Clinical trial NCT03131167
Conditions: Primary Open-angle Glaucoma (POAG) Ocular Hypertension
Sponsor: Shire
Start date: 2017-05-10; Completion date: 2018-05-30
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Safety and tolerability of three different concentrations (0.1%, 03%, 0.6%) of the investigational SHP639 eye drops will be evaluated in participants with high eye pressure or primary open-angle glaucoma.

Detailed description:

Arms: arm 1: Participants are divided into groups called cohorts. There will be approximately 12 cohorts, each consisting of 7 participants. In each cohort 5 out of 7 participants will be assigned a specified concentration of SHP639 (0.1%, 0.3%, or 0.6%) ophthalmic solution and a specific dosing schedule (the study participants will be instructed to insill the study drug one, two, three, or four times a day) in both eyes during the study. arm 2: In each cohort 2 out of 7 participants will be assigned a placebo ophthalmic solution matched to 0.1%, 0.3%, and 0.6% SHP639 ophthalmic solution and specific dosing schedule (the study participants will be instructed to instill the study drug one, two, three, or four times a day) in both eyes during the study.
Interventions: intervention 1: SHP639 (n=60) intervention 2: Placebo Comparator (n=24)
Intervention descriptions: intervention 1: Drug SHP639 is a 9-amino acid, synthetic, C-type natriuretic peptide (CNP) analog. intervention 2: Drug: Vehicle Ophthalmic placebo solution of the same composition as the test product.

Protocol documents:
Prot_000.pdf: 
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CONFIDENTIAL
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11 May 2018
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................4
ADDITIONAL CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
ABBREVIATIONS .......................................................................................................................13
STUDY SYNOPSIS ......................................................................................................................15
STUDY SCHEDULES..................................................................................................................22
1.
BACKGROUND INFORMATION.......................................................................................34
1.1
Indication and Current Treatment Options...............................................................34
1.2
Product Background.................................................................................................35
1.2.1
Nonclinical Information.........................................................................................35
1.2.2
Clinical Information...............................................................................................36
1.3
Risk/Benefit and Ethical Assessment.......................................................................37
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................39
2.1
Rationale for the Study.............................................................................................39
2.2
Study Objectives ......................................................................................................39
2.2.1
Primary Objectives.................................................................................................39
2.2.2
Secondary Objectives.............................................................................................39
2.2.3
Exploratory Objectives ..........................................................................................39
3.
STUDY DESIGN ...................................................................................................................40
3.1
Study Design and Flow Chart ..................................................................................40
3.1.1
Designated Study Eye............................................................................................40
3.1.2
Screening Period....................................................................................................41
3.1.3
Study Parts .............................................................................................................41
3.1.4
Cohorts A1-A3.......................................................................................................41
3.1.4.1
Cohorts A1-A3: Single-dose Treatment Period .....................................41
3.1.4.2
Cohorts A1-A3: Multiple-dose Treatment Period..................................42
3.1.5
Cohorts B1-B3, C1-C3, and D1-D3.......................................................................42
3.2
Duration and Study Completion Definition .............................................................43
3.3
Sites and Regions .....................................................................................................43
4.
STUDY POPULATION.........................................................................................................44
4.1
Inclusion Criteria......................................................................................................44
4.2
Exclusion Criteria.....................................................................................................45


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4.3
Restrictions...............................................................................................................47
4.4
Reproductive Potential .............................................................................................47
4.4.1
Female Contraception............................................................................................47
4.4.2
Male Contraception................................................................................................48
4.5
Discontinuation of Subjects .....................................................................................48
4.5.1
Subject Withdrawal Criteria ..................................................................................48
4.5.2
Reasons for Discontinuation..................................................................................49
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................49
4.5.4
Stopping Criteria for Dose Escalation ...................................................................49
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................51
5.1
Prior Treatment ........................................................................................................51
5.2
Concomitant Treatment............................................................................................51
5.2.1
Permitted Treatment...............................................................................................51
5.2.2
Prohibited Treatment .............................................................................................51
6.
INVESTIGATIONAL PRODUCT ........................................................................................54
6.1
Identity of Investigational Product...........................................................................54
6.1.1
Masking the Treatment Assignment ......................................................................54
6.2
Administration of Investigational Products..............................................................54
6.2.1
Interactive Response Technology for Investigational Product Management ........54
6.2.2
Allocation of Subjects to Treatment ......................................................................55
6.2.3
Dosing....................................................................................................................55
6.2.3.1
Dosing Procedures..................................................................................55
6.2.3.2
Dose Escalation......................................................................................56
6.2.4
Unmasking the Treatment Assignment..................................................................58
6.3
Labeling, Packaging, Storage, and Handling ...........................................................58
6.3.1
Labeling .................................................................................................................59
6.3.2
Packaging...............................................................................................................59
6.3.3
Storage ...................................................................................................................59
6.3.4
Special Handling....................................................................................................60
6.4
Drug Accountability.................................................................................................60
6.5
Subject Compliance..................................................................................................61
6.6
Retention of Bioavailability and Bioequivalence Testing Samples.........................61
7.
STUDY PROCEDURES........................................................................................................62
7.1
Study Schedule.........................................................................................................62
7.1.1
Screening Period....................................................................................................62
7.1.1.1
Screening Failure....................................................................................63
7.1.1.2
Rescreening of Subjects .........................................................................63
7.1.1.3
Washout Period 1 ...................................................................................63


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7.1.2
Treatment Period....................................................................................................63
7.1.2.1
Day -2 Through Day 2, Single-dose Treatment Period (Cohort A 
Only).......................................................................................................63
7.1.2.2
Day -2 Through Day 29, Multiple-dose Treatment Period (All 
Cohorts)..................................................................................................64
7.1.3
Follow-up...............................................................................................................65
7.1.4
Additional Care of Subjects after the Study ..........................................................65
7.2
Study Evaluations and Procedures ...........................................................................65
7.2.1
Demographic and Other Baseline Characteristics .................................................65
7.2.2
Safety .....................................................................................................................65
7.2.2.1
Medical and Medication History............................................................66
7.2.2.2
Physical Examination (Including Height and Weight) ..........................66
7.2.2.3
Ophthalmologic Examination ................................................................67
7.2.2.4
Adverse Event Collection.......................................................................71
7.2.2.5
Vital Signs..............................................................................................72
7.2.2.6
Clinical Laboratory Evaluations.............................................................74
7.2.2.7
Pregnancy Test .......................................................................................75
7.2.2.8
Drug and Alcohol Screen .......................................................................75
7.2.2.9
Serology Screen......................................................................................76
7.2.2.10
Antidrug Antibody Testing ....................................................................76
7.2.2.11
Electrocardiogram ..................................................................................76
7.2.3
Pharmacokinetic Procedures..................................................................................77
7.2.3.1
Pharmacokinetic Sample Collection and Handling Procedures.............78
7.2.3.2
Shipment of Pharmacokinetic Samples..................................................78
7.2.3.3
Plasma Drug Assay Methodology..........................................................78
7.2.4
Pharmacodynamic Assessments ............................................................................79
7.2.5
Volume of Blood to Be Collected from Each Subject...........................................79
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................81
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................81
8.1.1
Severity Categorization..........................................................................................81
8.1.2
Relationship Categorization...................................................................................82
8.1.3
Outcome Categorization ........................................................................................82
8.1.4
Ocular and Nonocular Categorization ...................................................................83
8.1.5
Symptoms of the Disease under Study ..................................................................83
8.1.6
Clinical Laboratory and Other Safety Evaluations................................................83
8.1.7
Pregnancy...............................................................................................................83
8.1.8
Abuse, Misuse, Overdose, and Medication Error..................................................84


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8.2
Serious Adverse Event Procedures ..........................................................................85
8.2.1
Reference Safety Information................................................................................85
8.2.2
Reporting Procedures.............................................................................................85
8.2.3
Serious Adverse Event Definition .........................................................................85
8.2.4
Serious Adverse Event Collection Time Frame.....................................................86
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................86
8.2.6
Fatal Outcome........................................................................................................86
8.2.7
Regulatory Agency, Institutional Review Board, and Site Reporting...................86
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................88
9.1
Data Collection.........................................................................................................88
9.2
Clinical Data Management.......................................................................................88
9.3
Data Handling Considerations..................................................................................88
9.4
Statistical Analysis Process......................................................................................88
9.5
Planned Interim Analysis, Adaptive Design, and Dose Escalation Committee.......89
9.6
Sample Size Calculation and Power Considerations................................................89
9.7
Study Population ......................................................................................................90
9.8
Pharmacokinetic and Pharmacodynamic Analyses..................................................90
9.8.1
Pharmacokinetic Analysis......................................................................................90
9.8.1.1
Pharmacokinetic Endpoints....................................................................90
9.8.1.2
Statistical Analysis of Pharmacokinetic Parameters ..............................90
9.8.2
Pharmacodynamic Analysis...................................................................................91
9.8.2.1
Pharmacodynamic Endpoints.................................................................91
9.8.2.2
Statistical Analysis of Pharmacodynamic Parameters ...........................91
9.8.3
Pharmacokinetic and Pharmacodynamic Analysis ................................................92
9.9
Safety Analyses........................................................................................................92
9.9.1
Safety Endpoints....................................................................................................92
9.9.2
Statistical Analysis of Safety Data.........................................................................92
9.10
Other Analyses .........................................................................................................92
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................93
10.1
Sponsor’s Responsibilities .......................................................................................93
10.1.1 Good Clinical Practice Compliance.......................................................................93
10.1.2 Public Posting of Study Information......................................................................93
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................93
10.1.4 Study Suspension, Termination, and Completion..................................................94
10.2
Investigator’s Responsibilities .................................................................................94
10.2.1 Good Clinical Practice Compliance.......................................................................94
10.2.2 Protocol Adherence and Investigator Agreement..................................................94


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11 May 2018
10.2.3 Documentation and Retention of Records.............................................................95
10.2.3.1
Case Report Forms.................................................................................95
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................95
10.2.3.3
Audit/Inspection.....................................................................................96
10.2.3.4
Financial Disclosure...............................................................................96
10.3
Ethical Considerations..............................................................................................96
10.3.1 Informed Consent...................................................................................................96
10.3.2 Institutional Review Board or Ethics Committee..................................................97
10.4
Privacy and Confidentiality......................................................................................97
10.5
Study Results/Publication Policy .............................................................................98
11. REFERENCES .....................................................................................................................100
12. APPENDICES ......................................................................................................................102
Appendix 1
Protocol History ...................................................................................103
Appendix 2
Anterior Segment Graded Assessments ...............................................110


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11 May 2018
LIST OF TABLES
Table 1
Overall Schedule of Events ...........................................................................22
Table 2
Detailed Schedule of Events – Cohort A.......................................................26
Table 3
Detailed Schedule of Events – Cohort B.......................................................28
Table 4
Detailed Schedule of Events – Cohort C.......................................................30
Table 5
Detailed Schedule of Events – Cohort D.......................................................32
Table 6
Dose Margins Based on SHP639 Concentration and Dosing Regimen........38
Table 7
Dose Margins Based on SHP639 Daily Dose ...............................................38
Table 8
Common Excluded Medications and Associated Washout Period ...............52
Table 9
SHP639 Drug Substance per Drop of SHP639 Ophthalmic Solution...........54
Table 10
Anticipated Dose-escalation Scheme ............................................................57
Table 11
Volume of Blood to Be Collected from Each Subject in Each 
Treatment Regimen: Cohort A ......................................................................79
Table 12
Volume of Blood to Be Collected from Each Subject in Each 
Treatment Regimen: Cohorts B, C, and D ....................................................80
LIST OF FIGURES
Figure 1
Procedures for Screening Vital Signs (Blood Pressure – Pulse) ...................73


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CONFIDENTIAL
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11 May 2018
ABBREVIATIONS
ADA
antidrug antibody
AE
adverse event
AMD
age-related macular degeneration
AUC0-t
area under the observed concentration vs time curve from time zero (predose) to the time of 
the last measurable concentration
AUC0-τ
area under the observed concentration vs time curve over the dosing interval 
AUC0-∞
area under the observed concentration vs time curve from time zero (predose) extrapolated to 
infinity
BCVA
best-corrected visual acuity
-hCG
beta-human chorionic gonadotropin
BID
twice daily
cGMP
cyclic guanosine monophosphate
CI
confidence interval
CL/F
apparent clearance
Cmax
maximum observed concentration
CNP
C-type natriuretic peptide
CS
clinically significant
CRO
contract research organization
EC50
half maximum effective concentration
ECG
electrocardiogram
eCRF
electronic case report form
Emax
maximum percentage intraocular pressure reduction from baseline
EMA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HVF
Humphrey visual field
IA
interim analysis
IB
investigator's brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IOP
intraocular pressure
IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous


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CONFIDENTIAL
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SHP639-101 Protocol Amendment 3
SHP639
11 May 2018
MDTP
multiple-dose treatment period
MWOA
midwashout ophthalmic assessment
NCS
not clinically significant
NHP
nonhuman primates
NOAEL
no-observed-adverse-effect level
NPDR
nonproliferative diabetic retinopathy
NPR-A
natriuretic peptide receptor A
NPR-B
natriuretic peptide receptor B
OHT
ocular hypertension
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
POAG
primary open-angle glaucoma
QD
once daily
QID
4 times daily
QTcB
QT interval corrected for heart rate using the Bazett formula
QTcF
QT interval corrected for heart rate using the Fridericia formula
Rac(AUC)
accumulation ratio based on area under the curve
Rac(Cmax)
accumulation ratio based on maximum observed concentration
SAE
serious adverse event
SAP
statistical analysis plan
SDTP
single-dose treatment period
t½
apparent terminal phase elimination half-life
TEmax
time to the maximum reduction
TID
3 times daily
tmax
time to reach maximum observed concentration
US
United States
Vz/F
apparent volume of distribution


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CONFIDENTIAL
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11 May 2018
A sufficient number of subjects will be screened and enrolled to ensure that at least 6 of 7 subjects complete each 
treatment in their assigned cohort. In the event that a sufficient number of subjects do not complete a cohort, 
replacement subjects may be enrolled. Each replacement subject will follow the same screening procedures and 
randomization sequence as the subject who is discontinued, regardless of when the subject discontinued. The 
anticipated doses being studied for each dosing regimen are as follows:
Treatment Regimen
Doses
Single-dose or QD
A1
0.1%/Placebo
A2
0.3%/Placebo
A3
0.6%/Placebo
BID
B1
0.1%/Placebo
B2
0.3%/Placebo
B3
0.6%/Placebo
TID
C1
0.1%/Placebo
C2
0.3%/Placebo
C3
0.6%/Placebo
QID
D1a
0.1%/Placebo
D2
0.3%/Placebo
D3
0.6%/Placebo
BID=twice daily; QD=once daily; QID= 4 times daily; TID= 3 times daily.
a The dose-escalation committee decided not to enroll cohort D1, agreeing that the results would not add to the understanding 
of the safety of SHP639.
Screening Period
For all cohorts, the maximum duration of the screening period is 42 days. On the initial visit to the site, the subject 
will first give informed consent. This will be the date that he/she enters the screening period. After giving consent, 
the subject will be evaluated against the inclusion and exclusion criteria and undergo screening procedures. During 
the screening period, subjects will return to the site approximately every 2 weeks for safety evaluations. If 
necessary, subjects will undergo a washout period from their current medications.
Following the screening visit, subjects who continue to meet the protocol-specific inclusion and exclusion criteria 
will return to the site on either Day-3 or Day -2, to reconfirm eligibility criteria for participation and undergo 
predose safety and ophthalmologic assessments.
Study Parts
The study will consist of 2 parts, Part 1 and Part 2.

