, and PT003 on BMD, ocular 
assessments, and safety and tolerability in subjects with moderate to very severe COPD. 
This 52 week study will be conducted in a sub-set of US subjects who completed the 24-week 
PT010006 study. The study is to be conducted at approximately 70 sites, contributing 
approximately 8 subjects per site. Across these sites, approximately 500 subjects randomized to 
double blind treatment will be included in Study PT010008 to provide approximately 425 
subjects to complete the study at Visit 14 (Week 52). Subjects will receive the same treatment 
(BGF MDI, GFF MDI, or BFF MDI) they were randomized to in Study PT010006. 
This safety study will evaluate the effects of BGF MDI, BFF MDI, and GFF MDI on BMD 
measurement, lenticular opacity, and ocular pressure assessments. 
Baseline and demographic characteristics collected in Study PT010006 will be used for subjects 
participating in this study. Baseline assessments (BMD, lenticular opacity, fundoscopic 
examination, intraocular pressure, pupil dilatation, and visual acuity assessments) will be 
performed prior to randomization in Study PT010006. If the first two BMD scans differ by more 
than 5% (as determined by the local facility) for either site (i.e. first two hip or first two lumbar 
sites) a third scan should be obtained. The screening period may be extended up to a maximum 
of 21 additional days if additional time is needed to complete the assessments. 
Subjects who complete visit 10a of Study PT010006 will transition to the remaining 28 weeks of 
treatment by completing Visit 10b (Week 24). Post-baseline lenticular opacity, fundoscopic 
examination, intraocular pressure, and visual acuity assessments will be performed prior to Visit 
11 (Week 28) and Visit 14 (Week 52) or Treatment Discontinuation/Withdrawal Visit. A post-
baseline BMD assessment will be performed prior to Visit 14 (Week 52) or Treatment 
Discontinuation/Withdrawal Visit. Subjects will return to the clinic at Visit 12 (Week 36), and 
Visit 13 (Week 44) to complete the required study procedures, return used medication and obtain 
new study drug. Subjects will return to the clinic at Visit 14 (Week 52) to complete the final 
study visit procedures. 


 
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Date:  17 Jul 2017 
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All subjects will continue to receive sponsor-provided Ventolin
 HFA for rescue use throughout 
the study. 
After Visit 14 (Week 52), a follow-up telephone call (TC) will be performed at least 14 days 
after the last study drug dose. For subjects who withdraw consent, a follow-up telephone call will 
be scheduled at least 14 days after the last dose of study drug unless the final visit was performed 
>14 days post the last study dose.  
If a subject chooses not to continue with study assessments, at a minimum the subject will 
complete the Treatment Discontinuation/Withdrawal Visit (refer to Protocol Table 8-1). For 
subjects discontinuing treatment at any time during the study, including the time during which 
they are participating in Study PT010006, lenticular opacity, fundoscopic examination, 
intraocular pressure, pupil dilation and visual acuity assessments should be performed as soon as 
possible. For subjects discontinuing treatment after Visit 10b (Week 24), BMD assessments 
should also be obtained as soon as possible (Note: Subjects who discontinue prior to Visit 10b 
will not complete BMD assessments). These subjects will return to appropriate maintenance 
COPD medications, per the investigators discretion. These subjects will be followed for vital 
status at 52 weeks post-randomization in accordance with the informed consent. 
The Schedules of Events and Timed Assessments are in the study protocol. 
The overall study design is summarized and illustrated in Figure 1. 
 
 


 
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Date:  17 Jul 2017 
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Figure 1 
Study Design 
 
Abbreviations: BFF = Budesonide and Formoterol Fumarate; BGF = Budesonide, Glycopyrronium, and Formoterol Fumarate; 
BID = bis in die, twice daily; BMD = Bone Mineral Density; EOS = End of Study; GFF = Glycopyrronium and Formoterol 
Fumarate; MDI = metered dose inhaler; TBH = Turbuhaler; V = visit; W = week. 
 
3.1.2 
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other 
Restrictions (if applicable) 
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 eCRF. All 
concomitant medications taken during the study will be recorded on the Concomitant 
Medications eCRF page with indication, total daily dose, dose regimen, and dates of drug 
administration. Refer to the Protocol for information about prohibited medications. 
3.2 
Hypothesis Testing 
Hypothesis testing for change from baseline in LOCS III (P) scores at Week 52 is as follows. 
The primary null (H0) and alternative (H1) hypotheses with µ representing the mean are: 
 H0: µBGF ≥ µGFF + 0.5  
H1: µBGF < µGFF + 0.5 


 
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 H0: µBFF ≥ µGFF + 0.5 
H1: µBFF < µGFF + 0.5 
Hypothesis testing for percent change from baseline in lumbar spine BMD scores is as follows. 
The primary null (H0) and alternative (H1) hypotheses with  representing the percent treatment 
difference are: 
 H0: BGF-GFF ≤ -2  
H1: BGF-GFF > -2 
 H0: BFF-GFF ≤ -2  
H1: BFF-GFF > -2 
3.3 
Interim Analysis 
No interim analyses are planned for this study. 
The Data Monitoring Committee (DMC) that was initiated in Study PT010006 will also provide 
systematic and unbiased assessment of safety for Study PT010008 and will review safety data 
approximately every 6 months. Further detail is given in the DMC Charter. 
3.4 
Sample Size 
 
 
 
 
 
 
 
 
 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE 
The overall quality assurance procedures for the study data, statistical programming and analyses 
are described in Standard Operating Procedures (SOPs) of 
. Detailed 
data management procedures are documented in the study Data Management Plan (DMP), Data 
Validation Check Specifications, and Integrated Safety Data Review Plan. Detailed statistical 
and programming quality control and quality assurance procedures are documented in the 
Statistical Analysis and Programming QC/QA Plan. 


 
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5. 
ANALYSIS POPULATIONS 
5.1 
Population Definitions 
5.1.1 
Safety Population 
The Safety Population is defined as all subjects who signed informed consent for PT010008 (i.e. 
have a non-missing PT010008 informed consent date) and received any amount of study 
treatment (other than Symbicort). Subjects will be analyzed according to treatment received 
rather than randomized. If a subject received more than one study treatment, they will be 
analyzed and included in summaries according to the treatment they received the most. Subjects 
who received no study treatment will be excluded, as will subjects who have no post-dose safety 
assessments. A subject who used a study treatment but took less than one full dose of treatment 
will qualify for this population. 
The PT010008 Safety Population is defined as all subjects in the Safety Population who met the 
PT010008 continuing eligibility criteria at Visit 10b or who attended at least one of Visits 11, 12, 
13, or 14. Tabulations for the PT010008 Safety Population will use information only on or after 
(the date of) Visit 10b. 
5.1.2 
BMD Analysis Population 
The BMD Analysis Population is defined as all evaluable subjects in the Safety Population who 
have a baseline BMD assessment and at least one on-treatment BMD assessment. Subjects will 
be analyzed according to actual treatment received. 
A reason for exclusion from the BMD Analysis Population will include, but is not limited to, the 
following: 
 Subjects received treatment with a post-baseline bisphosphonate medication. 
Further criteria may be established at the BDRM (Blinded Data Review Meeting). 
5.1.3 
Ophthalmologic Analysis Population 
The Ophthalmologic Analysis Population is defined as all evaluable subjects who have a 
baseline ophthalmologic assessment and at least one on-treatment ophthalmologic assessment. 
This may possibly include some subjects who have not met the criteria for inclusion in the Safety 
Population but who have post-baseline ophthalmologic assessments prior to Visit 10b. Subjects 
will be analyzed according to actual treatment received. 
 
A reason for exclusion from the Ophthalmologic Analysis Population will include, but is not 
limited to, the following: 
 Subjects underwent a cataract extraction surgery (artificial ocular lens implantation). 
 


 
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Further criteria may be established at the BDRM. 
 
5.1.4 
mITT Population 
The mITT Population is defined as the subgroup of mITT subjects from Study PT010006, who 
enrolled in PT010008 (i.e. have a non-missing PT010008 informed consent date) and who 
received any amount of study treatment (other than Symbicort). Subjects will be analyzed 
according to the active treatment they were assigned to at randomization in Study PT010006. 
Data collected from both Study PT010006 and PT010008 will be included (other than Symbicort 
treatment).  
6. 
STATISTICAL ANALYSIS 
PT010008 analyses will be performed when the PT010008 final database is available. 
All data collected contributing to the analysis will be provided in listings. Data for all subjects 
who are randomized will be included in the subject data listings. Data for non-randomized 
subjects will be listed where available. 
All safety, (including but not limited to BMD and ocular) and efficacy parameters will be 
summarized by treatment unless specified otherwise. 
Demographics will be summarized for the Safety Population. Demographics will also be 
summarized for the BMD and Ophthalmologic Analysis Populations if these are different from 
the Safety Population. Analyses of ocular endpoints will be performed on the Ophthalmologic 
Analysis Population, and those of BMD endpoints will be performed on the BMD Analysis 
Population. All other safety analyses will be presented for the Safety Population. Some selected 
adverse event tables (overall summary of AEs, incidence of AEs by SOC, and incidence of SAEs 
by SOC) will also be repeated for the PT010008 Safety Population. Efficacy will be presented 
for the mITT Population. Continuous variables will be summarized with descriptive statistics 
(the number of non-missing values, mean, standard deviation, median, minimum, and 
maximum). Additionally, the 25th and 75th percentiles will be presented when appropriate based 
on historical knowledge of the normality or non-normality distribution of underlying data. 
Categorical variables will be summarized with frequency counts and percentages (where 
appropriate). 
6.1 
Data Handling Rules and Definitions, Including Handling of Missing Data 
Missing data will be maintained as missing in the analysis datasets, unless specified otherwise. 
For variables where missing data are imputed, the analysis dataset will contain a new variable 
with the imputed value and the original variable value will be maintained as missing. 


 
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Data Imputation for Adverse Events Summaries by Severity and Relationship to Study Drug 
For the AE summaries by severity (mild, moderate, or severe), an AE with missing severity will 
be deemed as severe. For the AE summaries by relationship to study drug, an AE with a missing 
relationship to study drug will be deemed as definitely related. Imputed values will not be listed 
in data listings. 
Data Imputation for Laboratory, Vital Sign, and ECG Summaries (Continuous Parameters) 
Data from unscheduled visits will not be used for this analysis, unless a prior or subsequent visit 
is missing where a value was scheduled to be collected. That is, data obtained during 
unscheduled visits will be allocated to the scheduled visit prior to the unscheduled visit (not 
more than 4 weeks prior) if it was missed or to the next missing scheduled visit (not more than 4 
weeks subsequent) if the previous scheduled visit was not missing. 
Protocol Deviations and Criteria for Exclusion from Study Populations 
Reasons subjects were not enrolled in PT010008, including inclusion and exclusion criteria, will 
be tabulated (Table 1.1.3) and listed (Listing 1.4). 
The definitive criteria for study-population exclusions (including the BMD Analysis Population 
and the Ophthalmologic Analysis Population) will be established and documented at the BDRM 
(Blinded Data Review Meeting). 
Data Imputation (All Laboratory Summaries) 
Laboratory values of ‘>=x’ or ‘<=x’ will be taken as the value of x in the analyses. If a 
laboratory value is prefixed with‘>’: the available original value +0.001 will be used for table 
summaries; if a laboratory value is prefixed with ‘<’, then the original value –0.001 will be used 
in table summaries. 
Study Dates and Day of Assessment or Event 
Study Day and Day of Assessment or Event definitions are provided in Appendix 1, Data 
Handling Rules. 
6.2 
Subject Disposition and Analysis Populations 
A disposition table for PT010008 for all subjects randomized in PT010006 will be provided 
(Table 1.1.1). This tabulation will include the number of subjects in each randomized treatment 
who were not treated in PT010006 or PT010008, who received the study treatment in PT010006 
and PT010008, who discontinued treatment prematurely in PT010008, and who completed the 
PT010008 study. The number and percentage of randomized subjects included in the Safety, 


 
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BMD, Ophthalmologic, mITT, and PT010008 Safety Populations will also be tabulated 
(Table 1.1.1). Informed consent is listed in Listing 9.7. 
The numbers of subjects randomized and in the analysis populations will be provided by country, 
center, and treatment in Table 1.1.2. 
A summary of reasons subjects were not enrolled in PT010008 will be provided for all subjects 
screened for PT010008 but not enrolled in PT010008 (Table 1.1.3). A listing of reasons subjects 
were not enrolled in PT010008 will be provided (Listing 1.4). Subjects excluded from the BMD, 
Ophthalmologic and mITT analysis populations will be summarized (Table 1.1.4) for the Safety 
Population. The reason for exclusion from the BMD, Ophthalmologic, and mITT Populations of 
a subject or of partial data (at some but not all time points) for a subject will be listed for the 
Safety Population (Table 1.1.4). Reasons for premature discontinuation from study treatment will 
be summarized for the Safety Population (Table 1.1.5). 
The eligibility information (inclusion/exclusion criteria with any waivers granted) of all subjects 
who are randomized will be listed (Listing 2.1). 
The number and percentage of subjects with changes in smoking status after the start of study 
treatment will be tabulated by study treatment, by visit and overall during the study for the 
Safety Population (Table 1.8.1) (Listing 1.5). 
6.3 
Demographic and Baseline Characteristics and Extent of Exposure 
The definitions for the derived demographic or baseline characteristic variables can be found in 
Appendix 1. 
6.3.1 
Demography, Physical Characteristics, Baseline 
Subject demographics, total CAT score, use of inhaled corticosteroids at screening, and smoking 
status/history will be summarized for the Safety, BMD and Ophthalmologic Analysis 
Populations and for subjects screened for PT010008 but not enrolled in PT010008 (Tables 1.2.1 
through 1.2.4, respectively, and Listing 1.2). Inhaled corticosteroid use (yes/no) will be 
summarized for all populations except for the subjects screened for PT010008 but not enrolled in 
PT010008. 
Demographic and baseline characteristic variables summarized will include the following: 
 Age 
 Age Group 
 Gender 
 Race 
 Ethnicity 


 
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 COPD Assessment Test (CAT) total score and total score category (<10, ≥10, <15, ≥15, <20, 
≥20, Missing) 
 Used inhaled corticosteroids at Screening (all populations except for subjects screened for 
PT010008 but not enrolled in PT010008) 
 Smoking status (current vs. former smoker) 
 Number of years smoked 
 Average number of cigarettes smoked per day 
 Number of pack years smoked, calculated as (number of cigarettes per day/20) x number of 
years smoked 
 Weight 
 Height 
 BMI (body mass index) 
 Baseline BMD (DEXA Scan) t-score (≤-2.5, >-2.5 and ≤-1, >-1) 
 Visual Acuity 
 Fundoscopic Examination (Horizontal Cup-to-Disc Ratio) 
 Intraocular Pressure 
 Whether the subject was taking ophthalmic medications at baseline as eye drops 
 
Screening and pre-treatment CAT data will be listed (Listing 4.2). 
Baseline BMD Endpoints (for all BMD endpoints) will be summarized with descriptive statistics 
for the following two populations: (1) The BMD Analysis Population and (2) Subjects in the 
Safety Population but Not in the BMD Analysis Population (Tables 1.2.5 and 1.2.6). Baseline 
Ophthalmologic Endpoints (for all ophthalmologic endpoints) will be summarized with 
descriptive statistics for the following two populations: (1) The Ophthalmologic Analysis 
Population and (2) Subjects in the Safety Population but Not in the Ophthalmologic Analysis 
Population (Tables 1.2.7 and 1.2.8). 
6.3.2 
COPD History, Screening/Baseline 
Duration of COPD and the number of years prior to the start of study medication that COPD was 
first diagnosed calculated as (Date of First Dose of Study treatment in the study – Date COPD 
First Diagnosed) /365.25 will be summarized for the Safety, BMD, Ophthalmologic and mITT 
Populations by treatment and listed (Tables 1.5.1 and 1.5.2, and Listing 4.1). History of moderate 
or severe COPD exacerbations in the prior year will be summarized and listed (Table 1.4.4, 
Table 1.4.5 and Listing 4.3). 
Severity and duration of COPD will be summarized by treatment and for all subjects for the 
Safety and mITT Populations (Tables 1.3.1 and Table 1.3.2). 


 
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6.3.3 
Medical and Surgical History at Screening, Reproductive Status and Pregnancy 
Testing 
Medical and Surgical History at Screening will be summarized for the Safety Population and 
listed for the Safety Population (Table 1.4.1, and Listing 4.4). Cardiovascular medical history of 
interest at Screening will be summarized for the Safety Population and listed for the Safety 
Population (Table 1.4.2 and Listing 4.5). Ophthalmic history of interest at Screening will be 
summarized for the Safety Population and listed for the Safety Population (Table 1.4.3 and 
Listing 4.6). 
Screening Reproductive Status and Pregnancy Testing Results will be listed (Listing 4.7). 
Subjects’ history of moderate and severe COPD exacerbations within the past 12 months will be 
summarized for the Safety Population and mITT Population (Table 1.4.4 and Table 1.4.5 
respectively). 
6.3.4 
Prior, Concomitant, and Post-Treatment Medications/Treatments 
All prescription and OTC medications taken by the subject during 30 days before Screening will 
be recorded on the Concomitant Medications case report form (CRF) page. 
Coding: Verbatim medication/treatment terms will be coded by
 and 
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 (version: 
3Q2016 or later). 
Multiple ATC assignments: If there are multiple ATC codes assigned to the same concomitant 
medication, the “primary” one based on a Pearl medical evaluation will be used. All prior 
medication taken by the subject within 30 days of Screening for the study and all concomitant 
therapy taken by the subject while on study will be recorded in the eCRF. 
Prior medication/treatment is any medication/treatment taken prior to study treatment, even if 
this medication continued to be taken on the day of the start of study treatment in the study or 
afterward (Appendix 1). 
Concomitant medication/treatment is any medication/treatment reported as being taken after 
the start of the study treatment in the study to the date prior to the last dose of study treatment for 
the subject. A medication with an onset date on or after the last dose of study treatment for the 
subject will not be considered concomitant, but will be considered a Post-Treatment 
medication/treatment. 
Any medication/treatment which cannot be identified as Prior, Concomitant, or Post-Treatment 
will be considered as being in each of the categories that are possible from the available 
information. 