Part 1 consists of Cohorts A1, A2, and A3, each of which is a single-dose and QD multiple-dose cohort 
(1 cohort for each of the 3 dose levels), followed by Cohorts B1, B2, and B3, each of which is a BID 
multiple-dose cohort (1 cohort for each dose level).

Part 2 consists of Cohorts C1, C2, and C3, each of which is a TID multiple-dose cohort (1 cohort for each dose 
level), followed by Cohorts D1, D2, and D3, each of which is a QID multiple-dose cohort (1 cohort for each 
dose level).
Cohorts A1-A3
In Cohorts A1, A2, and A3, there will be a single-dose treatment period (SDTP) followed by a multiple-dose 
treatment period (MDTP).
In the SDTP, subjects will be randomized prior to administration of investigational product on Day 1 after all entry 
criteria have been confirmed. One drop of investigational product will be administered topically to a designated eye. 
The first 3 of 7 subjects will be dosed with a minimum of 1-hour intervals between the subjects for safety purposes. 
The subject will then undergo safety, ophthalmologic, and PK assessments. Subjects will be observed for the next 
24 hours with appropriate medical oversight. An ophthalmologist will be on call to assess ophthalmic-related 
medical issues. If no adverse events (AEs) occur that are consistent with the predefined stopping criteria, the rest of 


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the subjects in the cohort can be administered investigational product in 1 designated eye. 
After completion of the assessments scheduled for Day 2 of the SDTP, subjects will enter a washout period. The 
duration of the washout period will last between 3 and 14 days. A dose escalation meeting will occur prior to the 
advancement to the multidose part of each cohort. Following a decision to commence the MDTP for Cohorts A1, 
A2, and A3, subjects will attend the site on Days -2 and -1 to undergo the scheduled safety and ophthalmic 
assessments. In Cohorts A1, A2, and A3 MDTP, all subjects will be administered investigational product in both 
eyes. The same dose concentration that was administered during the SDTP of Cohorts A1, A2, or A3 will be 
administered during the MDTP QD for the next 28 days. Subjects are to place 1 drop in each eye at approximately 
the same time each day.
Within each cohort (A1, A2, or A3), subjects will continue to self-administer investigational product QD for the 
duration of the MDTP. Between Day 2 and Day 26, subjects will return to the site for scheduled outpatient visits. On 
Day 26, subjects will be readmitted to the site. On Day 27, subjects will continue to self-administer investigational 
product while undergoing the scheduled assessments. The last dose will be administered on the morning of Day 28. 
Following completion of the assessments scheduled for Day 29, subjects will then be discharged from the site.
Subjects will receive a follow-up telephone call approximately 7 days after being discharged from the site. They will 
return to the site to undergo antidrug antibody (ADA) sampling approximately 60 days after the last dose of 
investigational product.
Cohorts B1-3, C1-3, and D1-3
Authorization from the sponsor to proceed from 1 cohort to the next is to be received before subjects enter the 
screening period for Cohorts B, C, and D. Once authorization has been received from the sponsor, subjects are to be 
admitted to the screening period of the appropriate cohort as previously described in this section.
Subjects will undergo the scheduled safety and ophthalmic assessments on Day -2 and Day -1. Subjects will then be 
administered investigational product per the sponsor’s authorization to proceed to that cohort. In Cohorts B, C, and 
D, subjects will be administered investigational product in both eyes.
Subjects will continue to self-administer investigational product as instructed for the duration of the cohort. Between 
Day 2 and Day 26, subjects will return to the site for scheduled outpatient visits. On Day 26, subjects will be 
readmitted to the site. On Day 27, subjects will continue to self-administer investigational product while undergoing 
the scheduled assessments. The last dose will be administered on the morning of Day 28. After completion of the 
assessments scheduled for Day 29, subjects will then be discharged from the site.
Subjects will receive a follow-up telephone call approximately 7 days after being discharged from the site. 
They will return to the site to undergo ADA sampling approximately 60 days after the last dose of investigational 
product.
Inclusion and exclusion criteria:
Inclusion criteria
1.
Subjects must provide written, signed and dated informed consent to participate in the study in accordance with 
the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 and applicable 
regulations, before completing any study-related procedures.
2.
Subjects must be aged from 18 through 90 at the time of consent. This inclusion criterion will only be assessed 
at the screening visit.
3.
Subjects must have OHT or stable early POAG in both eyes with acceptable Humphrey visual fields (HVF). 
Early POAG for this protocol is defined as healthy appearing anterior chamber angles (Shaffer classification 
system grade 3 or 4) and focal and/or generalized thinning of the optic disc rim characteristic of glaucomatous 
disease. An acceptable HVF must have been performed within approximately one year of screening, have a 
false- positive rate of 25% maximum, false-negative rate of 25% maximum, and fixation loss rate of 33% 
maximum, and mean deviation of no worse than -6.00 dB.
4.
On Day -1, subjects must have a mean IOP of ≥24 mmHg at 8:00 AM and a mean IOP of ≥22 mmHg at 
10:00 AM in at least 1 eye, with an IOP difference of <4 mmHg between eyes at both of these time points. If 


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11 May 2018
only 1 eye meets this criterion, then it will be the designated study eye for PD analysis; this eye will also be 
used for dosing in Cohort A SDTP. 
5.
Subjects must have a best-corrected visual acuity (BCVA) in both eyes of 65 letters on the Early Treatment 
Diabetic Retinopathy Study chart (Snellen equivalent ∼20/60) or better at the screening and baseline 
assessments.
6.
Subjects must be males or females who are nonpregnant and nonlactating at screening (negative serum beta-
human chorionic gonadotropin [β-hCG]); if sexually active during the study, they must agree to comply with 
the applicable contraceptive requirements of the protocol throughout the study period and for 60 days following 
the last dose of investigational product.
7.
Subjects must have a satisfactory medical assessment with no clinically significant or relevant abnormalities as 
determined by medical history, physical examination, and clinical and laboratory evaluation (hematology, 
biochemistry, urinalysis) as assessed by the investigator.
8.
Subject must understand and be able, willing, and likely to fully comply with study procedures and restrictions.
9.
Subjects must be nonsmokers or have had stable use of tobacco or nicotine-containing products for a 3-month 
period before signing the informed consent form (ICF).
10. Subjects who drink alcohol must have had stable use of alcohol for a 3-month period before signing the ICF.
Exclusion criteria:
1.
Subject has an anatomically narrow angle, synechiae or evidence of prior inflammation, angle closure 
glaucoma, normal tension glaucoma, pseudoexfoliation syndrome or pigmentary dispersion syndrome with or 
without glaucoma, or secondary glaucoma.
2.
Subject has corneal endothelial cell counts of less than 2000 cells/mm2 (measured by noncontact specular 
microscopy) at the screening or baseline assessments. 
3.
Subject has central corneal thickness less than 500 µm or greater than 620 µm at the screening or baseline 
assessments.
4.
Subject has IOP greater than 32 mmHg in either eye before randomization.
5.
Subject has used topical ocular hypotensive medications as follows: prostaglandin analogs, β-adrenoceptor 
antagonists, α-adrenergic agonists, or epinephrine-related medications within 4 weeks before the first dose of 
investigational product; or pilocarpine or carbonic anhydrase inhibitors within 7 days before the first dose of 
investigational product.
6.
Subject has a history of angle closure, ocular surgery, microinvasive glaucoma surgery device insertion, or laser 
surgery, except for the following procedures, which are allowed: uncomplicated cataract surgery, laser 
peripheral iridotomy with resultant angle of Shaffer grade 3 or 4, and postcataract neodymium-doped yttrium-
aluminum-garnet (Nd:YAG) laser posterior capsulotomy. Cataract surgery and other procedures must have 
occurred a minimum of 3 months before randomization.
7.
Subject has a history of significant ocular trauma or ocular disease including but not limited to moderate to 
severe dry eye disease that requires chronic treatment or punctal plugs.
8.
Subject has evidence of ocular infection, inflammation, degeneration, or dystrophy at the screening or baseline 
assessments, including but not limited to moderate to severe blepharitis (mild blepharitis is allowed), 
conjunctivitis (allergic or infectious), corneal dystrophy (epithelial, stromal, or endothelial), corneal haze of 
grade 1 or greater based on the Hwang Grading Scale of Corneal Haze, corneal opacities, keratitis, uveitis, or 
vitritis.
9.
Subject has retinal disease including but not limited to: moderate or severe nonproliferative diabetic retinopathy 
(NPDR) (early NPDR is allowed), proliferative diabetic retinopathy, intermediate or advanced dry age-related 
macular degeneration (AMD) (early dry AMD is allowed), all geographic atrophy, or all wet AMD.


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SHP639-101 Protocol Amendment 3
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11 May 2018
10. Subject has any nonglaucomatous optic neuropathy or other significant nonglaucomatous ocular disease that is 
likely to affect visual function.
11. Subject has any corneal or ocular surface pathology in either eye that prevents proper IOP measurement, 
pachymetry, or other study data collection procedures.
12. Subject has had changes to their existing prescription medication regimen for chronic disease, including those 
medicines that affect IOP, within 14 days or 5 half-lives before screening, whichever is longer.
13. Subject has started any new prescription drug medication for chronic disease, including those medications that 
affect IOP, within 14 days or 5 half-lives before screening, whichever is longer.
14. Subject has a history of corticosteroid use within 3 months before randomization, except for nonperiocular 
dermatologic use, which is allowed. 
15. Subject has used belladonna alkaloids (scopolamine, hyoscyamine, atropine) within 7 days prior to 
randomization, cannabinoids or opioids within 28 days before randomization, or B-type natriuretic peptides 
within the past year before randomization; or a subject has an anticipated need for any of the aforementioned 
drugs/drug categories during the study. 
16. Subject has used amantadine within 28 days before randomization.
17. Subject is unable to discontinue contact lens use during and for 60 minutes following instillation of study 
medication, during ophthalmologic examinations, and during study visits.
18. Subject has a current or relevant history of any physical, medical, mental, or psychiatric illness, disorder, or 
condition that may require treatment during the study and/or that may interfere with the subject complying with 
the study rules and procedures or completing the study.
19. Subject has any condition that presents undue risk from use of the investigational product, assessment tools, or 
procedures.
20. Subject is a woman who is pregnant (positive serum β-hCG pregnancy test at the time of screening), lactating, 
or less than 90 days post partum at randomization. 
21. Subject has donated blood within 60 days before first dose of investigational product. 
22. Subject has donated plasma within 28 days before first dose of investigational product. 
23. Subject has used another investigational product within 30 days before the first dose of investigational product 
or is actively enrolled in a drug or vaccine clinical study.
24. Subject has a positive human immunodeficiency virus, hepatitis B surface antigen, or hepatitis C virus 
antibodies screen.
25. Subject has a positive drugs of abuse screen or alcohol breathalyzer test.
26. Subject has been previously enrolled in this study.
27. Subject has known hypersensitivity or allergy to any of the ingredients of the investigational product. 
28. Subject consumes more than 21 units of alcohol per week or is unable to refrain from alcohol consumption 
within 48 hours before a scheduled visit. (1 alcohol unit=1 beer or 1 wine [5 oz/150 mL] or 1 liquor 
[1.5 oz/40 mL] or 0.75 oz alcohol.)
29. Subject is unable to refrain from tobacco or any products containing nicotine within 8 hours before a scheduled 
visit.


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SHP639-101 Protocol Amendment 3
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Maximum duration of subject involvement in the study:
The subjects’ maximum duration of participation in the study is expected to be 146 days or approximately 5 months 
(Cohort A1, A2, and A3). The subjects’ maximum duration of participation in the study for Cohorts B, C, and D is 
expected to be 130 days or approximately 4.5 months.

Maximum planned duration of screening and Washout 1: 42 days

Planned duration of treatment period: 2 days for SDTP (Cohort A only) and 29 days for MDTP (all cohorts)

Planned duration of Washout 2 (Cohort A only): 3-14 days
Planned duration of follow-up: until Day 88±4 days
Endpoints and statistical analysis:
Study Population
The safety set will consist of all subjects who have been randomized and who have received at least 1 dose of 
investigational product. 
The PK set will consist of all subjects in the safety set for whom the primary PK data are considered sufficient and 
interpretable.
The PD set will consist of all subjects in the safety set for whom the primary PD data are evaluable.
Pharmacokinetic Endpoints
Plasma concentrations of SHP639 will be measured using a fully validated bioanalytical method. If data permit, PK 
parameters for SHP639 will be calculated based on plasma concentration-time data using a noncompartmental 
approach). Pharmacokinetic parameters may include, but are not limited to, the following: maximum observed 
concentration (Cmax); time to reach Cmax (tmax); area under the observed concentration vs time curve from time zero 
(predose) to the time of the last measurable concentration (AUC0-t), over the dosing interval (AUC0-τ) for each 
multiple-dose regimen, and from time zero (predose) extrapolated to infinity (AUC0-∞); apparent terminal phase 
elimination half-life (t½); apparent clearance (CL/F); apparent volume of distribution (Vz/F); and accumulation 
ratios based on AUC and Cmax for each multiple-dose regimen.
Pharmacodynamic Endpoints
Intraocular pressure (IOP; mmHg) will be measured using Goldmann applanation tonometry. Pharmacodynamic 
parameters will be estimated as appropriate and may include, but are not limited to, the following: change from 
baseline in IOP; time to the maximum change from baseline in IOP; and proportion of subjects maintaining IOP 
reduction after specified days of treatment. 
Specific endpoints in order to understand the effect of SHP639 on IOP will be defined in the SAP.
Safety Endpoints
Safety and tolerability will be assessed by monitoring AEs, vital sign measurements, clinical laboratory assays, 
electrocardiogram (ECG), ADA, drop comfort assessment, and ophthalmologic examinations.
Sample Size Justification 
The number of subjects in this study is not based on statistical power considerations because the statistical analyses 
are primarily descriptive in nature. However, if at least 7 subjects complete each cohort, then there will be at least 
65- 85% probability of observing at least 1 occurrence of any AE with a true incidence rate for a given dose group 
of at least 15- 25%, respectively.
It is estimated that dose escalation will occur for up to 3 dose levels (4 cohorts within each dose level). Each cohort 
will include 5 subjects randomized to active drug and 2 subjects randomized to placebo for an estimated total of at 
least 84 subjects.
For each cohort, the number of subjects will be increased as needed based on safety and IOP response. Any cohort
can be repeated to confirm findings with regard to safety or IOP response.