 
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Concomitant COPD and Non-COPD related medications/treatments will be summarized by 
preferred term and actual treatment received for the Safety Population (Tables 1.6.1 and 1.6.2). 
Prior, concomitant/post-treatment COPD and Non-COPD medications will be displayed in 
separate listings (Listings 4.7 and 4.8, respectively). 
Reported Prior Medication for COPD and non-COPD-Related Medications will be tabulated for 
the Safety Population (Tables 1.5.1 and 1.5.2) and listed separately (Listings 4.8 and 4.9, 
respectively). 
Prior COPD Medications will be tabulated (for the Safety population) for subjects having 
received any one, two, all three, or none of the following treatments for at least 30 days prior to 
screening: (1) a muscarinic antagonist, (2) a β2 agonist, and (3) an inhaled corticosteroid (Table 
1.5.3). Tabulations for long-acting muscarinic antagonists and long-acting β2 agonists will also 
be included. 
6.3.5 
Extent of Exposure to Study Medication and Compliance 
Subject’s exposure to a study treatment will be determined by the duration of time (days) for 
which the doses were administered, defined as “([End date of treatment – Date of first dose of 
treatment] + 1)”. Percent compliance is defined as (total number of puffs of study treatment 
taken on a study day/total expected puffs taken on a study day) averaged across all days of a 
subject’s dosing between start of study treatment and last day on study treatment) x 100. The 
expected number of puffs for a test day which is the last date of treatment will be 2, and the 
expected number of puffs for the last date of treatment which is not a test day will be 4 when a 
PM dose is taken but will be 2 otherwise; the expected number of puffs on dates prior to the last 
date of treatment will be 4. 
 
The number of days of exposure to study treatment will be summarized for each treatment for the 
Safety Population (Table 1.7.1). The total person-years of exposure for a treatment group, 
defined as the total exposure in the study across all subjects on the treatment, will also be 
provided by treatment. The number and percent of subjects with exposure >= 24 weeks and >=48 
weeks will also be tabulated. 
 
In addition, a summary of treatment compliance will be provided. The treatment compliance will 
be categorized into 7 different groups depending on the degree of compliance: 0 – <20%, ≥20 – 
<40%, ≥40 – <60%, ≥60 – <80%, ≥80 – ≤100%, >100 – ≤120%, and >120% (Table 1.7.1 for the 
Safety Population). Descriptive statistics (n, mean, standard deviation, median, minimum and 
maximum) for percent compliance by treatment will also be provided. Treatment compliance 
will be reported in Listing 5.3. A listing of treatment dosing and dispensing information will be 
provided in Listing 5.1. Any comments related to study medication or any other additional study 
comments will be listed (Listing 9.6). 
 


 
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6.4 
Safety Analyses 
All safety analyses for PT010008 are based on the Safety Population. Some selected adverse 
event tables (overall summary of AEs, incidence of AEs by SOC, and incidence of SAEs by 
SOC) will also be repeated for the PT010008 Safety Population. 
Safety data will be summarized cumulatively over 52 weeks using data observed during 
PT010006 and PT010008. Analyses involving change from baseline will use baseline values 
from Study PT010006. 
Any AEs, clinically significant laboratory values, vital signs, and ECG values during the 
Treatment Period will be tabulated according to their onset date into the following study periods 
and listed. 
 
Events occurring during the Treatment Period (include events with an onset date on or 
after the first date of dose and up to and including the day of discontinuation from or 
completion of study treatment). Events known to have occurred before the time of the 
first dose of study treatment are not included. 
 
Events occurring during the Post-treatment-discontinuation Follow-up (include events 
with an onset date on (or after) the day after discontinuation from or completion of study 
treatment). 
 
Any AEs, clinically significant laboratory values, vital signs, and ECG values during the 
Treatment Period will be tabulated and listed. Beginning on the day after the date of 
discontinuation from or completion of study medication, any new clinically significant ECGs, 
laboratory values, and vital signs will not be included in the tabulation or the computation of 
incidence rates, but will still be listed. Any new AEs, SAEs, and deaths during the Post- 
treatment-discontinuation Follow-up will be tabulated and listed. Tabulations of the incidence of 
deaths, AEs by SOC, and SAEs by SOC will be provided using information collected after 
treatment discontinuation or treatment completion (as alternative tables). 
6.4.1 
Bone Mineral Density Analyses 
All BMD analyses are based on the BMD Population. 
End-of-Treatment (EoT) is defined as the latest post-baseline assessment available, either 
scheduled or unscheduled. For bone mineral density (BMD) parameters, baseline BMD score is 
defined as the median BMD value of available scans (or values) prior to randomization in 
PT010006. 


 
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6.4.1.1 
Percent Change from Baseline in BMD of the Lumbar Spine Measured Using DEXA 
Scans of L2-L4 
The percent change from baseline in BMD of the lumbar spine at Week 52 and at EoT will be 
analyzed using an Analysis of Covariance (ANCOVA) model. The dependent variable for the 
ANCOVA analysis will be the natural-logarithmically transformed lumbar spine BMD at 52 
weeks (or similarly at EoT) minus the natural-logarithmically transformed lumbar spine BMD at 
baseline – i.e. the change from baseline after performing a logarithmic transformation to both the 
week-52 (or similarly EoT) value and the baseline value. The model includes treatment group 
and gender as categorical covariates, and natural-log-transformed baseline lumbar spine BMD 
score, age, and age by gender interaction as continuous covariates. Point estimates with 95% 
confidence interval (CI) for the adjusted mean treatment difference (BGF MDI versus BFF MDI, 
BGF MDI versus GFF MDI, and BFF MDI versus GFF MDI) will be estimated. Estimates from 
the ANCOVA model – for within-treatment means and between-treatment mean differences – 
will be transformed back using the exponential function. After the back-transformation, 1 is 
subtracted from the within-treatment-mean estimate and the result is multiplied by 100 to 
provide an estimate of percent change from baseline. After the back-transformation, 1 is 
subtracted from the between-treatment mean-difference estimate and the result is multiplied by 
100 to provide an estimate of percent treatment difference (Llombart et al. 2012). Estimates for 
the adjusted mean treatment difference will be given as percentages (Table 2.1.1). Non-
inferiority for lumbar spine BMD scores will be declared if the lower confidence bound for the 
percent treatment difference is greater than -2. The empirical cumulative distribution function of 
the logarithm of the ratio to baseline will be plotted by treatment (with all treatments on the same 
page) for the statistical methods appendix of the CSR. 
T-scores will be presented as shifts from baseline to each respective time point. A BMD t-score 
shift table will be produced using the categories of “≤ -2.5”, “> -2.5 and ≤ -1”, and “> -1” (Table 
2.1.3). In the shift table, for each treatment, the subject’s BMD baseline t-score category will be 
cross-tabulated by the subject’s post-baseline BMD t-score category during the treatment. 
Percentages of subjects in each post-baseline BMD t-score category for a treatment will be 
calculated for each baseline BMD t-score category.  
6.4.1.2 
Percent Change from Baseline in Total Hip BMD of the Hip Measured Using DEXA 
Scans 
The percent change from baseline in BMD of the total hip at Week 52 and at EoT will be 
analyzed using an ANCOVA in a similar fashion to the percent change from baseline in BMD of 
the lumbar spine. The dependent variable for the ANCOVA analysis will be the natural-
logarithmically transformed total hip BMD at 52 weeks (or similarly at EoT) minus the natural-
logarithmically transformed total hip BMD at baseline – i.e. the change from baseline after 
performing a logarithmic transformation to both the week-52 (or similarly EoT) value and the 
baseline value. The natural-log-transformed baseline BMD of the total hip will be used instead of 
baseline lumbar spine BMD in the model. The estimates with 95% confidence interval for the 
percent change from baseline within a treatment group and for the adjusted mean percent 


 
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treatment difference will be given (Table 2.1.2). A BMD t-score shift table will be produced 
using the categories of “≤ -2.5”, “> -2.5 and ≤ -1”, and “> -1” (Table 2.1.4).  
6.4.2 
Ocular Analyses 
All ocular analyses are based on the Ophthalmologic Population. 
The IOP will be measured 3 times per eye and the analysis value will be calculated as the median 
of the IOP measurements for a given eye. 
End-of-Treatment (EoT) is defined as the latest non-missing post-baseline assessment, either 
scheduled or unscheduled. For ocular assessments, the baseline value is the last value obtained 
prior to randomization in PT010006. 
6.4.2.1 
Change from Baseline in Each of the LOCS III (P, NO, NC, and C) Scores 
Changes from baseline (assessed at screening) in each scale of the LOCS III scores (P, NO, NC, 
and C) at each post-randomization visit (Week 28 and Week 52) will be analyzed using a 
repeated measures linear mixed model. The mixed model will include treatment, visit, and 
treatment by visit interaction as categorical covariates, and corresponding baseline LOCS III 
scale score (P, NO, NC, or C), smoking pack years, and age as continuous covariates. For this 
model, eye (within subject) will be included as a random effect. An unstructured correlation 
matrix will be used to account for within-subject-within-eye correlation across visits. Point 
estimates and two-sided 95% confidence intervals (CI) will be computed for pair-wise 
differences of BGF minus GFF and BFF minus GFF. Non-inferiority for LOCS III (P) scores 
will be declared if the upper confidence bound is less than 0.5. These LOCS III analysis results 
are tabulated in Tables 2.1.5 through 2.1.8. 
Changes from baseline in each scale of the LOCS III scores (P, NO, NC, and C) at EoT will be 
analyzed using a linear mixed model. The model will include treatment as a categorical covariate 
and corresponding baseline LOCS III scale score (P, NO, NC, or C), smoking pack years, and 
age as continuous covariates. Eye (within subject) will be treated as a random effect. Point 
estimates and two-sided 95% confidence intervals (CI) will be computed for pair-wise 
differences of BGF minus GFF and BFF minus GFF. Non-inferiority for LOCS III (P) scores 
will be declared if the upper confidence bound is less than 0.5. These LOCS III analysis results 
are tabulated in Tables 2.1.5 through 2.1.8. 
The empirical cumulative distribution function of the change from baseline in the LOCS III (P) 
score will be plotted by treatment (with all treatments on the same page) for the statistical 
methods appendix of the CSR. 
The analysis of the change from baseline in LOCS III (P) scores at Week 52 will be the primary 
ocular analysis, with analyses at Week 28 and EoT for P and other subscale scores presented as 
supportive analyses. 


 
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6.4.2.2 
Proportion of Subjects with LOCS III Grade Increases of ≥ 0.5 (Class 1), ≥ 1.0 (Class 
2), or ≥ 1.5 (Class 3) Units in Each of the 4 Scales 
The proportion of subjects with LOCS III grade increases in either eye of ≥ 0.5 (Class 1), ≥ 1.0 
(Class 2), and ≥ 1.5 (Class 3) units in each of the 4 scales (P, NO, NC, C) at Week 28, at Week 
52, and at EoT will be summarized by treatment group (Tables 2.1.9 through 2.1.12).  
6.4.2.3 
Change from Baseline in Intraocular Pressure 
The change from baseline in IOP at Week 28, Week 52, and EoT will be analyzed using a similar 
model as described above in section 6.4.2.1 for the LOCS III (P, NO, NC, and C) scores, but 
with the baseline IOP as a continuous covariate to replace baseline LOCS III scale score in the 
model (Tables 2.1.13) .  
6.4.2.4 
Proportion of Subjects with IOP ≥ 22 mmHg and the Proportion of Subjects with 
Change from baseline in IOP of ≥ 7 mmHg 
The proportion of subjects with IOP ≥ 22 mmHg and with IOP increases from baseline of ≥ 7 
mmHg in either eye at Week 28, Week 52, and EoT will be summarized by treatment group 
(Tables 2.1.14 and 2.1.15, respectively).  
6.4.2.5 
Change from Baseline in LogMAR Visual Acuity Using ETDRS Charts 
The change from baseline in LogMAR visual acuity scores using ETDRS will be analyzed across 
eyes (irrespective of subject) at each visit by treatment group using descriptive statistics (Table 
2.1.16). Each subject is to contribute a measure for each eye at each time point.  
6.4.2.6 
Change from Baseline in Horizontal Cup-to-disc Ratio 
The change from baseline in horizontal cup to disc ratio will be summarized across eyes 
(irrespective of subject) at each visit by treatment group using descriptive statistics (Table 
2.1.17). Each subject is to contribute a measure for each eye at each time point. 
6.4.2.7 
Incidence of Ocular TEAEs including Cataract and Glaucoma 
The proportion of subjects with ocular TEAEs in each treatment group will be summarized 
overall and by individual AE including cataract and glaucoma (Table 2.1.18). 
 
6.4.3 
Adverse Events 
The version of the Medical Dictionary for Regulatory Activities (MedDRA) that is current at the 
time of database lock will be used to code verbatim terms for AEs for final analysis of the data. 
A glossary of MedDRA preferred terms used for adverse events reported in the study along with 
the associated Investigator’s verbatim term will be provided in Listing 7.2. 


 
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An adverse event (AE) is considered treatment-emergent if an event occurs after the first dose of 
study medication in the study, or if the AE worsened during the study after the first dose of study 
medication in the study (intensity and/or severity changed to a worsened grade. An adverse event 
that begins on the same date as the first dose of study medication is treatment-emergent if the AE 
begins after the time of first dose or if the time of AE onset is unknown. Adverse events that 
occur between the time the subject signs the informed consent form for the PT010006 study and 
the time when that subject is randomized are to be recorded as medical history unless the event 
met the definition of a serious AE (SAE). 
The number and incidence of AEs, SAEs, adverse events of special interest (AESI) by category, 
and study drug discontinuations due to adverse events will be summarized by treatment group. 
The incidence of an AE will be defined as the number and percentage of subjects experiencing 
an event. Adverse events will be tabulated at the level of the Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and the MedDRA system organ class. Tabulations will be 
broken down by severity, by relationship to study drug, and AEs leading to treatment 
discontinuation. No hypothesis tests will be performed. 
Events with Irregular Onset Dates: All treatment-emergent adverse events will be included in 
the data listings regardless of the completeness of the onset dates. Partial dates will be imputed in 
order to determine if an AE is treatment-emergent using the imputation rules in Appendix 1; 
however, imputed dates will not be provided in the data listings. 
All adverse events, whether treatment-emergent or not, will be included in the listings. Reported 
adverse events by system organ class (SOC), preferred term (PT), treatment, country, center, 
subject and onset day will be provided (Listing 7.1). Reported adverse events by treatment, 
country, center, subject, and onset date will be presented in Listing 7.3. 
The listing of adverse events will provide the severity, relationship to study drug, action taken 
and outcome for each adverse event. Any SAEs reported will be listed for all subjects screened 
(Tables 4.1.13). Adverse events leading to permanent discontinuation of study treatment will be 
listed for the Safety Population (Table 4.1.10). 
A listing of any reported deaths during the study (prior to randomization, during Treatment 
Period, or during the Post-treatment-discontinuation Follow-up) will be provided (Table 
4.1.30c); study treatment taken prior to the death and the number of days since the last dose of 
this study treatment at the time of the death will be included in the listing. An overview table will 
be prepared with the incidences of subjects, for all subjects and for each treatment, with the 
following: at least one treatment-emergent adverse event, at least one treatment-emergent related 
adverse event, at least one treatment-emergent serious adverse event, at least one treatment-
emergent serious related adverse event, at least one treatment-emergent adverse event leading to 
premature discontinuation, at least one treatment-emergent serious adverse event leading to 


 
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withdrawal, and a report of death for the Safety Population (Table 4.1.1.1). This table will also 
be repeated for the PT010008 Safety Population (Table 4.1.1.2). 
Summary tabulations of the following will be prepared for all subjects, for each treatment, for 
each primary SOC, and for each PT within a SOC, the majority which pertain to the Treatment 
Period: 
1. The incidence of all treatment-emergent adverse events by SOC and Preferred Term 
(Table 4.1.2.1). This table will also be repeated for the PT010008 Safety Population 
(Table 4.1.2.2). 
2. The incidence of subjects with adverse events by SOC during the Post-treatment-
discontinuation Follow-up (Table 4.1.3) 
3. The incidence of treatment-emergent adverse events occurring in SMQs (Standard 
MedDRA Queries)/groupings of interest (Table 4.1.5). 
4. The incidence of non-serious treatment-emergent adverse events occurring in ≥5% of 
subjects in a treatment (Table 4.1.6). 
5. The incidence of all treatment-related treatment-emergent adverse events (Table 
4.1.8). 
6. The incidence of discontinuation from study treatment due to a treatment-emergent 
adverse event (Table 4.1.9). 
7. The incidence of treatment-emergent serious adverse events by SOC and Preferred 
Term (Table 4.1.11.1). This table will also be repeated for the PT010008 Safety 
Population (Table 4.1.11.2). 
8. The incidence of subjects with serious adverse events by SOC during the Post-
treatment-discontinuation Follow-up (Table 4.1.12) 
9. The incidence of all treatment-related treatment-emergent serious adverse events 
(Tables 4.1.16). 
10. The incidence of subjects with neoplasm (all cancer) and the incidence of subjects 
with neoplasm (excluding non-melanoma skin cancer) (Tables 4.1.17, 4.1.18). 
11. The incidence of all treatment-emergent adverse events by highest severity to 
treatment (Tables 4.1.21 through 4.1.23 for the three treatments). 
12. The incidence of treatment-emergent adverse events occurring in at least 2% of 
subjects in any treatment (Table 4.1.4 sorted by descending frequency of events in a 
preferred term). 
13. In addition, to control for possible differences in exposure between the treatments, the 
following AE and SAE summaries will be presented with the frequency and rate of 
occurrence (total number of events per 1000 person-years of exposure) by treatment, 
primary SOC, and PT: 
a) Frequency and rate of AEs (Tables 4.1.7). 
b) Frequency and rate of SAEs (Tables 4.1.15). 


 
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c) Frequency and rate of neoplasms (Tables 4.1.19, 4.1.20). 
 