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Statistical Methodology for Pharmacokinetic Endpoints
All plasma PK analyses will be performed using the PK set. Summary statistics (number of observations, mean, 
standard deviation [SD], coefficient of variation, median, maximum [max], minimum [min], and geometric mean) 
will be determined for all plasma PK parameters and will be presented by dose, cohort, treatment period (single dose 
or multiple dose; Cohort A only), and study day. Plasma concentrations at each nominal sampling time will also be 
summarized using descriptive statistics.
For accumulation ratios, the 95% confidence interval (CI) for the arithmetic mean of the difference (for example, 
AUC0-τ [Day 27] - AUC0-τ [Day 1]) on the logarithmic scale (natural base) will be calculated. The results will be 
back-transformed to give the ratio of geometric means together with the corresponding 95% CI.
Before statistical comparisons, dose-dependent parameters (Cmax, AUC0-t, AUC0-τ, and AUC0-∞) will be normalized 
to a common dose, assuming linearity. Additionally, the linear dose proportionality will be evaluated for Cmax, 
AUC0-τ, AUC0-t, and AUC0-∞using the power function model (eg, Cmax=α·Doseβ or equivalently 
log[Cmax]=log[α]+β·log[Dose], where Cmax is considered to increase linearly proportional to dose if β is not 
significantly different from 1.0.
Statistical Methodology for Pharmacodynamic Endpoints
All PD analyses will be performed using the PD set.
Descriptive summary statistics for IOP (number of subjects, mean, SD, median, min, and max) will be provided by 
dose, cohort, treatment period (single dose or multiple dose; Cohort A only), and study day. Additionally, 95% CIs 
for each estimate and summary statistics of change from baseline along with 95% CIs will be calculated. 
Pharmacodynamic parameters will be calculated and summarized by dose, cohort, treatment period (single dose or 
multiple dose; Cohort A only), and study day as applicable.
All IOP data will be listed by dose, cohort, subject, treatment period (single dose or multiple dose; Cohort A only), 
and study day.
Statistical methodology for PK/PD relationship
The relationship between dose of SHP639 ophthalmic solution, plasma PK parameters, and changes in IOP may be 
explored using graphical and/or regression methods if the data permit.
Statistical Methodology for Safety Endpoints
All safety analyses will be performed using the safety set. The placebo subjects will be pooled together as a pooled 
placebo group.
All vital sign, clinical laboratory, ECG, ADA, drop comfort assessment, and ophthalmologic examination data (per 
schedule of events) will be listed by dose, cohort, subject, treatment period (single dose or multiple dose; 
Cohort A only), visit, day, and time point (for days with multiple assessments per day). If the ranges are available 
then abnormalities will be flagged. Summary statistics with number of subjects, mean, standard deviation, median, 
minimum, and maximum will be provided by dose, cohort, treatment period (single dose or multiple dose; Cohort A 
only), visit, day, and time point (for days with multiple assessments per day).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The number of events, 
incidence, and percentage of treatment-emergent AEs will be calculated overall and by system organ class and 
preferred term by dose and cohort. Treatment-emergent AEs will be further summarized by severity and relationship 
to investigational product. Adverse events related to investigational product, AEs leading to withdrawal, serious 
AEs, and deaths will be similarly summarized/listed. All information obtained on AEs will be displayed by dose, 
cohort, subject, treatment period (single dose or multiple dose; Cohort A only), visit, and day. A subject with 
multiple AEs within a body system will be counted only once.










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Table 2
Detailed Schedule of Events – Cohort A
Assessment
Days Performed (Screening through D29)f
Predose/
Morninga 0 m
30 
m
1 h 2 h 3 h 4 h 6 h
8 h
12 h
Assessment Window (minutes)
0
±5 ±15 ±15 ±15 ±15 ±15 ±15
±15
Dosing
SDTP: D1. MDTP: D1 through D28g
X
PK blood sampling
SDTP: D1. MDTP: D1, D27
X
X
X
X
X
X
Drop comfort assessmentb
SDTP: D1. MDTP: D1, D7, D14, D21, D27, D28
X
Physical examination
SCR. SDTP: D-2, D2. MDTP: D-2, D14, D26, D29
X
Vital signs 
All visits except Day 88/FU
X
X
X
X
ECG 
All visits except MWOA, Day 28, and Day 88/FUh
X
X
X
X
BCVA 
All visits except Day 26 and Day 88/FU
X
X
X
Manifest refraction
SCR. SDTP: D-2 MDTP: D-2, D29.
X
Slit lamp examination of 
anterior segmentc
SCR, D-14, SDTP: D-2, D-1, D1, D2. MDTP: D-2 and D-1, D1, 
D2, D7, D14, D21, D27, D28, D29
X
X
X
Conjunctival redness
SCR, D-14, SDTP: D-2,D-1, D1, D2. MDTP: D-2 and D-1, D1, D2, 
D7, D14, D21, D27, D28, D29.
X
X
X
X
X
Corneal haze
SCR, D-14. SDTP:D-2,D-1, D1, D2. MDTP: D-2 and D-1), D1, 
D2, D7, D14, D21, D27, D28, D29
X
X
X
X
X
Corneal epithelial integrity 
using fluorescein stain
SCR, D-14, SDTP: D-2, D-1, D1, D2. MDTP: D-2,D-1, D1, D2, 
D7, D14, D21, D27, D28, D29
X
X
X
X
X
Anterior chamber cell and flare SCR, D-14, SDTP: D-2, D-1, D1, D2. MDTP: D-2, D-1), D1, D2, 
D7, D14, D21, D27, D28, D29
X
X
X
Lens opacification
SCR, D29
X
IOP, abbreviated schedule
SCRe, D-14d, MDTP: D7, D14, D21, D29d
X
X
X
X
X
IOP, full schedule
SDTP: D-2, D-1, D1, D2. MDTP: D-2 and D-1, D1, D2, D27, D28.
X
X
X
X
X
X
X
X
X
Posterior segment examination
SCR (dilated). SDTP: D-2; nondilated. MDTP: D-2; nondilated, 
D29 (dilated)
X
Gonioscopye
SCR,D29
X
Specular microscopy, 
noncontact
SCR. SDTP: D-1, D2. MDTP: D-1, D14, D29
X
Corneal pachymetry
SCR. SDTP: D-1D1, D2. MDTP: D-1, D1, D2, D7, D14, D29
X
X
X
X
X
Antidrug Ab blood sampling
D-2, D14, D29, D88/FU. 
X
Drugs of abuse
SCR, D-14, SDTP: D-2, MDTP: D-2 and D-1, D1, D14, D21, D26. 
X


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CONFIDENTIAL
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Table 2
Detailed Schedule of Events – Cohort A
Assessment
Days Performed (Screening through D29)f
Predose/
Morninga 0 m
30 
m
1 h 2 h 3 h 4 h 6 h
8 h
12 h
Assessment Window (minutes)
0
±5 ±15 ±15 ±15 ±15 ±15 ±15
±15
Alcohol breath test
SCR, D-14, SDTP: D-2, MDTP: D-2 and D-1, D1, D14, D21, D26. 
X
Serum pregnancy test (female 
subjects)
SCR, SDTP: D-2, MDTP: D-2, D1, D26, D29
X
Biochemistry, hematology, and 
urinalysis
SCR, SDTP: D-2, D2. MDTP: D-2, D1, D7, D14, D21, D26, D27, 
D29.
X
Ab=antibody; BCVA=best-corrected visual acuity; D=day; ECG=electrocardiogram; FU=follow up; h=hours; IOP=intraocular pressure; m=minutes; MDTP=multiple-dose 
treatment period; PK=pharmacokinetic; SCR=screening; SDTP=single-dose treatment period.
a Assessments will take place 60-30 minutes before dosing or in the morning on nondosing days.
b Drop comfort assessments will be obtained immediately, 1, 2, and 3 minutes after instillation of the investigational product; to be assessed at morning doses only. If the score is 
not ≤3 at minute 3, the drop comfort assessment should be repeated at minutes 5, 10, and 15 until the score is ≤3. If the score is >3 at minute 15, it should be recorded as an 
adverse event.
c Slit lamp examination of anterior segment will be performed only during the morning assessment on the following days: Screening, Day -14, SDTP Day -2, SDTP Day -1, 
MDTP Day -2, MDTP Day -1, and Day 29.
d At screening IOP may be done at any time during the day. At MWOA (D-14), IOP should be done at 10:00am +3 hours. IOP only needs to be done at one time during 
screening, MWOA, and Day 29.
e Gonioscopy at screening can be done at any time of day. Gonioscopy on Day 29 will be performed at the morning time point.
f Ophthalmologic assessments on screening, MWOA (D-14), and Day 29 need to be done one time during the day only. 
These assessments include: BCVA, Manifest Refraction (Screening), Slit Lamp examination of anterior segment, Conjunctival Redness, Corneal Haze, Corneal Epithelial 
integrity using fluorescein stain, Anterior Chamber cell and flare, Lens Opacification, IOP, Posterior Segment Examination, dilated (Screening and Day 29), Specular 
Microscopy, Noncontact (Screening and Day 29), Corneal Pachymetry (Screening and Day 29)
g Subjects will be administered the last dose of study drug on the morning of Day 28.
h ECG is to be performed at one time point only on Day 26 and Day 29
Timings relate to dose administration or the equivalent morning assessment. Refer to Section 7.1 for guidance on the priority order of assessments. Assessments on nondosing days 
(screening, baseline, and Day 29) will take place once in the morning only unless otherwise specified.


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Table 3
Detailed Schedule of Events – Cohort B
Assessment
Days Performed (Screening through D29)f
Predose/
Morninga 0 m
30 m 1 h 2 h 3 h 4 h
6 h
8 h 12 h
Assessment Window (minutes)
0
±5
±15 ±15 ±15 ±15 ±15 ±15 ±15
Dosing
D1 through D28g
X
X
PK blood sampling
D1, D27
X
X
X
X
X
X
Drop comfort assessmentb
D1, D7, D14, D21, D27, D28
X
Physical examination
SCR, D-2, D14, D26, D29
X
Vital signs 
All visits except Day 88/FU
X
X
X
X
ECG 
All visits except MWOA, Day 28, and Day 88/FUh
X
X
X
X
BCVA
All visits except Day 26 and Day 88/FU
X
X
X
Manifest refraction
SCR, D-2, D29
X
Slit lamp examination of anterior 
segmentc
SCR, D-14, D-2,D-1, D1, D2, D7, D14, D21, D27, D28, D29
X
X
X
Conjunctival redness
SCR, D-14,D-2,D-1, D1, D2, D7, D14, D21, D27, D28, D29
X
X
X
X
X
Corneal haze
SCR, D-14, D-2,D-1, D1, D2, D7, D14, D21, D27, D28, D29
X
X
X
X
X
Corneal epithelial integrity using 
fluorescein stain
SCR, D-14, D-2,D-1, D1, D2, D7, D14, D21, D27, D28, D29
X
X
X
X
X
Anterior chamber cell and flare 
SCR, D-14. D-2,D-1, D1, D2, D7, D14, D21, D27, D28, D29
X
X
X
Lens opacification
SCR, D29
X
IOP, abbreviated schedule
SCRe, D-14d, D7, D14, D21, D29d
X
X
X
X
X
IOP, full schedule
D-2, D-1, D1, D2, D27, D28.
X
X
X
X
X
X
X
X
X
Posterior segment examination
SCR (dilated), D-2; nondilated, D29 (dilated)
X
Gonioscopye
SCR, D29
X
Specular microscopy, noncontact SCR, D-1, D14, D29
X
Corneal pachymetry
SCR, D-1, D1, D2, D7, D14, D29
X
X
X
X
X
Antidrug Ab blood sampling
D-2, D14, D29, D88/FU 
X
Drugs of abuse
SCR, D-14), D-2 and D-1, D1, D14, D21, D26
X


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Table 3
Detailed Schedule of Events – Cohort B
Assessment
Days Performed (Screening through D29)f
Predose/
Morninga 0 m
30 m 1 h 2 h 3 h 4 h
6 h
8 h 12 h
Assessment Window (minutes)
0
±5
±15 ±15 ±15 ±15 ±15 ±15 ±15
Alcohol breath test
SCR, D-14, D-2, D-1, D1, D14, D21, D26
X
Serum pregnancy test (female 
subjects)
SCR, D-2 D1, D26, D29.
X
Biochemistry, hematology, and 
urinalysis
SCR, D-2, D1, D7, D14, D21, D26, D27, D29.
X
Ab=antibody; BCVA=best-corrected visual acuity; D=day; ECG=electrocardiogram; FU=follow up; h=hours; IOP=intraocular pressure; m=minutes; MDTP=multiple-dose 
treatment period; PK=pharmacokinetic; SCR=screening.
a Assessments will take place 60-30 minutes before the first dose of the day or in the morning on nondosing days.
b Drop comfort assessments will be obtained immediately, 1, 2, and 3 minutes after instillation of the investigational product; to be assessed at morning doses only. If the score is 
not ≤3 at minute 3, the drop comfort assessment should be repeated at minutes 5, 10, and 15 until the score is ≤3. If the score is >3 at minute 15, it should be recorded as an 
adverse event.
c Slit lamp examination of anterior segment will be performed only during the morning assessment on the following days: Screening, Day -14, Day -2, Day -1 and Day 29.
d At screening IOP may be done at any time during the day. At MWOA (D-14), IOP should be done at 10:00am +3 hours. IOP only needs to be done at one time during screening, 
MWOA, and Day 29.
e Gonioscopy at screening can be done at any time of day. Gonioscopy on Day 29 will be performed at the morning time point.
f Ophthalmologic assessments on screening, MWOA (D-14), and Day 29 need to be done one time during the day only. 
These assessments include: BCVA, Manifest Refraction (Screening), Slit Lamp examination of anterior segment, Conjunctival Redness, Corneal Haze, Corneal Epithelial 
integrity using fluorescein stain, Anterior Chamber cell and flare, Lens Opacification, IOP, Posterior Segment Examination, dilated (Screening and Day 29), Specular 
Microscopy, Noncontact (Screening and Day 29), Corneal Pachymetry (Screening and Day 29).
g Subjects will be administered the last dose of study drug on the morning of Day 28.
h ECG is to be performed at one time point only on Day 26 and Day 29.
Timings relate to the first dose of the day or the equivalent morning assessment. Refer to Section 7.1 for guidance on the priority order of assessments. Assessments on nondosing 
days (screening, baseline, and Day 29) will take place once in the morning only unless otherwise specified.


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Table 4
Detailed Schedule of Events – Cohort C
Assessment
Days Performed (Screening through D29)f
Predose/
Morninga
0 m
30 
m
1 h 2 h 3 h 4 h 6 h 8 h
12 h
Assessment Window (minutes)
0
±5 ±15 ±15 ±15 ±15 ±15 ±15
±15
Dosing
D1 through D28g
X
X
X
PK blood sampling
D1, D27
X
X
X
X
X
X
Drop comfort assessmentb
D1, D7, D14, D21, D27, D28
X
Physical examination
SCR, D-2, D14, D26, D29
X
Vital signs 
All visits except Day 88/FU
X
X
X
X
ECG 
All visits except MWOA, Day 28, and Day 88/FUh
X
X
X
X
BCVA
All visits except Day 26 and Day 88/FU
X
X
X
Manifest refraction
SCR, D-2, D29
X
Slit lamp examination of 
anterior segmentc
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29
X
X
X
Conjunctival redness
SCR, D-14, D-2,D-1, D1, D2, D7, D14, D21, D27, D28, D29
X
X
X
X
X
Corneal haze
SCR, D-14,D-2,D-1, D1, D2, D7, D14, D21, D27, D28, D29
X
X
X
X
X
Corneal epithelial integrity 
using fluorescein stain
SCR, D-14, D-2,D-1, D1, D2, D7, D14, D21, D27, D28, D29
X
X
X
X
X
Anterior chamber cell and flare SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29.
X
X
X
Lens opacification
SCR, D29
X
IOP, abbreviated schedule
SCRe, D-14d, D7, D14, D21, D29d
X
X
X
X
X
IOP, full schedule
D-2, D-1, D1, D2, D27, D28.
X
X
X
X
X
X
X
X
X
Posterior segment examination SCR (dilated), D-2; nondilated, D29 (dilated)
X
Gonioscopye
SCR, D29
X
Specular microscopy, 
noncontact
SCR, D-1 D14, D29
X
Corneal pachymetry
SCR, D-1 D1, D2, D7, D14, D29
X
X
X
X
X
Antidrug Ab blood sampling
D-2, D14, D29, D88/FU
X


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Table 4
Detailed Schedule of Events – Cohort C
Assessment
Days Performed (Screening through D29)f
Predose/
Morninga
0 m
30 
m
1 h 2 h 3 h 4 h 6 h 8 h
12 h
Assessment Window (minutes)
0
±5 ±15 ±15 ±15 ±15 ±15 ±15
±15
Drugs of abuse
SCR, D-14, D-2, D-1, D1, D14, D21, D26. 
X
Alcohol breath test
SCR, D-14), D-2, D-1, D1, D14, D21, D26. 
X
Serum pregnancy test (female 
subjects)
SCR, D-2, D1, D26, D29.
X
Biochemistry, hematology, and 
urinalysis
SCR, D-2, D1, D7, D14, D21, D26, D27, D29.
X
Timings relate to the first dose of the day or the equivalent morning assessment. Refer to Section 7.1 for guidance on the priority order of assessments. Assessments on nondosing 
days (screening, baseline, and Day 29) will take place once in the morning only unless otherwise specified.
Ab=antibody; BCVA=best-corrected visual acuity; D=day; ECG=electrocardiogram; FU=follow up; h=hours; IOP=intraocular pressure; m=minutes; MDTP=multiple-dose 
treatment period; PK=pharmacokinetic; SCR=screening
a Assessments will take place 60-30 minutes before the first dose of the day or in the morning on nondosing days.
b Drop comfort assessments will be obtained immediately, 1, 2, and 3 minutes after instillation of the investigational product; to be assessed at morning doses only. If the score is 
not ≤3 at minute 3, the drop comfort assessment should be repeated at minutes 5, 10, and 15 until the score is ≤3. If the score is >3 at minute 15, it should be recorded as an 
adverse event.
c Slit lamp examination of anterior segment will be performed only during the morning assessments on the following days: Screening, Day -14, Day -2, –Day 1, and Day 29.
d At screening IOP may be done at any time during the day. At MWOA (D-14), IOP should be done at 10:00am +3 hours. IOP only needs to be done at one time during screening, 
MWOA, and Day 29.
e Gonioscopy at screening can be done at any time of day. Gonioscopy on Day 29 will be performed at the morning time point. 
f Ophthalmologic assessments on screening, MWOA (D-14), and Day 29 need to be done one time during the day only. 
These assessments include: BCVA, Manifest Refraction (Screening), Slit Lamp examination of anterior segment, Conjunctival Redness, Corneal Haze, Corneal Epithelial 
integrity using fluorescein stain, Anterior Chamber cell and flare, Lens Opacification, IOP, Posterior Segment Examination, dilated (Screening and Day 29), Specular 
Microscopy, Noncontact (Screening and Day 29), Corneal Pachymetry (Screening and Day 29).
g Subjects will be administered the last dose of study drug on the morning of Day 28.
h ECG is to be performed at one time point only on Day 26 and Day 29.
Timings relate to the first dose of the day or the equivalent morning assessment. Refer to Section 7.1 for guidance on the priority order of assessments. Assessments on nondosing 
days (screening, baseline, and Day 29) will take place once in the morning only unless otherwise specified.


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Table 5
Detailed Schedule of Events – Cohort D
Assessment
Days Performed (Screening through D29)f
Predose/
Morninga
0 m 30 m 1 h
2 h
3 h
4 h
6 h
8 h
12 h
Assessment Window (minutes)
0
±5
±15
±15
±15
±15
±15
±15
±15
Dosing
D1 through D28g
X
X
X
X
PK blood sampling
D1, D27
X
X
X
X
X
X
Drop comfort assessmentb
D1, D7, D14, D21, D27, D28
X
Physical examination
SCR, D-2, D14, D26, D29
X
Vital signs 
All visits except Day 88/FU
X
X
X
X
ECG 
All visits except MWOA, Day 28, and Day 88/FUh
X
X
X
X
BCVA 
All visits except Day 26 and Day 88/FU
X
X
X
Manifest refraction
SCRD-2, D29
X
Slit lamp examination of 
anterior segmentc
SCR, D-14, D-2,D-1, D1, D2, D7, D14, D21, D27, 
D28, D29
X
X
X
Conjunctival redness
SCR, D-14, D-2,D-1, D1, D2, D7, D14, D21, D27, 
D28, D29
X
X
X
X
X
Corneal haze
SCR, D-14D-2,D-1, D-1, D1, D2, D7, D14, D21, 
D27, D28, D29
X
X
X
X
X
Corneal epithelial integrity 
using fluorescein stain
SCR, D-14, D-2,D-1, D1, D2, D7, D14, D21, D27, 
D28, D29
X
X
X
X
X
Anterior chamber cell and flare SCR, D-14, D-2 and D-1, D1, D2, D7, D14, D21, 
D27, D28, D29.
X
X
X
Lens opacification
SCR, D29
X
IOP, abbreviated schedule
SCRe, D-14d, D7, D14, D21, D29d
X
X
X
X
X
IOP, full schedule
D-2, D-1, D1, D2, D27, D28.
X
X
X
X
X
X
X
X
X
Posterior segment examination SCR (dilated), D-2; nondilated, D29 (dilated)
X
Gonioscopye
SCR D29
X
Specular microscopy, 
noncontact
SCR, D-1, D14, D29
X


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Table 5
Detailed Schedule of Events – Cohort D
Assessment
Days Performed (Screening through D29)f
Predose/
Morninga
0 m 30 m 1 h
2 h
3 h
4 h
6 h
8 h
12 h
Assessment Window (minutes)
0
±5
±15
±15
±15
±15
±15
±15
±15
Corneal pachymetry
SCR, D-1, D1, D2, D7, D14, D29
X
X
X
X
X
Antidrug Ab blood sampling
D-2, D14, D29, D88/FU
X
Drugs of abuse
SCR, D-14, D-2, D-1, D1, D14, D21, D26. 
X
Alcohol breath test
SCR, D-14, D-2, D-1, D1, D14, D21, D26. 
X
Serum pregnancy test (female 
subjects)
SCR, D-2, D1, D26, D29.
X
Biochemistry, hematology, and 
urinalysis
SCR, D-2D1, D7, D14, D21, D26, D27, D29.
X
Ab=antibody; BCVA=best-corrected visual acuity; D=day; ECG=electrocardiogram; FU=follow up; h=hours; IOP=intraocular pressure; m=minutes; MDTP=multiple-dose 
treatment period; PK=pharmacokinetic; SCR=screening
a Assessments will take place 60-30 minutes before the first dose of the day or in the morning on nondosing days.
b Drop comfort assessments will be obtained immediately, 1, 2, and 3 minutes after instillation of the investigational product; to be assessed at morning doses only. If the score 
is not ≤3 at minute 3, the drop comfort assessment should be repeated at minutes 5, 10, and 15 until the score is ≤3. If the score is >3 at minute 15, it should be recorded as an 
adverse event.
c Slit lamp examination of anterior segment will be performed only during the morning assessment on the following days: Screening, Day -14, Day -2, Day 1, and Day 29.
d At screening IOP may be done at any time during the day. At MWOA (D-14), IOP should be done at 10:00am +3 hours. IOP only needs to be done at one time during 
screening, MWOA, and Day 29.
e Gonioscopy at screening can be done at any time of day.Gonioscopy on Day 29 will be performed at the morning time point.
f Ophthalmologic assessments on screening, MWOA (D-14), and Day 29 need to be done one time during the day only. 
These assessments include: BCVA, Manifest Refraction (Screening), Slit Lamp examination of anterior segment, Conjunctival Redness, Corneal Haze, Corneal Epithelial 
integrity using fluorescein stain, Anterior Chamber cell and flare, Lens Opacification, IOP, Posterior Segment Examination, dilated (Screening and Day 29), Specular 
Microscopy, Noncontact (Screening and Day 29), Corneal Pachymetry (Screening and Day 29)
g Subjects will be administered the last dose of study drug on the morning of Day 28.
h
ECG is to be performed at one time point only on Day 26 and Day 29.
Timings relate to the first dose of the day or the equivalent morning assessment. Refer to Section 7.1 for guidance on the priority order of assessments. Assessments on nondosing 
days (screening, baseline, and Day 29) will take place once in the morning only unless otherwise specified.


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1.
BACKGROUND INFORMATION
SHP639 is a 9-amino acid, synthetic, C-type natriuretic peptide (CNP) analog that is a potent and 
selective agonist of natriuretic peptide receptor B (NPR-B). It is being developed by Shire for the 
treatment of glaucoma and ocular hypotension (OHT). Interaction of SHP639 with NPR-B 
would potentially have an intraocular pressure (IOP)-lowering effect with a novel mode of action 
that targets the primary outflow mechanism that is altered in these diseases.
Natriuretic peptides are potent activators of the cell membrane-bound guanylyl cyclases, thereby 
increasing the intracellular concentration of cyclic guanosine monophosphate (cGMP). C-type 
natriuretic peptide or CNP analog activation of NPR-B can consequently increase cGMP leading
to various physiological effects (eg, smooth muscle relaxation, vasorelaxation, and vascular 
remodeling) including trabecular meshwork relaxation. It has been reported in several 
publications that compounds that increase cellular concentrations of cGMP will lower IOP by 
potentially increasing aqueous humor outflow through relaxation of the trabecular meshwork 
(Becker, 1990; Nathanson, 1988; Nathanson, 1992; Stein and Clack, 1994). Targeting the 
trabecular meshwork pathway, which is the dominant ocular outflow mechanism responsible for 
the majority of aqueous humor drainage, can potentially translate into an attractive target for 
treating OHT and glaucoma.
In vitro, SHP639 has shown to be highly selective towards activating NPR-B receptors (50% of 
maximal effective concentration [EC50]=61.4±11.0nM) when compared with natriuretic peptide 
receptor A (NPR-A) receptors (EC50=2179±335nM), ie, SHP639 is 35 times more potent for the 
NPR-B receptor compared with NPR-A receptor.
In vivo, a robust lowering of IOP was noted in rabbits and dogs following topical ocular 
instillation of SHP639. In rabbit models, a dose-dependent IOP-lowering efficacy (≥40% IOP 
reduction at 0.6%) was observed and the IOP-lowering effect persisted for at least 8 hours for the 
highest dose tested (0.6%/180 µg per eye). Single-dose administration also significantly 
increased outflow facility (trabecular outflow) by 2.6-fold in the same species.
Topical ocular administration of SHP639, at a concentration up to 0.6%, was well tolerated in 
rabbits and monkeys. The no-observed-adverse-effect level (NOAEL) following 28 days of 
topical administration was 0.6%, administered as 1 drop, into both eyes, 4 times daily (QID) 
(total daily dose of 1.51 mg/day of SHP639).
1.1
Indication and Current Treatment Options 
Glaucoma is an optic neuropathy characterized by retinal ganglion cell degeneration and death, 
evident at the optic nerve head, and which results in visual field loss. Glaucoma can be classified 
by anatomy (open-angle or angle-closure glaucoma) or by etiology (primary, secondary, or 
congenital). Primary open-angle glaucoma (POAG) can progress asymptomatically for months 
or years, causing a delay in diagnosis and treatment. In contrast, OHT is a condition of elevated 
IOP without signs of early glaucoma but which increases the risk of developing the disease.


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Glaucoma is a leading cause of irreversible vision loss worldwide (Weinreb et al., 2014; Quigley 
and Broman, 2006). Primary open-angle glaucoma affected approximately 58 million people in 
2015; this number is projected to increase to approximately 66 million in 2020 (Kapetanakis et 
al., 2016). Additionally, approximately 2.71 million Americans had open-angle glaucoma in 
2011, a prevalence expected to almost triple to 7.32 million by 2050 (Vajaranant et al., 2012). 
Intraocular pressure is the major modifiable risk factor of glaucoma (Leske et al., 2003), 
including in patients with IOP in the statistically “normal” range (Collaborative Normal-Tension 
Glaucoma Study Group, 1998). Reduction of IOP has been demonstrated in landmark studies to 
protect against further damage to the optic nerve in patients with early (Heijl et al., 2002) and 
advanced (AGIS Investigators, 2000) glaucoma and to decrease the risk of progression to 
glaucoma in patients with OHT (Kass et al., 2002).
Based on data from the Early Manifest Glaucoma Trial (Heijl et al., 2002) and Collaborative 
Initial Glaucoma Treatment Study (Lichter et al., 2001), ophthalmologists consider a patient’s 
clinical status, age, and lifestyle in order to decide on an initial target IOP, along with the 
therapeutic measures to achieve that IOP. While closely following the patient’s visual fields and 
optic disc status, the target IOP will be reassessed periodically or if the patient demonstrates 
evidence of glaucoma progression. 
Intraocular pressure elevation can occur because of a decrease in aqueous humor outflow 
through the trabecular meshwork (conventional pathway) or uveoscleral outflow (unconventional 
pathway) or a relative increase in aqueous humor production compared to outflow (Goel et al., 
2010). Pharmacotherapy options can target any or all of these mechanisms. The main classes of 
topical ocular hypertensive either decrease aqueous humor production (prostaglandin analogs, 
α-adrenergic agonists, and cholinergic agonists) or increase aqueous humor outflow (carbonic 
anhydrase inhibitors, β-blockers, and α-adrenergic agonists). Orally administered carbonic 
anhydrase inhibitors are more effective at lowering IOP compared with topically applied 
medication; however, the high incidence of systemic side effects associated with an oral regimen 
(Weinreb and Khaw, 2004) makes it an unacceptable option for routine clinical use.
1.2
Product Background
1.2.1
Nonclinical Information
In vitro and in vivo primary pharmacology studies, in vitro secondary pharmacology studies to 
assess “off-target” potential, and in vivo pharmacokinetics and distribution studies were 
performed. Good Laboratory Practice (GLP)-compliant safety pharmacology studies using 
SHP639 were conducted in vitro in a human ether-à-go-go-related gene assay and in vivo by the 
intravenous (IV) route in rats and nonhuman primates (NHPs). Pivotal GLP-compliant 4-week 
toxicology studies with topical SHP639 were conducted in rabbits and NHPs, with 
accompanying toxicokinetics. A 4-week toxicology and toxicokinetics study with intravenously 
administered SHP639 was performed to assess potential systemic toxicity. Rabbits and NHPs are 
both pharmacologically relevant species and both are commonly used species to assess topical 
and systemic toxicity in ocular drug development. The topical safety studies in both species 
included a full assessment of potential systemic toxicity (toxicokinetics, clinical pathology, and 
anatomic pathology for a full list of organs), such that a single species (NHP) to assess the IV 