6.4.3.1 
Adverse Events of Special Interest 
 Adverse events of special interest (AESIs) have been defined based on known effects of 
LAMAs, LABAs, and ICS. These include but are not limited to cardiovascular effects, ocular 
disorders, urinary retention, gastrointestinal disorders, and anticholinergic effects for LAMAs; 
cardiovascular, tremor effects, hyperglycemia, and hypokalemia for LABAs; and local (e.g., 
candidiasis and voice effects) and systemic (e.g., bone and skin effects, diabetes control, ocular 
and taste effects, adrenal suppression) steroid class effects and lung infection for ICS.  
Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries (SMQs) will be 
utilized when possible, and a selection of high-level group terms (HLGTs), high-level terms 
(HLTs), and preferred terms (PTs) will be utilized to represent other situations. The terms 
proposed to be used in the assessment of AESIs associated with ICS, LAMAs, and LABAs are 
listed in Table 1. Standardized MedDRA queries will be utilized when possible and a selection of 
preferred terms in other situations (Appendix 5). 
Table 1 
Terms for the Assessment of Adverse Events of Special Interest 
Medical Concept 
Selection of MedDRA Terms 
Adrenal suppression 
Adrenal cortical hypofunctions HLT 
Agitation or anxiety 
Collection of PTs 
Anticholinergic effectsa 
Anticholinergic syndrome SMQ 
Dry mouth PT 
Bone fracture 
Collection of HLGTs, HLTs, and PTs. 
Candidiasis  
Collection of PTs 
Cardiovascular 
Cardiac arrhythmias SMQ 
Cardiac failure SMQ 
Ischemic heart disease SMQ 
Torsades de Pointe/QT prolongation SMQ 
Cardiovascular death 
Collection of PTs 
Cerebrovascular condition 
CNS haemorrhages and cerebrovascular conditions 
SMQ 
Diabetes mellitus 
Hyperglycaemia/new onset diabetes mellitus SMQ 
Dysgeusia or ageusia 
Collection of PTs 
Dysphonia or aphonia 
Collection of PTs 
Gastrointestinal 
Gastrointestinal perforation, ulceration, haemorrhage 
or obstruction SMQ 
Gastrointestinal obstruction SMQ 
Headache  
Headache (PT) 
Hypercortisolism 
Collection of PTs 


 
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Medical Concept 
Selection of MedDRA Terms 
Hypertension 
Blood pressure ambulatory increased (PT) 
Blood pressure increased (PT) 
Blood systolic increased (PT) 
Hypokalemia 
Collection of PTs 
Lower respiratory tract infections other than 
pneumonia 
Bronchitis (PT) 
Bronchitis viral (PT) 
Bronchitis bacterial (PT) 
Lower respiratory tract infection (PT) 
Lower respiratory tract infection viral (PT) 
Lower respiratory tract infection bacterial (PT) 
Infective exacerbation of chronic obstructive airway 
disease (PT) 
Ocular effects 
Visual disorders HLT 
Glaucoma SMQ 
increased intraocular pressure collection of PTs 
Cataract collection of PTs 
Osteoporosis and osteopenia 
Osteoporosis/osteopenia (SMQ) 
Palpitation 
Palpitations PT 
Paradoxical bronchospasm 
Collection of PTs 
Pneumonia  
Collection of PTs 
Psychiatric effect 
Collection of PTs 
Skin effects 
Skin atrophy (PT) 
Skin striae (PT)  
Acne (PT)  
Contusion (PT)  
Ecchymosis (PT)  
Increased tendency to bruise (PT)  
Petechiae (PT)  
Purpura (PT)  
Malassezia folliculitis (collection of PTs)  
Hypertrichosisa (collection of PTs)  
Alopecia (collection of PTs) 
Sleep effects 
Initial insomnia (PT) 
Insomnia (PT) 
Sleep disorder (PT) 
Sudden death 
Collection of PTs 
Throat irritation 
Collection of PTs 
Tremor 
Tremor HLT 
Urinary retention 
Collection of PTs 
Weight gain 
Collection of PTs 
Abbreviations: CNS=central nervous system. 
a 
This medical concept is uniquely associated with LAMAs. 
 


 
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Appendix 5 (which will be based on the latest version of MedDRA available at the time of database lock) provides 
detail on selection of terms (narrow/wide designations for preferred terms are provided). 
Adverse Events in MedDRA SMQs/Groupings of Interest by Term will be tabulated (Table 
4.1.24). 
6.4.3.2 
MACE Events Determined by Clinical Endpoint Committee 
The clinical endpoint committee (CEC) will review and adjudicate serious cardiovascular and 
cerebrovascular (CCV) events as major adverse cardiovascular event (MACE). MACE events 
are defined as the following: 
 
• Cardiovascular death 
• Non-fatal myocardial infarction (MI) 
• Non-fatal stroke 
The CEC will review and assess these non-fatal serious CCV events and all deaths as to whether 
or not they fulfill criteria (based on CEC working practices) for MACE. 
MACE events will be summarized by adjudicated CRF category and treatment group (Table 
4.1.25). The assessment of MACE events will include the rate of confirmed MACE events 
(Table 4.1.26). Adjudicated MACE events will be listed in Listing 7.4. 
The incidence of subjects with adjudicated MACE AEs by category will be summarized in Table 
4.1.27. 
6.4.3.3 
Pneumonia Events Determined by Clinical Endpoint Committee 
All AEs/SAEs with preferred terms that could relate to pneumonia will be adjudicated to provide 
a more complete assessment of all physician-reported pneumonias. The incidence of confirmed 
pneumonia events will be tabulated (Tables 4.1.28). The assessment of pneumonia events will 
include the rate of confirmed pneumonia events (Table 4.1.29). Adjudicated pneumonia events 
will be listed in Listing 7.4. 
 
The incidence of subjects with adjudicated pneumonia AEs by category will be summarized in 
Table 4.1.27. 
6.4.3.4 
Cause of Death Determined by Clinical Endpoint Committee 
Causes of death will be listed (Table 4.1.30c) by subject and summarized by treatment for (1) all-
cause mortality, (2) mortality of probable cardiovascular cause, (3) mortality of probable 
respiratory cause and (4) mortality of probable other causes using the Safety Population based on 
(A) cases reported during the active Treatment Period and (B) cases reported during the active 
Treatment Period plus the following 14 days. The incidence of subjects with a death event will 


 
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be tabulated by adjudicated CRF category and treatment during the Treatment Period (Table 
4.1.30a) and during the Post-treatment-discontinuation Follow-up (Table 4.1.30b). To control for 
possible differences in exposure between treatments, the death will be summarized with 
frequency and rate of occurrence (total number of events per 1000 person-years of exposure) by 
treatment, primary system organ class, and preferred term (Table 4.1.31). Adjudicated death 
events will be listed in Listing 7.4. 
6.4.4 
Clinical Laboratory Measurements 
Lab parameters collected include the following: 
 
 


 
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Table 2 
Lab Parameters 
Hematology 
Hemoglobin  
Mean corpuscular 
hemoglobin  
Hematocrit  
Mean corpuscular 
hemoglobin concentration 
White blood cell count with differential  
Mean corpuscular 
volume  
Red blood cell count  
Eosinophils 
Platelet count  
 
Clinical Blood Chemistry 
 
Liver Enzyme and Other Liver Function Tests 
Other Clinical Blood 
Chemistry 
Alanine aminotransferase  
Albumin 
Aspartate aminotransferase  
Blood Urea Nitrogen 
(BUN) 
Alkaline phosphatase  
Calciuma 
Bilirubin, total  
Chloridea 
Gamma-glutamyl transferase  
Cholesterol  
 
Bicarbonate 
 
Creatininea 
 
Glucosea 
 
Magnesium  
 
Potassiuma 
 
Phosphate 
 
Protein, total  
 
Sodiuma 
Urinalysis 
Macroscopic examination including specific gravity, pH, protein, glucose, ketones, blood, and  
urobilinogen. 
Other Tests: 
Pregnancy test (women of childbearing potential only): serum hCG at Visit 10a of Study PT010006 and at 
Visit 14 (Week 52) the Treatment Discontinuation/Withdrawal Visit of this study.  
Creatinine clearance will be estimated by the CKD-EPI formula [Levey, 2009]. 
Abbreviations: CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; hCG=human chorionic  
gonadotropin. a Parameters included in the Basic Metabolic Panel. 
 
 
A Clinically Significant Laboratory Abnormality as identified by the investigator after the 
start of study treatment will be recorded as an Adverse Event and tabulated as an AE in the AE 


 
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analysis. Abnormalities occurring prior to the start of treatment will be noted in medical history 
and presented in a data listing. Per protocol, the criteria for a "clinically significant" laboratory 
abnormality are: 
a. A laboratory abnormality that leads to a dose-limiting toxicity (e.g., an abnormality that 
results in study drug dose reduction, suspension or discontinuation) 
b. A laboratory abnormality that results in any therapeutic intervention (i.e., concomitant 
medication or therapy) 
c. Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (e.g., significant fall in hemoglobin not requiring transfusion) 
All laboratory data will be stored in the database with the units in which they were originally 
reported. Laboratory data not reported in International System of Units (SI units; Système 
International d’Unités) will be converted to SI units before data analysis. 
Individual clinical laboratory variables for hematology and clinical chemistry and kidney 
function, including creatinine clearance, will be provided in listings (Listing 8.1 for hematology, 
Listing 8.2 for blood chemistry and kidney function, Listing 8.3 for urinalysis, and Listing 4.7 for 
pregnancy test results at screening and after the start of treatment). Data will be listed in SI units 
where available. Comments for laboratory testing will be listed (Listing 8.4). For listings, 
laboratory values will be flagged as Low or High based on the reference ranges provided by the 
central laboratory, LabCorp Laboratories (Appendix 4). 
The baseline measurement for a laboratory parameter will be the last available measurement 
prior to the start of dosing. 
Table 3 Analysis Study Time Windows for Clinical Lab Assessments 
Calculated Study Time Window 
Time Interval for the Study Time Window 
Pre-dose 
≥0 min. prior to dose 
Note that minutes are rounded to the nearest whole number before applying time 
windows. 
If there are multiple laboratory values for the same parameter at pre-dose of a visit, the last value 
will be chosen for analysis. 
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) for the 
baseline assessment and for the pre-dose value and change from baseline at each post-baseline 
visit and EoT for scheduled lab assessments of continuous laboratory variables including serum 
potassium and glucose will be tabulated. “End of Treatment” is defined as the last non-missing 
assessment during the treatment period.  