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toxicity of SHP639 was considered appropriate. The SHP639 formulation used in the pivotal 
topical studies is identical to the proposed clinical formulation. This formulation contains 
standard components typically used in topical ocular formulations. In vitro and in vivo 
genotoxicity studies were also GLP compliant.
The nonclinical studies demonstrated that topically administered SHP639 has robust and 
dose-dependent IOP-lowering efficacy in rabbits and dogs, is distributed to relevant ocular 
tissues with minimal systemic absorption, and is well tolerated in rabbits and NHPs when 
administered up to QID for 1 month of treatment at concentrations of up to 0.6% SHP639 (30 µL 
drop). Clinical signs of ocular discomfort were minimal, transient, and not associated with any 
ocular pathology or toxicity. Following topical administration, systemic exposure to SHP639 is 
very low to nondetectable, suggesting a low risk of producing systemic toxicities. Central 
nervous system, cardiovascular, respiratory, and renal safety pharmacology and systemic toxicity
were characterized following IV SHP639 administration, and SHP639 was well tolerated. The 
nonclinical findings following IV administration were generally transient and monitorable and/or 
occurred at systemic exposures markedly higher than those expected clinically. SHP639 was 
nongenotoxic in in vitro and in vivo assays.
The nonclinical data therefore adequately support the initiation of this clinical study. Refer to the 
latest version of the SHP639 investigator’s brochure (IB) for additional nonclinical information.
1.2.2
Clinical Information
There have been no prior clinical studies administering the topical ophthalmic solution of 
SHP639 that will be used for this study. Alcon, the previous sponsor of intravitreally 
administered SHP639 (formerly known as AL-59412C), initiated a study in adult subjects with 
no light perception vision in their study eye to assess the safety and efficacy of intravitreally 
administered SHP639. Subjects were randomized to receive either 30 µg SHP639 in a phosphate 
vehicle as a 50 µL intravitreal (IVT) injection or 80 ng travoprost via a 50 µL IVT injection. The 
SHP639 IVT formulation was a different formulation from the SHP639 topical ophthalmic 
solution that will be used in this study.
Four subjects were recruited for the first cohort and 3 of the 4 subjects received their IVT 
injection: 2 subjects randomized to SHP639 and 1 subject to travoprost. One of the 
2 SHP639-treated subjects developed moderate corneal edema 10 minutes after SHP639 
administration, which resolved within 8 hours (no treatment was required for the event). The 
other experienced a marked rise in IOP, in addition to corneal edema, immediately after SHP639 
administration. The subject was treated for the events; however, the elevated IOP persisted for 
2 weeks. The subject who received 80 ng travoprost did not develop any significant adverse 
findings; travoprost was administered by the IVT route with a different formulation to that of 
SHP639.
Based on the unexpected occurrence of these corneal findings in the 2 subjects who received the 
50 µL IVT injection containing 30 µg SHP639, further enrollment in the study was suspended. 
Alcon initiated some exploratory IVT toxicity studies in rabbits to better understand the effects 
noted.


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Always refer to the latest version of the SHP639 investigator’s brochure (IB) for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP639.
1.3
Risk/Benefit and Ethical Assessment
There are no expected benefits to the subjects enrolled in this study. The safety profile of 
topically administered SHP639 in rabbits and NHPs shows that the compound is well tolerated 
with no adverse effects up to 0.6% when administered QID as 1 drop (30 µL) in both eyes. 
Although, following IVT administration, corneal opacity was seen clinically, the topical ocular 
toxicity studies in rabbits and NHPs using an exaggerated dosing regimen of QID for 4 weeks 
did not demonstrate corneal adverse effects up to 0.6% (in a 30 µL drop; total daily dose of 
1.51 mg). 
The topical formulation used for this study is the same as that evaluated nonclinically in rabbits 
and NHPs, and utilizes a well-characterized and widely used vehicle, similar to the marketed 
MAXIDEX® vehicle. Refer to Section 3.3 of the current SHP639 IB for further details.
Considering topical administration, the safety margin for SHP639 ocular drops is calculated 
based on approximate conjunctival surface area. As the corneal and conjunctival surface areas in 
rabbits and humans are similar, the human-equivalent dose to the rabbit NOAEL is equivalent to 
a drop of 0.6% topical solution when administered QID in both eyes, equivalent to a dose of 
1.51 mg SHP639 per eye per day.
As the anticipated toxicities for SHP639 are local ocular discomfort, as noted in the animal 
studies, the proposed topical concentrations to be administered clinically to both eyes (with the 
exception of Cohort A single-dose treatment period [SDTP], which will occur in 1 designated 
study eye only) will initiate as a once daily (QD) administration, and will be escalated to 
multiple times daily based on clinical tolerability. Frequent, serial ophthalmologic examinations, 
including thorough slit lamp and retinal examinations, will ensure that any corneal or other 
effects will be detected early, although it is considered highly unlikely that any such effects may 
occur. The tables below show the margins for each of the dose and dose schedule escalations 
proposed, based on 1) SHP639 concentrations/drop numbers, and 2) based on SHP639 µg/day, 
using a nonclinical NOAEL (both eyes) of 0.6% QID or 1.51 mg/eye/day. 
Margins to proposed clinical concentrations, based on concentration of SHP639 and the number 
of drops/day, are shown in Table 6.


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Table 6
Dose Margins Based on SHP639 Concentration and Dosing Regimen
Topical 
Concentration
Dose Margina
QD/Both Eyes
BID/Both Eyes
TID/Both Eyes
QID/Both Eyes
0.1% (50 µg/drop)
24-fold
12-fold
9-fold
6-fold
0.3% (150 µg/drop)
8-fold
4-fold
3-fold
2-fold
0.6% (300 µg/drop)
4-fold
2-fold
1.5-fold
1-fold
BID=twice daily; NOAEL=no-observed-adverse-effect level; QD=once daily; QID=4 times daily; TID=3 times daily
a
Dose margin is based on concentration and number of drops per day; nonclinical single eye NOAEL/clinical dose.
Rabbit NOAEL for both eyes is 0.6%, 8 drops per day (4 drops per eye).
Margins to proposed clinical doses, based on SHP639 µg/day, are shown in Table 7.
Table 7
Dose Margins Based on SHP639 Daily Dose
Topical 
Concentration
Dose Margina
QD/Both Eyes
BID/Both Eyes
TID/Both Eyes
QID/Both Eyes
0.1% per 50 µL 
(50 µg/drop)
15-fold
7.5-fold
5-fold
3.75-fold
0.3% per 50 µL 
(150 µg/drop)
7.5-fold
3.75-fold
2.5-fold
~2-fold
0.6% per 50 µL 
(300 µg/drop)
2.5-fold
1.3-fold
~1-fold
0.6-fold
BID=twice daily; NOAEL=no-observed-adverse-effect level; QD=once daily; QID=4 times daily; TID=3 times daily
a
Dose margin is based on µg/day dose; nonclinical single eye NOAEL/clinical dose.
The NOAEL is 0.6% = 0.6 mg/100 µL = 0.18 mg/30 µL drop; the actual drop size in the animal studies was 31.5 µL drop 
(equivalent to 189 µg/drop).
189 µg/drop × both eyes × QID = 1.51 mg (free-base equivalent); the clinical studies propose a maximal volume of 50 µL drop.
Always refer to the latest version of the SHP639 investigator’s brochure (IB) for the overall 
benefit/risk assessment and the most accurate and current information regarding drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP639


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
SHP639 is being developed for reduction of IOP in glaucoma patients. It is expected to act 
through a novel mode of action (NPR-B agonism) that leads to an increase in trabecular 
meshwork outflow, thus reducing the IOP. SHP639-101 is a first-in-human clinical study for a 
topical ophthalmic formulation of SHP639. Up to 3 different concentrations (0.1%, 0.3%, and 
0.6%) will be explored and safety and tolerability of SHP639 ophthalmic solution will be 
evaluated. As a secondary objective, the study will also aim to characterize the 
pharmacodynamics (PD) of SHP639, using IOP as a PD biomarker. The pharmacokinetic 
(PK)-PD relationship will be explored if the data permit.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to investigate the safety and tolerability of single and 
multiple ascending doses of SHP639 ophthalmic solution in subjects with OHT or with POAG.
2.2.2
Secondary Objectives
The secondary objective of this study is to evaluate reduction of IOP, as a PD biomarker, 
following different SHP639 dosing regimens.
2.2.3
Exploratory Objectives
The exploratory objective for this study is to explore the PK-PD relationship of SHP639 in 
subjects with OHT or POAG. 


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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a multicenter, randomized, double-masked, placebo-controlled, single- and multiple-dose 
escalation study. Three different SHP639 concentrations will be studied: 0.1%, 0.3%, and 0.6%. 
There will be up to 12 cohorts in total, 1 cohort for each dose level and different dosing regimen. 
Each cohort will consist of 7 subjects for a total of 84 subjects in the study. Eligible subjects will 
be randomized in a 5:2 ratio to receive either SHP639 or placebo, respectively. The anticipated 
doses being studied for each dosing regimen are presented in the dose-escalation scheme in 
Table 10.
A sufficient number of subjects will be screened and enrolled to ensure that at least 6 of 
7 subjects complete each treatment in their assigned cohort. In the event that a sufficient number 
of subjects do not complete a cohort, replacement subjects may be enrolled. Each replacement 
subject will follow the same screening procedures and randomization sequence as the subject 
who is discontinued, regardless of when the subject discontinued.
3.1.1
Designated Study Eye
For the purpose of overall analysis, 1 eye will be designated as the primary eye for the duration 
of the subject’s participation in the trial. In Cohort A SDTP, the investigational product will be 
dosed in the designated study eye only. For all subjects participating in the MDTP, a designated 
study eye will be also identified and the investigational product will be dosed in both eyes. The 
following procedure will be used to determine the designated study eye:

For each subject, the mean baseline IOP at a time point will be the mean of the IOPs on 
days -2 and -1 at that time point.

The designated study eye will be the eye with the highest mean baseline IOP at the 
predose time point.

If both eyes have equal mean baseline IOPs, the eye with the highest mean IOP at the 
+2-hour time point will be the designated study eye.

If both eyes have equal mean IOPs at the +2-hour time point, the eye with the highest 
mean IOP at the +4-hour time point will be the designated study eye.

If both eyes have equal mean IOPs at the +4-hour time point, the eye with the highest 
mean IOP at the +8-hour time point will be the designated study eye.

If both eyes have equal mean IOPs at the +8-hour time point, the right eye will be the 
designated study eye.


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3.1.2
Screening Period
For all cohorts, the maximum duration of the screening period is 42 days. On the initial visit to 
the site, the subject will first give informed consent. This will be the date that he/she enters the 
screening period. After giving consent, the subject will be evaluated against the inclusion and 
exclusion criteria and undergo the procedures as outlined in Table 1.
During the screening period, subjects will return to the site approximately every 2 weeks for 
safety evaluations. Subjects requiring a washout from current medications will begin their 
washout period as required in Section 5.2.2 and Table 8.
Following the screening visit, subjects who continue to meet the protocol-specific inclusion and 
exclusion criteria will return to the site on either Day -3 or Day -2, to reconfirm eligibility 
criteria for participation and undergo the predose safety and ophthalmologic assessments as 
outlined in Table 1.
3.1.3
Study Parts
The study will consist of 2 parts, Part 1 and Part 2.

Part 1 consists of Cohorts A1, A2, and A3, each of which is a single-dose and QD 
multiple-dose cohort (1 cohort for each of the 3 dose levels), followed by Cohorts B1, B2, 
and B3, each of which is a twice daily (BID) multiple-dose cohort (1 cohort for each dose 
level). 

Part 2 consists of Cohorts C1, C2, and C3, each of which is a 3 times daily (TID) 
multiple-dose cohort (1 cohort for each dose level), followed by Cohorts D1, D2, and D3, 
each of which is a QID multiple-dose cohort (1 cohort for each dose level). 
3.1.4
Cohorts A1-A3
In Cohorts A1, A2, and A3, there will be an SDTP followed by a multiple-dose treatment period 
(MDTP).
3.1.4.1
Cohorts A1-A3: Single-dose Treatment Period
Subjects will be randomized prior to administration of investigational product on Day 1 after all 
entry criteria have been confirmed.
One drop of investigational product will be administered topically to a designated eye. The first 
3 of 7 subjects will be dosed with a minimum of 1-hour intervals between the subjects for safety 
purposes. The subject will then undergo assessments at the time points outlined in Table 1 and 
Table 2.
Subjects will be observed for the next 24 hours with appropriate medical oversight. An 
ophthalmologist will be on call to assess ophthalmic-related medical issues. If no adverse events 
(AEs) occur that are consistent with the predefined stopping criteria, the rest of the subjects in 
the cohort can be administered investigational product in 1 designated eye.


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3.1.4.2
Cohorts A1-A3: Multiple-dose Treatment Period
After completion of the assessments scheduled for Day 2 of the SDTP, subjects will enter a 
washout period. The duration of the washout period will last between 3 and 14 days. A dose 
escalation meeting will occur prior to the advancement to each cohort (refer to Section 6.2.3.2
for additional details). For each cohort, following a decision to commence the MDTP, subjects 
will attend the site on Days -2 and -1 to undergo the scheduled safety and ophthalmic 
assessments. In Cohorts A1, A2, and A3 MDTP, all subjects will be administered investigational 
product in both eyes. The same dose concentration that was administered during the SDTP of the 
relevant cohort (A1, A2, or A3) will be administered during the MDTP QD for the next 28 days. 
Subjects are to place 1 drop in each eye at approximately the same time each day. Refer to 
Table 1 and Section 6.2.3 for additional details.
Subjects will be admitted to the site on Day 1 and will be discharged after completion of all 
Day 2 assessments. On Days 7, 14, and 21, subjects will return to the site as described in Table 1. 
On Day 26, subjects will be readmitted to the site. On Day 27, subjects will continue to 
self-administer investigational product while undergoing the scheduled assessments. The last 
dose will be administered on the morning of Day 28. After completion of the assessments 
scheduled for Day 29, subjects will then be discharged from the site. 
Subjects will receive a follow-up telephone call approximately 7 days after being discharged 
from the site. They will return to the site to undergo antidrug antibody (ADA) sampling 
approximately 60 days after the last dose of investigational product (Day 88).
3.1.5
Cohorts B1-B3, C1-C3, and D1-D3
Authorization from the sponsor to proceed from 1 cohort to the next is to be received before 
subjects enter the screening period for Cohorts B, C, and D. Once authorization has been 
received from the sponsor, subjects are to be admitted to the screening period of the appropriate 
cohort as previously described in this section.
Subjects will undergo the scheduled safety and ophthalmic assessments on Day -2 and Day -1
(refer to Table 1). Subjects will then be administered investigational product per the sponsor’s 
authorization to proceed to that cohort. In Cohorts B, C, and D, subjects will be administered 
investigational product in both eyes. Refer to Section 6.2.3 for additional details.
Subjects will continue to self-administer investigational product as instructed for the duration of 
the MDTP. Subjects will be admitted to the site on Day 1 and will be discharged after 
completion of all Day 2 assessments. On Days 7, 14, and 21 (±2 days, each), subjects will return 
to the site as described in Table 1. On Day 26, subjects will be readmitted to the site. On Day 27, 
subjects will continue to self-administer investigational product while undergoing the scheduled 
assessments. The last dose will be administered on the morning of Day 28. After completion of 
the assessments scheduled for Day 29, subjects will then be discharged from the site.
Subjects will receive a follow-up telephone call approximately 7 days after being discharged 
from the site. They will return to the site to undergo ADA sampling approximately 60 days after 
the last dose of investigational product (Day 88).


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3.2
Duration and Study Completion Definition
The subjects’ maximum duration of participation in the study is expected to be 146 days or 
approximately 5 months (Cohort A1, A2, and A3). The subjects’ maximum duration of 
participation in the study for Cohorts B, C, and D is expected to be 130 days or approximately 
4.5 months.

Maximum planned duration of screening and Washout 1: 42 days

Planned duration of treatment period: 2 days for SDTP (Cohort A only) and 29 days 
for MDTP (all cohorts)

Planned duration of Washout 2 (Cohort A only): 3-14 days 

Planned duration of follow-up: until Day 88±4 days (final assessment visit and 
anticipated Study Completion Date for each subject)
The study will be completed in approximately 56 weeks.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
SHP639-101 will be a multicenter study conducted in the United States. Approximately 7 sites 
will participate in the study.


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
Subjects cannot be enrolled or randomized before all inclusion criteria (including test results) are 
confirmed.
1.
Subjects must provide written, signed and dated informed consent to participate in the study 
in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guideline E6 and applicable regulations, before completing any study-related 
procedures.
2.
Subjects must be aged from 18 through 90 at the time of consent. This inclusion criterion will 
only be assessed at the screening visit.
3.
Subjects must have OHT or stable early POAG in both eyes with acceptable Humphrey 
visual fields (HVF). Early POAG for this protocol is defined as healthy appearing anterior 
chamber angles (Shaffer classification system grade 3 or 4) and focal and/or generalized 
thinning of the optic disc rim characteristic of glaucomatous disease. An acceptable HVF 
must have been performed within approximately one year of screening, have a false-positive 
rate of 25% maximum, false-negative rate of 25% maximum, and fixation loss rate of 33% 
maximum, and mean deviation of no worse than -6.00 dB.
4.
On Day -1, subjects must have a mean IOP of ≥24 mmHg at 8:00 AM and a mean IOP of 
≥22 mmHg at 10:00 AM in at least 1 eye, with an IOP difference of <4 mmHg between eyes 
at both of these time points. If only 1 eye meets this criterion, then it will be the designated 
study eye for pharmacodynamic analysis; this eye will also be used for dosing in Cohort A 
SDTP (designated study eye criteria are detailed in Section 3.1.1).
5.
Subjects must have a best-corrected visual acuity (BCVA) in both eyes of 65 letters on the 
Early Treatment Diabetic Retinopathy Study chart (Snellen equivalent ∼20/60) or better at 
the screening and baseline assessments.
6.
Subjects must be males or females who are nonpregnant and nonlactating at screening 
(negative serum beta-human chorionic gonadotropin [β-hCG]); if sexually active during the 
study, they must agree to comply with the applicable contraceptive requirements (refer to 
Section 4.4) throughout the study period and for 60 days following the last dose of 
investigational product. 
7.
Subjects must have a satisfactory medical assessment with no clinically significant or 
relevant abnormalities as determined by medical history, physical examination, and clinical 
and laboratory evaluation (hematology, biochemistry, urinalysis) as assessed by the 
investigator.


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8.
Subject must understand and be able, willing, and likely to fully comply with study 
procedures and restrictions.
9.
Subjects must be nonsmokers or have had stable use of tobacco or nicotine-containing 
products for a 3-month period before signing the informed consent form (ICF).
10. Subjects who drink alcohol must have had stable use of alcohol for a 3-month period before 
signing the ICF.
4.2
Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met:
1.
Subject has an anatomically narrow angle, synechiae or evidence of prior inflammation, 
angle closure glaucoma, normal tension glaucoma, pseudoexfoliation syndrome or 
pigmentary dispersion syndrome with or without glaucoma, or secondary glaucoma.
2.
Subject has corneal endothelial cell counts of less than 2000 cells/mm2 (measured by 
noncontact specular microscopy) at the screening or baseline assessments.
3.
Subject has central corneal thickness less than 500 µm or greater than 620 µm at the 
screening or baseline assessments.
4.
Subject has IOP greater than 32 mmHg in either eye before randomization.
5.
Subject has used topical ocular hypotensive medications as follows: prostaglandin analogs, 
β-adrenoceptor antagonists, α-adrenergic agonists, or epinephrine-related medications within 
4 weeks before the first dose of investigational product; or pilocarpine or carbonic anhydrase 
inhibitors within 7 days before the first dose of investigational product.
6.
Subject has a history of angle closure, ocular surgery, microinvasive glaucoma surgery 
device insertion, or laser surgery, except for the following procedures, which are allowed: 
uncomplicated cataract surgery, laser peripheral iridotomy with resultant angle of Shaffer 
grade 3 or 4, and postcataract neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser 
posterior capsulotomy. Cataract surgery and other procedures must have occurred a 
minimum of 3 months before randomization.
7.
Subject has a history of significant ocular trauma or ocular disease including but not limited 
to moderate to severe dry eye disease that requires chronic treatment or punctal plugs.
8.
Subject has evidence of ocular infection, inflammation, degeneration, or dystrophy at the 
screening or baseline assessments, including but not limited to moderate to severe blepharitis 
(mild blepharitis is allowed), conjunctivitis (allergic or infectious), corneal dystrophy 
(epithelial, stromal, or endothelial), corneal haze of grade 1 or greater based on the Hwang 
Grading Scale of Corneal Haze, corneal opacities, keratitis, uveitis, or vitritis.
9.
Subject has retinal disease including but not limited to: moderate or severe nonproliferative 
diabetic retinopathy (NPDR) (early NPDR is allowed), proliferative diabetic retinopathy, 
intermediate or advanced dry age-related macular degeneration (AMD) (early dry AMD is 
allowed), all geographic atrophy, or all wet AMD.
10. Subject has any nonglaucomatous optic neuropathy or other significant nonglaucomatous 
ocular disease that is likely to affect visual function.


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11. Subject has any corneal or ocular surface pathology in either eye that prevents proper IOP 
measurement, pachymetry, or other study data collection procedures.
12. Subject has had changes to their existing prescription medication regimen for chronic 
disease, including those medicines that affect IOP, within 14 days or 5 half-lives before 
screening, whichever is longer.
13. Subject has started any new prescription drug medication for chronic disease, including those 
medicines that affect IOP, within 14 days or 5 half-lives before screening, whichever is 
longer.
14. Subject has a history of corticosteroid use within 3 months before randomization, except for 
nonperiocular dermatologic use, which is allowed.
15. Subject has used belladonna alkaloids (scopolamine, hyoscyamine, atropine) within 7 days 
prior to randomization, cannabinoids or opioids within 28 days before randomization, or 
B-type natriuretic peptides within the past year before randomization; or a subject has an 
anticipated need for any of the aforementioned drugs/drug categories during the study.
16. Subject has used amantadine within 28 days before randomization.
17. Subject is unable to discontinue contact lens use during and for 60 minutes following 
instillation of study medication, during ophthalmologic examinations, and during study 
visits.
18. Subject has a current or relevant history of any physical, medical, mental, or psychiatric 
illness, disorder, or condition that may require treatment during the study and/or that may 
interfere with the subject complying with the study rules and procedures or completing the 
study.
19. Subject has any condition that presents undue risk from use of the investigational product, 
assessment tools, or procedures.
20. Subject is a woman who is pregnant (positive serum β-hCG pregnancy test at the time of 
screening), lactating, or less than 90 days post partum at randomization. 
21. Subject has donated blood within 60 days before first dose of investigational product. 
22. Subject has donated plasma within 28 days before first dose of investigational product. 
23. Subject has used another investigational product within 30 days before the first dose of 
investigational product or is actively enrolled in a drug or vaccine clinical study.
24. Subject has a positive human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C virus (HCV) antibodies screen.
25. Subject has a positive drugs of abuse screen or alcohol breathalyzer test.
26. Subject has been previously enrolled in this study.
27. Subject has known hypersensitivity or allergy to any of the ingredients of the investigational 
product.


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28. Subject consumes more than 21 units of alcohol per week or is unable to refrain from alcohol 
consumption within 48 hours before a scheduled visit. (1 alcohol unit=1 beer or 1 wine 
[5 oz/150 mL] or 1 liquor [1.5 oz/40 mL] or 0.75 oz alcohol.)
29. Subject is unable to refrain from tobacco or any products containing nicotine within 8 hours 
before a scheduled visit.
4.3
Restrictions
1.
Subjects should refrain from strenuous physical exercise from 48 hours before admission to 
the site and during the visit.
2.
Subjects must refrain from alcohol from 48 hours before admission to the site and during the 
visit.
3.
Subjects should refrain from foods or beverages containing caffeine/xanthine from 48 hours 
before admission to the site and during the visit.
4.
During washout periods, subjects should attempt to limit the use of alcohol and tobacco or 
nicotine-containing products.
5.
Subjects must avoid using tobacco and other nicotine-containing products (smoking, 
chewing, patch, etc.) from 8 hours before admission to the site and during the visit.
6.
Subjects must adhere to the restrictions on use of artificial tears as detailed in Section 5.2.2.
4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of childbearing potential must use an acceptable form of contraception 
throughout the study period and for 60 days following the last dose of investigational product. If 
hormonal contraceptives are used, they should be administered according to the package insert. 
Females of childbearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 60 days following the last dose of investigational product.
Female subjects should be one of the following:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and age 51 years)

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks after sterilization, or

A female of childbearing potential with a negative serum -hCG pregnancy test at the 
screening visit and before randomization. Females of childbearing potential must agree to 
abstain from sexual activity that could result in pregnancy or agree to use acceptable methods 
of contraception.
Acceptable methods of contraception are:


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
Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days before the first dose of investigational product, plus condoms. Note: If subject 
becomes sexually active during the study, they should use one of the other acceptable 
methods noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days.
4.4.2
Male Contraception
Male subjects will be required to use a condom in conjunction with spermicidal gel, foam, 
cream, film, or suppository from the time of first dosing until 60 days after the last dose of 
investigational product.
Childbearing female partners of male study participants will be required to follow the acceptable 
methods of contraception for this study (described in Section 4.4.1) from the time of first dosing 
until 60 days after the last dose of investigational product.
Male subjects must not donate sperm for 3 months after the last dose of investigational product.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the early withdrawal
evaluations listed in Table 1 are to be performed as completely as possible. Whenever possible, 
all discontinued subjects should also undergo the protocol-specified follow-up. Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents. The reason for termination and date of stopping investigational product must be 
recorded in the electronic case report form (eCRF) and source documents.
Randomized subjects who discontinue from the study may be replaced at the sponsor’s discretion 
to ensure that at least 6 out 7 subjects complete a dosing regimen cohort. Replacement subjects 
will be assigned to the same treatment group as the subject they are replacing.
4.5.1
Subject Withdrawal Criteria
At any time in the study, subjects will be discontinued from the study if the IOP measurement in 
either eye reaches a reading greater than 36 mmHg or a reading less than 8 mmHg. If the subject 
falls outside the above measurements, rescue treatment will be started by the investigator as per 
the current standard of care.
If subjects experience corneal hazing of grade 3 or greater on the Hwang Grading Scale of 
Corneal Haze, they will be discontinued from the study and standard of care will be initiated. 


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The early termination evaluations listed in Table 1 are to be performed as completely as possible. 
Whenever possible, all discontinued subjects should also undergo the protocol-specified 
follow-up.
4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the eCRF.
Reasons for discontinuation include but are not limited to:

Completed

Adverse event

Withdrawal by subject

Noncompliance with investigational product

Physician decision

Study terminated by sponsor

Lost to follow-up

Pregnancy

Protocol deviation

Screen failure

Other 
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point before the last scheduled contact (office visit or telephone contact). At least 
one of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgement of receipt request) asking that 
they return to the site for final safety evaluations and return any unused investigational product.
4.5.4
Stopping Criteria for Dose Escalation
1.
Progressing from a dosing regimen cohort to the next or from a study part to the next will not 
occur in the presence of moderate or severe drug-related ocular AEs in 2 or more 
SHP639-treated subjects in a given cohort.
2.
If 1 or more subjects experience corneal hazing of grade 3 or greater on the Hwang Grading 
Scale of Corneal Haze, they will be discontinued from the study. At that time, the study will 
stop for further evaluation by the Shire’s Dose Escalation Committee.


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3.
If 2 or more subjects in a given cohort receiving active drug have a severe AE in the same 
organ or body system, no further subjects will be enrolled or dosed until further evaluation of 
the available data is made by the medical monitor and investigator to determine whether to 
stop or proceed with the study. Following a safety review of the event, study enrollment or 
dosing of currently enrolled subjects may be restarted if the medical monitor and the 
investigator determine that it is safe to proceed with the study.
4.
If any other drug-related event occurs in subjects receiving active drug and is deemed to pose 
an unacceptable risk to subjects by the investigator or medical monitor after further 
evaluation, no further subjects will be enrolled or dosed until further evaluation of the 
available data is made by the medical monitor and investigator to determine whether to stop 
or proceed with the study. Following a safety review of the event, study enrollment or dosing 
of currently enrolled subjects may be restarted if the medical monitor and the investigator 
determine that it is safe to proceed with the study.