 
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Data from unscheduled visits will not be used for the by-visit summaries but both scheduled-visit 
values and unscheduled-visit values are candidates for clinically significant values, for the end-
of-treatment summary, and for shift tables.  
Data from both scheduled and unscheduled visits will be listed. The summaries will be provided 
by treatment (Tables 4.1.33 through 4.1.36, for hematology, chemistry, kidney function, and 
urinalysis, respectively). 
Shift tables will be produced using the categories defined by the Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03 grades for the Safety Population (Tables 4.1.37, 
4.1.38, Table 4.1.39 and Table 4.1.40) for hematology, chemistry, kidney function and 
urinalysis, respectively). For these shift tables, for each treatment, the subject’s pre-dose grade 
will be cross-tabulated by the subject’s maximum post-baseline grade during the treatment; also, 
the subject’s maximum post-baseline grade during treatment will be tabulated for all baseline 
grades combined. Percentages of subjects in each maximum post-baseline grade for a treatment 
will be calculated for each pre-dose grade for the treatment and also for all baseline grades 
combined. Laboratory abnormal values on-treatment will be flagged as High or Low values 
based on laboratory reference ranges provided by LabCorp Laboratories (found in Appendix 4) 
as per Pearl, Inc. These flags along with the reference ranges will be provided in the laboratory 
data listings. 
Potentially Clinically Significant Laboratory Values Above/Below a Clinically Relevant 
Threshold on-treatment, based on CTCAE 4.03 and other criteria, will be identified based on the 
following thresholds: 
 
 


 
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Table 4 
Potentially Clinically Significant (PCS) Laboratory Parameter Criteria 
Parameter 
Post-Baseline Criteria 
Hematology 
 
Hemoglobin  
<8.0 g/dL (<80 g/L) 
 
Increase of >40 g/L to a value above the ULN
White Blood Cell Count 
<2,000/ µL  
 
>35,000/µL 
Platelet Count 
<50,000/µL 
 
>999,000/µL  
Chemistry 
 
eGFR-EPI  
<30 mL/min/1.73 m2 
AST 
>3 x ULN 
ALT 
>3 x ULN 
Alkaline Phosphatase 
>5 x ULN 
Total Bilirubin 
>2 x ULN 
Blood Glucose* (random values) <2.2 mmol/L (<39.6 mg/dL) 
 
>13.9 mmol/L (>250 mg/dL) if baseline is 
below or equal to 10.0 mmol/L (180 mg/dL), 
>16.7 mmol/L (>300 mg/dL) if baseline is 
greater than 10.0 mmol/L (180 mg/dL). 
Serum Potassium 
<3.0 mmol/L 
 
>6.0 mmol/L 
*CTCAE 4.03 criteria are based on fasting glucose values. However, subjects were not required to 
fast prior to obtaining blood glucose values. 
Since a reduction in potassium and an increase in blood glucose are known class effects of 
beta-agonists, all potassium or glucose assessments for subjects who experienced newly 
occurring or worsening potentially clinically significant values after start of the study treatment 
will be provided in separate listings (Table 4.1.41 and Table 4.1.42). For all laboratory 
parameters other than glucose and potassium noted in Table 2, all laboratory data for the 
parameter identified as potentially clinically significant for a subject will be listed (Table 4.1.43). 
6.4.5 
Vital Signs 
Changes from Baseline in on-treatment supine or seated systolic blood pressure, supine or 
seated diastolic blood pressure, heart rate, and body temperature will be evaluated, where 
baseline is defined as the mean of all available pre-dose measurements taken prior to the start of 
dosing at the Randomization Visit (Visit 4). If there are no Visit 4 pre-dose values, the baseline 
will be defined as the mean of pre-bronchodilator values at Visit 2 and Visit 3. No hypothesis 
testing will be performed. 


 
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A Clinically Significant Abnormality in vital signs identified by the investigator will be 
recorded as an Adverse Event if it occurs after the start of treatment. These adverse events will 
be included in the AE summaries; abnormalities prior to the start of treatment will be noted in 
medical history and listed. 
Potentially clinically significant changes in systolic and diastolic blood pressure will be 
defined based on the following criteria provided by Pearl, Inc.: 
Table 5 
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood Pressure 
Parameters 
Parameter (mmHg) 
Post-Baseline Criteria 
Systolic Blood Pressure, increase 
≥180 and increase from baseline ≥20  
Systolic Blood Pressure, decrease 
≤90 and decrease from baseline ≥20 
Diastolic Blood Pressure, increase 
≥105 and increase from baseline ≥15 
Diastolic Blood Pressure, decrease 
≤50 and decrease from baseline ≥15 
 
Potentially clinically significant (PCS) changes in heart rate will be assessed as follows: 
Table 6 
Potentially Clinically Significant Criteria for Heart Rate Parameters 
Parameter 
Post-Baseline Criteria 
Tachycardia Event 
≥110 bpm and increase ≥15% from baseline 
Bradycardia Event 
≤50 bpm and decrease ≥15% from baseline 
 
Vital sign measurements (heart rate, systolic blood pressure, diastolic blood pressure and body 
temperature) and height and weight during the study will be displayed in a vital signs listing 
(Listing 9.1). 
A summary of baseline weight, height, and BMI will be presented by treatment (Tables 1.2.1, 
1.2.2, 1.2.3 for the Safety, BMD and Ophthalmologic Populations, and in Table 1.2.4 for All 
Subjects Screened for PT010008 but Not Enrolled in PT010008 respectively). 
Summary statistics (n, mean, median, standard deviation and range) of the absolute value and 
change from baseline for systolic blood pressure, diastolic blood pressure, heart rate, and body 
temperature will be tabulated by treatment, visit, and time point. Baseline will be defined as the 
mean of the values prior to dosing at Visit 4 (Day 1). These summaries (Table 4.1.44) will be 
prepared for baseline and the scheduled post-baseline pre-dose nominal time point at each 
scheduled post-baseline visit and end of treatment. End of Treatment will be summarized for the 
scheduled post-baseline pre-dose time point (pre-dose) “End of Treatment” for the pre-dose 
assessment points is defined as the last non-missing on-treatment assessment available for the 
pre-dose time point. Post-dose time points are collected in PT010006 but not in PT010008 and 


 
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thus will not need to be summarized for PT010008 because they will have been fully 
summarized in the PT010006 clinical study report (CSR). Data from unscheduled visits will not 
be used for the by-visit summaries, but both scheduled-visit data and unscheduled-visit data are 
candidates for the end-of-treatment summary. Data from both scheduled and unscheduled visits 
will be listed. Time windows will be derived for each post-baseline visit using the time intervals 
for the study time windows detailed in Table 7. No hypothesis tests will be performed. 
Table 7 
Analysis Study Time Windows for Vital Signs Assessments 
Calculated Study Time Window 
Time Interval for the Study Time Window 
Pre-dose 
≥0 min. prior to dose 
Note that minutes are rounded to the nearest whole number before applying time 
windows. 
If there are multiple vital sign values for the same parameter at pre-dose assessments after Visit 4 
the last value will be chosen for analysis. 
Data from unscheduled visits will not be used for the by-visit summaries but both scheduled-visit 
data and unscheduled-visit data are candidates for clinically significant values and for the end-of-
treatment summary. 
The percentage of subjects with PCS values for vital signs at any time post-dose at a visit will be 
summarized by treatment based on the criteria in Table 5 and Table 6 (Table 4.1.45). All vital 
sign assessments for subjects with potentially clinically significant values will be listed (Tables 
4.1.46 and Table 4.1.47). 
6.4.6 
12-Lead Electrocardiogram Measurements 
Changes from baseline in Heart Rate, PR Interval, QRS Axis, QRS Interval, QT Interval and 
QTcF interval will be calculated where baseline is defined as the mean of the pre-dose 
measurements taken prior to the start of treatment at the randomization visit (Visit 4). If there are 
no Visit 4 pre-dose values, the baseline will be defined as the mean of the pre-bronchodilator 
values at Visit 2 and Visit 3. The QTcF (Fridericia Corrected QT) is defined as [QT/(RR1/3)]. 
Heart rate (bpm) is estimated as 60,000/RR, where RR is in units of ms. These assessments will 
be tabulated for each treatment and assessment time. 
 
A Clinically Significant Abnormality for a 12-Lead ECG measurement identified by the 
investigator as a clinically significant abnormality will be recorded as an Adverse Event if it 
occurred after the start of study treatment. These adverse events will be included in the AE 
summaries. 
All 12-Lead ECG measurements for the Safety Population will be listed (Listing 9.2). Summary 
statistics (mean, median, standard deviation and range) for raw values and change from baseline 


 
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values in Heart Rate, PR Interval, QRS Axis, QRS Interval, QT Interval and QTcF interval will 
be calculated, where baseline is defined as the mean of the pre-dose measurements taken prior to 
the start of treatment at Visit 4 (Day 1). These assessments will be tabulated for each treatment 
for the pre-dose nominal time point (derived using the time intervals for the study time windows 
detailed below in Error! Reference source not found.Table 8) at each visit and at end of 
treatment (Table 4.1.48). “End of Treatment” will be summarized for the scheduled post-baseline 
pre-dose time-point. Post-dose time points are collected in PT010006 but not in PT010008 and 
thus will not need to be summarized for PT010008 because they will have been fully 
summarized in the PT010006 clinical study report (CSR). End of Treatment for each of these 
assessment points is defined as the last non-missing on-treatment assessment available for the 
pre-dose time-point. Data from both scheduled and unscheduled visits will be listed. Mean pre-
dose change from baseline for heart rate and QTcF will be plotted across post-baseline visits by 
treatment (Figures 4.1.48a and 4.1.48b). ECG data from subjects with pacemakers will not be 
included in analyses, but will be listed. 
Table 8 
Analysis Study Time Window for ECG Assessments 
Calculated Study Time 
Window 
Time Interval for the Study Time 
Window 
Pre-dose 
≥0 min. prior to dose 
 Note: The minutes are rounded to the nearest whole number before 
 applying time windows. 
If there are multiple ECG values for the same parameter at pre-dose of a visit date (other than for 
Visit 4), the last value will be chosen for analysis. 
Data from unscheduled visits will not be used for the by-visit summaries but both scheduled-visit 
data and unscheduled-visit data are candidates for clinically significant values and for the end-of-
treatment summary. 
Table 9 
Criteria for PCS ECG Values 
Parameter 
Post-Baseline Criteria 
QTcF Prolongation 
(1) ≥ 500 msec if < 500 msec at study baseline and ≥ 15 msec change 
from study baseline 
 
(2) ≥ 530 msec if ≥ 500 msec at study baseline and ≥ 15 msec change 
from study baseline 
 
(3) Change of ≥60 msec from study baseline regardless of initial value  
 
(4) ≥ 500 msec and ≥ 15 msec change from study baseline 
 
Potentially clinically significant ECG parameter values will be identified based on criteria listed 
in Error! Reference source not found.. The number and percentage of subjects who had such 


 
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values observed any time post-dose will be tabulated for each treatment (Table 4.1.49) and listed 
(Table 4.1.50 for QTcF prolongation). No hypothesis tests will be performed. 
6.4.7 
Physical Examination 
Any physical examination abnormality reported after the start of treatment for a subject is to be 
reported as an adverse event. Thus, these will be included in listings of adverse events and 
summarized in adverse event summaries. Abnormalities seen at the Screening physical 
examinations will be recorded as Medical History and listed. 
6.4.8 
Control of Type I Error 
 Since the primary objectives are related to safety, all hypotheses will be tested at nominal 
alphas. There will be no controls for multiplicity.  
6.5 
Efficacy Analyses 
All efficacy analyses for PT010008 are based on the mITT Population. 
Summary statistics will be provided by randomized treatment group. 
6.5.1 
Rescue Ventolin HFA Use 
The number of puffs of rescue Ventolin HFA taken in the previous 12 hours will be recorded in 
the subject diary in the morning and evening. The mean daily number of puffs of rescue Ventolin 
HFA used by subjects during the study will be calculated overall and for each of the 4-week 
intervals during the treatment period and provided in a diary data listing (Listings 6.1.3 for the 
Safety Population). Diary data recorded during the last 7 days of the 28-day Screening Period (of 
PT010006) will be used to calculate the baseline. For every interval of time over which the mean 
number of puffs of rescue will be calculated for both overall as well as 4-week intervals, records 
with missing values will be ignored in both the numerator and denominator. As such, the 
denominator will be adjusted based on the number of days (including half days) with 
non-missing values. That is, the mean daily number of puffs of daytime rescue use (M_DT) will 
be set to the total number of daytime puffs divided by the number of half-days when daytime 
rescue use was recorded. The mean daily number of puffs of nighttime rescue use (M_DN) will 
be set to the total number of nighttime puffs divided by the number of half-days when the 
nighttime rescue use was recorded. The mean daily rescue use (puffs) is then two multiplied by 
the mean of M_DT and M_DN. 
The mean change from baseline in rescue use will be summarized by treatment group over 52 
weeks and over each post-randomization 4-week interval (Interval 1 to Interval 13) (Table 3.1.1). 
6.5.2 
Percentage of Days with No Rescue Ventolin HFA Use over the Treatment Period 
As a supportive analysis, percentage of days with ‘no rescue Ventolin HFA use’ over 52 weeks 
will be summarized by treatment using descriptive statistics (Table 3.1.4). A ‘day with no rescue 


 
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use’ is defined as any day where the subject reported having taken zero puffs of rescue Ventolin 
HFA. The rescue Ventolin HFA usage diary data from days where rescue Ventolin HFA usage 
data is non-missing will be used to ascertain the days with “no rescue Ventolin HFA use”. The 
percentage of days with no rescue use will be calculated as 100 x (number of days with no rescue 
Ventolin use over the entire treatment period / number of days with non-missing rescue Ventolin 
use data over the entire treatment period). For the mITT analysis, days after discontinuation of 
study medication will not be used. 
6.5.3 
Chronic Obstructive Pulmonary Disease Exacerbations 
Rate of COPD Exacerbations 
A COPD exacerbation will be defined as a change in the subject’s usual COPD symptoms that 
lasts 2 or more days, is beyond normal day-to-day variation, is acute in onset, and may warrant a 
change in regular medication. The change in symptoms must include at least one major COPD 
symptom and at least one other major (dyspnea, sputum volume, and sputum color) or minor 
symptom (cough, wheeze, sore throat, cold symptoms [rhinorrhea or nasal congestion], and fever 
without other cause). 
Exacerbations will be considered moderate if they result in: 
• 
Use of systemic corticosteroids and/or antibiotics for at least 3 days; a single depot injectable 
dose of corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids. 
Exacerbations will be considered severe if they result in:  
• 
An inpatient COPD-related hospitalization (documentation stating that the subject was 
hospitalized for the COPD exacerbation or a record of the subject being admitted for ≥24 
hours to an observation area, the emergency department, or other equivalent healthcare 
facility depending on the country and healthcare system). 
• 
COPD-related death. 
Moderate-to-severe COPD exacerbations will be entered in the eCRF. 
Additionally, the investigator may identify certain events (recorded on the same CRF page) 
which don’t entirely meet the criteria above as exacerbations; the justifications supporting the 
investigator’s judgment will be recorded on a separate page on the eCRF. 
COPD exacerbations not meeting the criteria for moderate or severe COPD exacerbations will be 
considered to be mild COPD exacerbations. For more detail about moderate-or-severe, severe, 
and any-severity COPD exacerbation events (and their start and end dates) and how they are 
operationally defined, see the subsections about “Duration of COPD Exacerbation”, “Moderate-


 
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to-Severe Exacerbation and Severe Exacerbation: Operational Definitions”, and “Exacerbation of 
any Severity: Operational Definition”. 
COPD exacerbations will be considered separate events provided that more than 7 days are 
between the recorded stop date of the earlier event and start date of the later event.  
For the mITT population, the time at risk is defined as time of exposure – not during or within 7 
days after an exacerbation (of equal or greater severity) – until the last dosing date. More 
precisely, this is the amount of time between the date of first dose of study medication and the 
date of discontinuation from or completion of study medication minus the number of days while 
the subject was experiencing any exacerbation and minus the seven days subsequent to any 
exacerbation. Any days subsequent to the date of discontinuation from or completion of study 
medication are not subtracted. 
The rate of exacerbations, the number of exacerbations, and the percentage of subjects who 
experience exacerbations will be summarized for moderate-or-severe COPD exacerbations 
(Tables 3.1.5.1 for the mITT Population). The rate of severe COPD exacerbations and the rate of 
COPD exacerbations of any severity will be presented in a similar manner (Tables 3.1.6 and 
3.1.7). 
Duration of COPD Exacerbation 
For moderate or severe exacerbations, the duration is defined by the length of prescribed 
treatment (using the eCRF exacerbation page), whereas for mild exacerbations, the duration is 
defined by the length of symptoms. 
For moderate or severe COPD exacerbations, the start date will be defined as the start date of 
prescribed treatment with a systemic corticosteroid or systemic antibiotic and the stop date will 
be defined as the last day of prescribed treatment with a systemic corticosteroid or systemic 
antibiotic. In order to ensure that the same event is not counted twice, concurrent moderate or 
severe COPD exacerbations with start and stop dates equal to or less than 7 days apart will be 
considered the same event and assigned the maximum severity between the two. 
For mild COPD exacerbations, start date will be defined as the onset of worsened symptoms as 
recorded by the subject in the electronic diary (eDiary), and the stop date will be defined as the 
last day of worsened symptoms. In order to ensure that the same event is not counted twice, mild 
COPD exacerbations with start and stop dates equal to or less than 7 days apart will be 
considered the same event. 
In addition, in order to not double count exacerbations that are moderate or severe, eDiary data 
from dates within 7 days of a moderate or severe exacerbation will not be included as additional 
mild COPD exacerbations. This implies that continuing worsened symptoms that meet the 
definition of a mild exacerbation would need to be present at least 2 days prior to the 7-day 


 
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period immediately preceding the start date of a moderate or severe COPD exacerbation in order 
to be considered a separate event. Similarly, worsened symptoms would need to be present for at 
least 2 days after the 7-day period immediately following a moderate or severe COPD 
exacerbation to be considered a separate event. 
Analyses of each severity of exacerbation will account for the time that subjects are at risk of 
having an exacerbation of that severity or greater. Time during or immediately following – i.e. 
within 7 days of – an exacerbation will not be considered as part of the time that the subject was 
at risk. However, time during or immediately following an exacerbation of lower severity will be 
included since, for example, a subject experiencing a mild exacerbation is still at risk of the event 
increasing in severity and becoming a moderate exacerbation. Moderate and severe COPD 
exacerbations occurring within 7 days of one another will be coalesced into a single COPD 
exacerbation event with the severity of “severe” (see details below).  
Moderate-to-Severe Exacerbation and Severe Exacerbation: Operational Definitions: 
 Moderate exacerbations and severe exacerbations will be defined solely based on 
information from the COPD Exacerbation eCRF page. A time interval from a single 
COPD exacerbation eCRF page will be designated as being during an event of a 
moderate-to-severe COPD exacerbation if for that interval: either antibiotics or oral 
corticosteroids were administered for the exacerbation 
 