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5.
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Treatment
Prior treatment includes all treatments (including but not limited to prescription treatments, 
investigational products, vitamins, herbal treatments, and nondrug therapies) received within 
30 days or 5 half-lives (whichever is longer) before the date of the first dose of investigational 
product and any procedures performed within the 5 years before the date of the first dose of 
investigational product. Prior treatment information must be recorded on the appropriate eCRF 
page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment and ocular procedure received between the dates of 
the first dose of investigational product and the end of the follow-up period, inclusive. 
Concomitant treatment information must be recorded on the appropriate eCRF page.
5.2.1
Permitted Treatment
Subjects should refrain from taking any medications (excluding those medications listed below) 
during the course of the study, until after discharge from the site on Day 29 of the MDTP; refer 
to Section 5.2.2 for details. Any medication that is considered necessary for the subject’s safety 
and well-being may be given at the discretion of the investigator. The administration of all 
medications (including investigational products) must be listed on the appropriate eCRF page.
The following medications are permitted during the study:

A stable dose (defined as at least 4 weeks) of prescription medication for chronic use (with 
the exception of those medications listed in Section 5.2.2, Table 8), including but not limited 
to:
–
Hormonal contraceptives for females of childbearing potential administered according to 
the package insert (see Section 4.4.1)
–
Hormone replacement therapy
–
Antihypertensive medication if the subject is on a stable dose for at least 4 weeks
–
A stable dose (defined as at least 4 weeks) of medication that can substantially alter IOP 
(with the exception of those medications listed in Table 8)

Occasional use of acetaminophen (paracetamol) and ibuprofen
Refer to Section 5.2.2 for information on use of artificial tears.
5.2.2
Prohibited Treatment
Table 8 details the washout period (relative to randomization) for common prior medications that 
are excluded for this study. Refer to Section 7.1.1.3 for details of the washout period for 
prohibited medications. Subjects must not take these medications until after discharge from the 
site on Day 29 of the MDTP, at which time they may resume taking their usual medication.


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Table 8
Common Excluded Medications and Associated Washout Period
Medication
Minimum Time Before Randomization
7 days
14 days
28 days
3 months
1 year
Steroids (except for 
nonperiocular 
dermatologic use)
X
Belladonna alkaloids 
(scopolamine, 
hyoscyamine, 
atropine)
X
B-type natriuretic 
peptides (eg, 
nesiritide)
X
Prostaglandins
X
β-adrenoceptor 
antagonists (eye 
drops)
X
α-adrenergic agonists 
(eye drops)
X
Epinephrine-related 
medications (eye 
drops)
X
Carbonic anhydrase 
inhibitors (eye drops)
X
Pilocarpine (all 
drops)
X
Carbachol (eye 
drops)
X
Echothiophate (eye 
drops)
X
Glycerol
X
Mannitol
X
Theophylline
X
Amantadine
X


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The use of all preserved artificial tears and any ocular gels and other lubricants is prohibited at 
all times during the study.
The use of nonpreserved artificial tears is prohibited during the following intervals, which 
include study visits:

Cohort A, SDTP: Day -2 to Day 2, after final assessment

Cohort A, MDTP: Day -2 to Day 29, after final assessment

Cohorts B, C, and D: Day -2 to Day 29, after final assessment
The use of nonpreserved artificial tears is allowed only during washout periods, according to 
the schedule below. 

Cohort A, SDTP, Washout 1: Start of screening until the evening of Day -2, SDTP

Cohort A, Washout 2: Day 2 after last assessment until the evening of Day -2, MDTP

Cohorts B, C, and D, Washout 1: Start of screening until the evening of Day -2
Refer to Section 4.3 for restrictions on the use of alcohol, tobacco, caffeine, and xanthine.
Other medications not listed in Table 8 may be considered allowable; see Section 5.2.1 for 
further details.


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is SHP639 ophthalmic solution, which will be provided as an ophthalmic 
solution packaged in 7.5 mL (filled to 5 mL) multiuse eye drop bottles. SHP639 ophthalmic 
solution is a sterile, colorless topical solution containing 0.1%, 0.3%, or 0.6% SRD006086 (as 
free-base equivalent). The SHP639 ophthalmic solution is preserved with benzalkonium chloride 
and will be supplied in a multiuse low-density polyethylene eye drop bottle. Additional 
information is provided in the current SHP639 IB. 
The quantities of SHP639 drug substance per drop of SHP639 ophthalmic solution are shown in 
Table 9.
Table 9
SHP639 Drug Substance per Drop of SHP639 Ophthalmic Solution
Topical Concentration (% weight/volume)
Quantity of SH639 Drug Substance per Drop (µg)
0.1
35
0.3
104
0.6
208
Quantities of drug substance per drop were calculated using a drop volume of 34.7 µL, which was the mean volume obtained at 
various temperatures, bottle orientations, and concentrations. Values have been rounded to the nearest microgram.
The reference product is placebo, which will be provided as an ophthalmic solution packaged in 
7.5 mL (filled to 5 mL) multiuse eye drop bottles identical to those used for the SHP639 
ophthalmic solution. The placebo solution will contain the same excipients as the SHP639 
ophthalmic solution but will not contain SHP639.
6.1.1
Masking the Treatment Assignment
This is a double-masked, placebo-controlled study. The packaging, appearance, and labeling of 
the investigational products will match. 
6.2
Administration of Investigational Products
6.2.1
Interactive Response Technology for Investigational Product Management
The actual treatment given to individual subjects is determined by a randomization schedule. The 
associated treatment assignments giving details of individual subject treatment are in the form of 
a randomization schedule created by the interactive response technology (IRT) vendor.
Each bottle/carton of SHP639 ophthalmic solution or matching placebo will be assigned a unique 
packaging identification number corresponding to the investigational product allocated to the 
subject, once eligibility has been determined. When a bottle/carton of SHP639 ophthalmic 
solution or matching placebo is assigned to a subject, the packaging identification number will 
be recorded in the eCRF and in the drug accountability records. Once assigned, it is important 
that the bottle/carton remains with the same subject throughout the study.


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6.2.2
Allocation of Subjects to Treatment
This is a double-masked, placebo-controlled study.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. This will be a 4-digit number starting at 
0001.
For screen failures, the screening number will be the identifying number used throughout the 
eCRF.
The actual treatment given to individual subjects is determined by a randomization schedule.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject and will be allocated before dosing after eligibility has been determined.
A randomization number is allocated before dosing once eligibility has been determined. Once a 
randomization number has been assigned, that number must not be used again, if for example, a 
subject is withdrawn from the study. If a randomization number is allocated incorrectly, the 
study monitor must be notified as soon as the error is discovered.
Replacement subjects are to be assigned the same treatment as subjects they are replacing.
Individual subject treatment is automatically assigned by the IRT.
Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment assignment as 
dictated by the study. In these cases, the same investigational product packing identification 
number may not be assigned to more than 1 subject.
6.2.3
Dosing
6.2.3.1
Dosing Procedures
After satisfying all screening and entry criteria for the study before dosing on Day 1 of each 
cohort, subjects will be randomized to receive either SHP639 ophthalmic solution or placebo, 
respectively. Investigational product (SHP639 ophthalmic solution or placebo) will be 
administered topically in 1 designated eye (Cohort A, SDTP only) or in both eyes (Cohort A, 
MDTP only, and Cohorts B, C, and D) at the time points specified in Table 1.
Subjects will receive their assigned dose as dispensed by the pharmacist or designee at each site. 
Investigational product will be administered by the principal ophthalmologist or trained designee 
at each site while subjects are on site, and will then be self-administered by each subject for the 
remainder of the treatment period.
Subjects should receive the single dose or first dose if multiple daily dosing (depending on 
cohort assignment) each day between 7:00am and 9:00am. This is particularly important for 
cohorts C and D as these subjects will receive 3 and 4 doses daily. 


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In Cohort A only, there will be a SDTP and an MDTP. The 2 treatment periods will be separated 
by a washout period of 3-14 days. In Cohort A, single-dose administration of the corresponding 
dose level (concentration) will occur first, followed by the multiple-dose administration of the 
same dose level (concentration) QD. The dosing regimens for Cohorts B, C, and D will consist 
of multiple-dose administration of the appropriate dose level concentration BID, TID, or QID, 
respectively. For all cohorts, the final dose during the MDTP will be administered on the 
morning of Day 28.
In Cohort A only, as a safety measure, the first 3 subjects in the SDTP will be dosed with a 
minimum of 1-hour intervals between subjects. Subjects will then be observed overnight and 
until the next day (24 hours after dosing) with an ophthalmologist on call. If no AEs occur that 
are consistent with the predefined stopping criteria, dosing the rest of the cohort (Cohort A, 
single dose) will proceed as previously outlined. Designated study eye criteria are detailed in 
Section 3.1.1.
6.2.3.2
Dose Escalation
Throughout the study, dose escalation meetings will commence at regular time points to review 
safety data and authorize progression into the next cohort. The anticipated dose escalation 
scheme is presented in Table 10.

Single-dose cohorts: a dose escalation meeting may convene after a minimum of 6 subjects 
have completed the 24-hour assessments for the SDTP. At the dose escalation meeting, a 
preselected Dose Escalation Committee will determine whether it is safe to continue to the 
anticipated cohort at either the next dose level or the next dosing regimen.

Multiple-dose cohorts: a dose escalation meeting may convene after a minimum of 6 subjects 
have completed the Day 14 assessments for the MDTP. At the dose escalation meeting, a 
preselected Dose Escalation Committee will determine whether it is safe to continue to the 
anticipated cohort at either the next dose level or the next dosing regimen. If the dose 
escalation meeting was held prior to the completion of the cohort, the remainder of the 
treatment period will be completed following the dose escalation meeting.


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Table 10
Anticipated Dose-escalation Scheme
Dose Authorized by Committee
Enabling Required Dose-escalation Activity
Before Switch from Single to Multiple Dose - BID, TID, or QID
Before Increasing Dose Level
Cohort
Dose
Regimen
Cohort
Dose
Regimen
Cohort
Dose
Regimen
A1
0.1%/Placebo
SD
NA
–
–
NA
–
–
A1
0.1%/Placebo
QD
A1
0.1%/Placebo
SD
NA
–
–
A2
0.3%/Placebo
SD
NA
–
–
A1
0.1%/Placebo
SD
A2
0.3%/Placebo
QD
A2
0.3%/Placebo
SD
A1
0.1%/Placebo
QD
A3
0.6%/Placebo
SD
NA
–
–
A2
0.3%/Placebo
SD
A3
0.6%/Placebo
QD
A3
0.6%/Placebo
SD
A2
0.3%/Placebo
QD
B1
0.1%/Placebo
BID
A1
0.1%/Placebo
QD
NA
/–
–
B2
0.3%/Placebo
BID
A2
0.3%/Placebo
QD
B1
0.1%/Placebo
BID
B3
0.6%/Placebo
BID
A3
0.6%/Placebo
QD
B2
0.3%/Placebo
BID
C1
0.1%/Placebo
TID
B1
0.1%/Placebo
BID
NA
/–
–
C2
0.3%/Placebo
TID
B2
0.3%/Placebo
BID
C1
0.1%/Placebo
TID
C3
0.6%/Placebo
TID
B3
0.6%/Placebo
BID
C2
0.3%/Placebo
TID
D1a
0.1%/Placebo
QID
C1
0.1%/Placebo
TID
NA
–/
–
D2
0.3%/Placebo
QID
C2
0.3%/Placebo
TID
D1
0.1%/Placebo
QID
D3
0.6%/Placebo
QID
C3
0.6%/Placebo
TID
D2
0.3%/Placebo
QID
BID=twice daily; NA= not applicable; QD=once daily; QID=4 times daily; SD=single dose; TID=3 times daily.
a Cohort D1 is not to be enrolled as it was decided that the resulting data would not contribute to the understanding of the safety of SHP639.


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Shire’s Dose Escalation Committee will consist of, at a minimum, the coordinating principal 
ophthalmologist, the Shire medical monitor, and the Shire ophthalmic study physician. 
Additional team members may be included as needed. 
At any time during the course of the study, subjects will be discontinued from the study if their 
IOP measurement reaches a reading of greater than 36 mmHg or a reading of less than 8 mmHg. 
Additionally, if subjects experience corneal hazing of grade 3 or greater on the Hwang Grading 
Scale of Corneal Haze, then they will be discontinued from the study. Should an event occur that 
requires a subject’s discontinuation from the study, the study will be halted for further evaluation 
by Shire’s Dose Escalation Committee.
The Dose Escalation Committee may authorize progression from 1 cohort to the next after the 
completion of the previous treatment regimen cohort and completion of the previous dose level 
cohort, as appropriate. Additionally, more than 1 cohort of safety data may be reviewed at a dose 
escalation meeting depending on scheduling and study progress. A minimum of 6 subjects 
should have completed the previous cohort(s) without clinically significant adverse changes; this 
includes findings on the ophthalmologic examination. Additionally, progression will not occur in 
the presence of moderate or severe drug-related ocular AEs in 2 or more subjects.
If, in the judgment of the coordinating principal ophthalmologist, the Shire medical monitor, and 
the Shire ophthalmic study physician, it is unclear whether there is a potential safety concern or 
whether dose escalation should occur, a dose level may be reduced, modified, or repeated 
depending on the outcome of the safety data review between doses or treatments. Further, based 
on the findings from the dose escalation review meetings, a cohort (or cohorts) may be 
determined to not be necessary to determine the safety of SHP639. Finally, upon completion of 
all dose cohorts, additional doses may be studied based on emergent safety, PD, and PK data 
following the necessary protocol amendment and Institutional Review Board (IRB) reviews.
6.2.4
Unmasking the Treatment Assignment
The treatment assignment code must not be broken during the study except in emergency 
situations where the identification of the investigational product is required for further treatment 
of the subject. The investigator should contact the medical monitor as soon as possible after the 
investigator has been unmasked.
In the event that the treatment assignment code is broken and the date and signature of the person 
who broke the code are recorded in the IRT and the source documents. The reason for breaking 
the code will be captured in the clinical database. Upon breaking the code, the subject is 
withdrawn from the study but should be followed up for safety purposes. Any code breaks that 
occur must be reported to the contract research organization (CRO) and sponsor. Code-break 
information is held by the pharmacist/designated person at the site.
6.3
Labeling, Packaging, Storage, and Handling
SHP639 ophthalmic solution will be supplied in a multiuse low-density polyethylene eye drop 
bottle containing 5 mL of ophthalmic solution. Each labeled bottle will be placed into a single
labeled carton. Bottles must be stored at refrigerated temperatures (2-8°C) at all times.


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6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container.
All investigational product is labeled with a minimum of the following: protocol number, 
medication identification number, dose form, directions for use, storage conditions, expiry date 
(if applicable), batch number and/or packaging reference number, the statements, “For clinical 
trial use only” and/or “CAUTION: New Drug – Limited by Federal (or US) Law to 
Investigational Use,” and the sponsor’s name and address. Any additional labeling requirements 
for participating countries and/or controlled substances will also be included on the label, if 
necessary. 
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
The investigational product bottles will be labeled and then each bottle will be placed into an 
individual labeled carton. This carton will then be secured with a tamper-evident seal. 
Changes to sponsor-supplied packaging before dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team (eg, site pharmacist or 
principal ophthalmologist). 
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. 


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Such a device (ie, certified minimum/maximum thermometer) would require manual resetting 
upon each recording. The sponsor must be notified immediately upon discovery of any excursion 
from the established range. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the investigational 
product and will provide supportive documentation as necessary. Under no circumstances should 
the product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
Not applicable. 
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed-upon number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content, and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer and dispense the investigational product only to 
subjects included in this study following the procedures set out in the study protocol. Each 
subject will be given only the investigational product carrying his/her treatment assignment with 
instructions as how to administer and store the product. All administered and dispensed 
medication will be documented in the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects. Due to 
the health/safety concerns with returning the investigational product container, the investigator 
must request that subjects keep the empty investigational product packaging after use and return 
it to the site for drug accountability purposes.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided the masking of the study is not compromised. 