Call this time interval a “P-Interval”. The start date of the P-Interval is the earliest start date of 
the above, and the stop date will be defined as the last stop day of the above. If the subject was 
hospitalized due to the exacerbation or if the exacerbation led to a COPD-related death, then the 
severity of “severe” will be assigned to this P-interval; otherwise the severity of “moderate” will 
be assigned. The latter of the stop date of the treatment with a systemic corticosteroid and the 
stop date of the treatment with an antibiotic will be the end date of the COPD exacerbation (i.e. 
the end of the P-Interval). 
 An overarching interval of (any number of) such P-Intervals – including any P-Intervals 
with an end date not more than 7 days prior to the start date of some other P-Interval or 
with a start date not more than 7 days after the end date of some other P-Interval – and 
including the days in any gaps between them – will be called an “QMS-Interval”. This 
QMS-interval will represent the consolidated duration of several exacerbations recorded 
on different CRF pages. This QMS-Interval will be considered to be a single event of a 
moderate-or-severe COPD exacerbation. See  
 Figure 2. 
 A P-Interval of severe COPD exacerbation is called a “severe” P-Interval. Any QMS interval 
that contains at least one “severe” P-Interval will also be called a “QS-Interval”. This QS-


 
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Interval will be considered to be a single event of a severe COPD exacerbation. See Error! 
Reference source not found..  
Figure 2  
Overarching Intervals of Moderate-to-Severe (QMS) and Severe (QS) COPD 
Exacerbations 
P 
(Severe) 
3 days 
P 
(Severe) 
 8  days  
P 
5 days 
P 
(Severe) 
QMS 
 
QMS 
QS 
 
QS 
A P-interval is a moderate-to-severe COPD exacerbation instance from a single CRF page. 
In a “Severe” P-Interval [denoted in the figure as “P (severe)”], the maximum severity of the COPD exacerbation is 
“severe”. 
A QMS interval is an overarching moderate-or-severe COPD exacerbation event encompassing multiple CRF pages. 
A QS interval is an overarching severe COPD exacerbation event encompassing multiple CRF pages. 
 
Exacerbation of any Severity: Operational Definition: 
 Using eDiary data, a day will be designated as being during an event of a COPD 
exacerbation of some severity if (1) there was at least one major symptom and there was 
at least one other major or minor symptom and if (2) on an adjacent day there was at least 
one major symptom and there was at least one other major or minor symptom. Denote 
such a day as a “Category-D” day. 
 An interval of (any number of) such Category-D days – including any Category-D days 
not more than 7 days apart from some other Category-D day – and including the days in 
any gaps between them – will be called an “I-Interval”. See Figure 3. 
 An overarching interval coalescing (any number of) P-Intervals and I-Intervals – 
including any such P-or-I-intervals with an end date not more than 7 days prior to the 
start date of some other P-or-I-Interval or with a start date not more than 7 days after the 
end date of some other P-or-I-interval – and including the days in any gaps between them 
– will be called a “QQ-Interval”. This QQ-interval will represent the consolidated 
duration of several exacerbations recorded on different CRF pages or identified from 
subject diary data. This QQ-Interval will be considered to be a single event of an any-
severity COPD exacerbation. See Figure 4. 
Figure 3  
Overarching Intervals (I) of Mild-Moderate-or-Severe COPD Exacerbation Events 
Based on e-Diary Symptom Data 
D D D D D D D D  5 days  D D D D D D  9 days  D D D      10 days    D D
I 
 
I 
 
I 
A Category-D day is a day with mild-moderate-or-severe COPD exacerbation based on e-diary symptom data. 


 
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Date:  17 Jul 2017 
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An I-Interval is an overarching mild-moderate-or-severe COPD exacerbation event encompassing multiple clusters 
of e-diary symptom days. 
 
Figure 4  
Overarching Intervals (QQ) of Mild-Moderate-or-Severe COPD Exacerbation 
Events Incorporating Both CRF Data and e-Diary Symptom Data  
P 
2 days 
I 
3 days
I 
 10 days  
P 
QQ 
 
QQ 
A P-Interval is a moderate-to-severe COPD exacerbation instance from a single CRF page. 
An I-Interval is an overarching mild-moderate-or-severe COPD exacerbation event based on e-diary symptom data. 
A QQ-Interval is an overarching mild-moderate-or-severe COPD exacerbation event – encompassing multiple P-
Intervals and I-Intervals – incorporating both CRF data and e-diary symptom data. 
 
In summary, we combine CRF based moderate-or-severe COPD exacerbation events if they are close 
enough together in time ( 
Figure 2). We also combine severe COPD exacerbation events with other severe COPD exacerbation 
events or with moderate-or-severe COPD exacerbation events if they are close enough together in time 
(Error! Reference source not found.) – thus forming a single severe COPD exacerbation event. We 
also combine mild-moderate-or-severe COPD exacerbations if they are close enough together in 
time; this coalescing is done first within-data-source (CRF [ 
Figure 2] or diary [Figure 3]) and then between the two sources (Figure 4). 
Time-at-Risk for COPD Exacerbations of Various Severities: Operational Definition 
 During a time when a subject is not experiencing a severe COPD exacerbation (i.e. QS 
interval) – and is not in the seven days following a severe COPD exacerbation – a subject 
is considered to be at risk of having a severe exacerbation. During a time when a subject 
is not experiencing a moderate-or-severe COPD exacerbation (i.e. QMS interval) – and is 
not in the seven days following a moderate-or-severe COPD exacerbation – a subject is 
considered to be at risk of having a moderate-or-severe exacerbation. During a time when 
a subject is not experiencing an any-severity COPD exacerbation (i.e. QQ interval) – and 
is not in the seven days following an any-severity COPD exacerbation – a subject is 
considered to be at risk of having an any-severity exacerbation. 
Overarching coalesced intervals (i.e. events) of COPD exacerbation will be listed for severe 
exacerbations, moderate -to-severe exacerbations, and any-severity exacerbations (Listing 
6.1.2.3). A severe COPD exacerbation event must be classified also as a moderate-to-severe 
event and also as an any-severity event. A moderate-to-severe COPD exacerbation event must be 
classified also as an any-severity event. 
The count of COPD exacerbations of any severity is the number of QQ-Intervals (for a subject) 
as defined previously. Time during an exacerbation (of any severity) or in the 7 days following 
an exacerbation (of any severity) will not be included in the calculation of exposure (i.e. time at 


 
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risk). Data related to COPD exacerbations of any severity are summarized in Table 3.1.7 and 
listed in Listings 6.1.2.1, 6.1.2.2 and 6.1.2.3. 
6.5.4 
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) 
The EXACT is a 14-item patient reported outcome (PRO) daily diary which will be used to 
measure the effect of treatment on exacerbations, and on the severity of respiratory symptoms. 
The E-RS is an 11-item subset which will be used to measure the effect of treatment on the 
severity of respiratory symptoms. 
Mean change from baseline in: the daily EXACT Total Score, the daily total symptom score 
(RS-Total Score), as well as 3 subscale scores, RS-Breathlessness, RS-Cough and Sputum, and 
RS-Chest Symptoms, will be calculated over each 4-week interval of the 52-week Treatment 
Period and over the entire 52-week Treatment Period. The last 7 days of the Screening Period 
from lead-in Study PT010006 will be used to calculate the baseline. The mean change from 
baseline in RS-Total Score, RS-Breathlessness, RS-Cough and Sputum, and RS-Chest 
Symptoms will be summarized by treatment group over 52 weeks and over each post-
randomization 4-week interval (Interval 1 to Interval 13) (Tables and Figures 3.1.8 and 3.1.9 and 
Tables 3.1.10, 3.1.11 and 3.1.12). 
EXACT data will be listed in Listing 6.1.5. 
6.5.5 
Baselines and Baseline Covariates for Analysis: 
For the diary symptom score parameters (including EXACT) and rescue medication usage, 
baseline will be the mean of the non-missing values from the diary data collected in the last 
seven days of the Screening Period. 
Baseline COPD exacerbation history 0, 1, ≥ 2 moderate or severe exacerbations) (from the Visit 
1 CRF page) is the number of COPD exacerbations in the last 12 months. 
ICS (inhaled corticosteroid) use at screening (Yes or No) is to be determined with the input of 
medical expert(s) based on a list of medications that subjects were taking during the screening 
period (and which may be but are not necessarily ongoing medications) prior to unblinding of the 
study database. 
Baseline age is the age in years at the time of Informed Consent. 
6.5.6 
Visits and Time Windows for Visit-Based Efficacy Assessments: 
Efficacy data obtained during unscheduled visits will not be used for by-visit analyses. Efficacy 
from scheduled and unscheduled visits will be listed. 


 
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7. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL  
The rate of severe COPD exacerbations has been added as an efficacy endpoint.  
Any further changes to statistical methods planned in the protocol or in this statistical analysis 
plan will be documented in a revision to this statistical plan prior to database lock, or identified 
in the clinical study report. 
8. 
STATISTICAL SOFTWARE 
Data processing, statistical screening, descriptive reporting and analysis of the efficacy and 
safety data will be
 
 
 


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9.
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