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With the written agreement of the sponsor, at the end of the study, all used and unused stock are 
to be sent to a nominated contractor on behalf of the sponsor. In this case, destruction records 
identifying what was destroyed, when and how, must be obtained with copies provided to the 
sponsor. Destruction of investigational products must be in accordance with local, state, and 
national laws. Based on entries in the site drug accountability forms, it must be possible to 
reconcile investigational products delivered with those used and returned. All investigational 
products must be accounted for and all discrepancies investigated and documented to the 
sponsor’s satisfaction.
6.5
Subject Compliance
Compliance must be assessed by observation of dosing by the investigator or designee during 
site visits. In addition, the site personnel should witness the ophthalmic drop administration by 
the subject during these visits to ensure proper technique of drop administration. The 
investigator/nominated person will record details on the drug accountability log(s) and/or source 
documents. In addition, in-clinic dosing details (time, date, dose level, dosing regimen) will be 
captured on the appropriate eCRF page.
Subjects must be instructed to bring their unused investigational product and empty/used 
investigational product packaging to every visit. Drug accountability must be assessed at the 
container/packaging level for unused investigational product that is contained within the original 
tamper-evident sealed container (eg, bottles, trays, vials) or at the individual count level for 
opened containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.
6.6
Retention of Bioavailability and Bioequivalence Testing Samples
Not applicable.


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7.
STUDY PROCEDURES
7.1
Study Schedule
See Table 1 for the visits at which each assessment and procedure will be performed. See 
Table 2, Table 3, Table 4, and Table 5 for the time points at which assessments and procedures 
will be performed for Cohorts A, B, C, and D, respectively.
Visit windows for the MDTP are as follows: 

Start of screening: For all subjects, the maximum duration of the screening period is 42 days. 

Days 7, 14, and 21: ±2 days

Follow-up telephone call: 7±2 days after the final dose administration

Day 88 follow-up visit: ±4 days
The following is a suggested “priority order” when more than 1 procedure or assessment is 
required at a particular time point. The actual order of procedures will be dictated by the clinical 
setting. Departure from the priority order below will not be considered a protocol deviation.

Spontaneous or solicited AE reporting

Vital signs

Electrocardiogram (ECG)

Physical examination

Clinical laboratory tests

Dosing

Drop comfort assessment (must not be performed within 30 minutes after instillation of 
topical anesthetic)

Ophthalmologic examination

Intraocular pressure measurement 

Pharmacokinetic blood sampling
NOTE: Blood sampling for PK evaluation must be performed at the precise protocol-scheduled 
time. Actual sampling time(s) must be accurately recorded in the source document and on the 
appropriate eCRF page.
7.1.1
Screening Period 
For all subjects, the maximum duration of the screening period is 42 days. All screening 
assessments and procedures are to be performed by the principal ophthalmologist or a qualified 
designee. See Table 1 for details of the screening procedures to be performed.


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Written, signed, and dated informed consent before the performance of any study-related 
procedures must be obtained by the principal ophthalmologist or a designee. A copy of the 
signed ICF must be given to the subject for their records.
7.1.1.1
Screening Failure
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least one of the exclusion criteria and has not been enrolled/randomized or 
administered investigational product.
For the purposes of data collection, subjects who give consent to the study but are not enrolled 
and/or randomized will be reported with a study discontinuation reason of “sponsor decision” in 
the eCRF if they were otherwise fully eligible for the study (for example, alternates/reserve 
subjects).
7.1.1.2
Rescreening of Subjects
Subjects who fail to meet all inclusion/exclusion criteria will not be permitted to be rescreened 
for the study at any point. Any subject who is qualified but not dosed (ie, an alternate subject) 
may be rescreened at a later date for the study. 
Eligible subjects who meet all inclusion/exclusion criteria but are unable to participate in the 
study due to scheduling conflicts/timing may be rescreened based on investigator discretion and 
sponsor approval should their availability to participate fall outside the screening window. In 
these cases, a new screening number must be assigned for each subject who is rescreened and a 
new ICF must be signed.
7.1.1.3
Washout Period 1
A washout period (Washout 1) of up to 28 days is required for certain predefined prescription 
medication as detailed in Section 5.2.2, Table 8. The washout will take place during the 
screening period and may start from Day -28 onwards depending on the length of washout 
required. Subjects will continue not to take prohibited medications until discharge from the site 
on Day 29 of the MDTP.
A midwashout ophthalmic assessment (MWOA) will be performed on both eyes 14±2 days after 
a subject either starts the washout period or undergoes a previous MWOA. Ophthalmic and 
safety assessments will be performed during the MWOA at the visits specified in Table 1; the 
time points during each visit are specified in Table 2, Table 3, Table 4, and Table 5 for Cohorts 
A, B, C, and D, respectively.
7.1.2
Treatment Period 
Investigational product will be administered by study staff when subjects are present at the site 
during study visits.
7.1.2.1
Day -2 Through Day 2, Single-dose Treatment Period (Cohort A Only)
Following screening and Washout 1, eligible subjects in Cohort A will be admitted to the site for 
the SDTP, either on Day -3 (optional early check-in to unit if more convenient for the subject) or 


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on the morning of Day -2. Subjects will undergo baseline assessments on Day -2 and Day -1 as 
specified in Table 1.
On Day 1 of the SDTP, before dosing, subjects who continue to be eligible will be randomized to 
SHP639 ophthalmic solution or placebo, as described in Section 6.2.2. In each treatment period, 
subjects will receive a single dose of investigational product in 1 eye, according to the treatment 
to which they are assigned.
On Day 1 of the SDTP, subjects will undergo assessments and procedures as specified by visit in 
Table 1 and by time point during each visit in Table 2.
Subjects will be discharged from the site on Day 2 after completion of the evening assessments. 
After subject checkout on Day 2 of the SDTP, subjects will have a washout period (Washout 2) 
of 3-14 days and then return for the MDTP. 
7.1.2.2
Day -2 Through Day 29, Multiple-dose Treatment Period (All Cohorts)
Subjects will attend the site daily on Day -2 and Day -1 for MDTP baseline procedures, as 
specified in Table 1.
Time points of ophthalmic assessments performed on Day -2 and Day -1 should be carried 
forward to assessments on Day 1. This ensures that the baseline IOP time points established 
before dosing begins are time-matched to the IOP assessments performed during dosing days for 
the duration of the study.
On the morning of Day 1 of the MDTP, subjects will be admitted to the site. Before dosing, 
subjects in Cohorts B, C, and D who continue to be eligible will be randomized to SHP639 
ophthalmic solution or placebo, as described in Section 6.2.2. Subjects will receive doses of 
investigational product according to the treatment to which they are assigned. (Subjects in 
Cohort A will continue to receive SHP639 ophthalmic solution or placebo according to the 
treatment assigned on Day 1 of the SDTP.) All subjects in the MDTP cohorts will receive 
investigational product in both eyes.
On Day 1 of the MDTP, subjects will receive dose(s) during the day depending on their cohort 
assignment (Cohort A, B, C, or D). They will undergo assessments and procedures as specified 
by visit in Table 1 and by time point during each visit in Table 2, Table 3, Table 4, and Table 5
for Cohorts A, B, C, and D, respectively.
Subjects will be discharged on Day 2 following study procedures and the dispensing of SHP639 
ophthalmic solution for subject use on an outpatient basis. Subjects will be trained on SHP639 
ophthalmic solution administration and will be provided with diaries to record dosing times.
On Days 3-26, subjects will be responsible for their outpatient dosing and for recording dosing in 
their diaries.
On each of Days 7, 14, and 21, subjects will attend the site for assessments and procedures as 
specified by visit in Table 1 and by time point during each visit in Table 2, Table 3, Table 4, and 
Table 5 for Cohorts A, B, C, and D, respectively.


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Subjects will be readmitted to the site on the evening of Day 26. Subjects will continue to receive 
their assigned doses, with the final dose being administered on the morning of Day 28. Subjects 
will undergo assessments and procedures as specified by visit in Table 1 and by time point 
during each visit in Table 2, Table 3, Table 4, and Table 5, for Cohorts A, B, C, and D, 
respectively. They will be discharged from the site after completion of the morning assessments 
on Day 29.
Subjects who are prematurely discontinued from the study will complete the Day 29 assessments 
as fully as possible.
7.1.3
Follow-up
A follow-up telephone call will take place 7±2 days after the final dose (Day 28 of the MDTP). 
Site staff will query subjects for serious AEs (SAEs), AEs, and concomitant treatments. In the 
event that a subject is prematurely discontinued from the study, every attempt should be made to 
complete the follow-up assessments.
On Day 88±4 days, subjects will attend the site for ADA blood sample collection. Site staff will 
query subjects for serious AEs (SAEs), and AEs. Adverse events that occur from Day 33 to Day 
88 should be captured on the AE eCRF page. Concomitant medications during this period will 
also be captured. All AEs and SAEs that are not resolved at the time of this contact will be 
followed for an additional 30 days (see Section 8.1).
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
7.2.2
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
Actual safety assessment times will be monitored and recorded. The sponsor’s expectation is that 
the investigator will ensure that every effort is made to perform all assessments at the precise 
protocol-scheduled time. Any safety assessment that deviates from the scheduled assessment 
time set forth in the protocol by more than 15 minutes will be considered a protocol deviation.
Ophthalmic assessments are considered safety assessments. If an ophthalmic assessment deviates 
from the scheduled assessment time set forth in the protocol by more than 15 minutes (or 5
minutes for the 15-minute and 30-minute time points), it will be considered a protocol deviation.
All AEs, prior medication use, and concomitant medication use will be assessed and monitored 
from the time the subject signs the ICF to completion of the study (including to time of screen 
failure or drop out/discontinuation); see Sections 7.2.2.4 and 8.1 for further details. The AEs will 
include nontreatment-emergent AEs (ie, those occurring from the time of informed consent 


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signature to the first dose of investigational product) and treatment-emergent AEs (ie, AEs 
occurring after the first dose). While housed at the site, subject safety will also be closely 
monitored through study procedures and physician oversight. 
7.2.2.1
Medical and Medication History
A complete medical and medication history, as well as demographic information, will be 
collected at the screening visit by a qualified licensed physician, physician’s assistant, or a nurse 
practitioner. The medical history will be reviewed and recorded, including:

Date of birth

Sex

Race and ethnicity

Recent ingestion of medication (Section 5.1)

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, and other diseases
7.2.2.2
Physical Examination (Including Height and Weight)
A complete physical examination will be performed at the visits specified in Table 1 by a 
qualified licensed physician, physician’s assistant, or nurse practitioner.
The physical examination will include a review of the following body systems:

General appearance

Skin

Head, eyes, ears, nose, and throat

Spine/neck/thyroid

Musculoskeletal

Respiratory

Cardiovascular

Neurological

Abdomen (including liver and kidneys)
Abnormalities identified at the screening visit will be documented in the subject’s source 
documents and on the medical history eCRF page. Clinically significant changes after the 
screening visit will be captured as AEs on the AE eCRF page, as deemed by the investigator.
Height and weight will be recorded at screening only.


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7.2.2.3
Ophthalmologic Examination 
Ophthalmologic examinations of both eyes will be performed at the visits specified in Table 1; 
the time points during each visit are specified in Table 2, Table 3, Table 4, and Table 5 for 
Cohorts A, B, C, and D, respectively. Both eyes will be assessed at each examination unless 
otherwise specified.
Manifest Refraction
Manifest refraction will be determined at the following visits in order to assess BCVA:

Screening

SDTP (Cohort A only): Day -2

MDTP (all cohorts): Day -2 and Day 29
The manifest refraction will be repeated if the BCVA has decreased by 10 or more letters. Full 
instructions for performing the manifest refraction are included in the ophthalmology procedures 
manual.
Best-Corrected Visual Acuity
Using the manifest refraction, the BCVA will be assessed at distance before slit lamp 
examination at the following visits:

Screening

Midwashout assessment

SDTP (Cohort A only): Days -2 and -1 and Days 1 and 2

MDTP (all cohorts): Days -2 and -1 and Days 1, 2, 7, 14, 21, 27, 28, and 29
See Table 2, Table 3, Table 4, and Table 5 for detailed timings by cohort.
Full instructions for measuring BCVA are provided in the ophthalmology procedures manual.
A decrease in BCVA by 6 or more letters may be considered clinically significant (CS) or not 
clinically significant (NCS) and requires a dilated posterior segment examination. A 10-letter 
loss in BCVA is considered CS and requires a repeat manifest refraction and dilated posterior 
segment examination. Clinically significant changes should be recorded as AEs in the source 
document and eCRF.
Slit Lamp Biomicroscopy
Slit lamp biomicroscopy will be performed at the following visits:

Screening

Midwashout assessment


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
SDTP (Cohort A only): Days -2 and -1 and Days 1 and 2

MDTP (all cohorts): Days -2 and -1 and Days 1, 2, 7, 14, 21, 27, 28, and 29
See Table 2, Table 3, Table 4, and Table 5 for detailed timings by cohort.
The anterior segment will be examined through the slit lamp before performing IOP 
measurements, pachymetry, or graded assessments. The following structures will be evaluated as 
normal or abnormal. If abnormal, the findings should be described and recorded as either CS or 
NCS. Any CS findings should be recorded as AEs; the investigator may use his/her discretion to 
determine whether a finding considered NCS is reported as an AE. Findings and assessment of 
clinical significance should be recorded in the source documents and eCRF.
The following will be examined at each visit: 

Lids/lashes/lacrimal

Conjunctiva

Cornea

Anterior chamber

Iris

Lens
Anterior Segment Graded Assessments
Anterior segment graded assessments will be performed at the following visits:

Screening

Midwashout assessment

SDTP (Cohort A only): Days -2 and -1 and Days 1 and 2

MDTP (all cohorts): Days -2 and -1 and Days 1, 2, 7, 14, 21, 27, 28, and 29
See Table 2, Table 3, Table 4, and Table 5 for detailed timings by cohort.
Anterior segment graded assessments should be performed during the slit lamp examination but 
before IOP measurement. The following assessments will be performed:

Conjunctival redness score assessment

Corneal haze assessment

Corneal epithelial integrity assessment by fluorescein staining

Anterior chamber cell and flare

Lens opacification (performed during dilated examination only)


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The procedures are outlined in Appendix 2; full instructions are provided in the ophthalmology 
procedures manual.
Any abnormal findings should be described and recorded as either CS or NCS. Any CS findings 
should be recorded as AEs; the investigator may use his/her discretion to determine whether a 
finding considered NCS is reported as an AE. Findings and assessment of clinical significance 
should be recorded in the source document and eCRF.
Intraocular Pressure
Intraocular pressure will be measured at the following visits:

Screening

Midwashout assessment

SDTP (Cohort A only): Days -2 and -1, Days 1 and 2

MDTP (all cohorts): Days -2 and -1 and Days 1, 2, 7, 14, 21, 27, 28, and 29
See Table 2, Table 3, Table 4, and Table 5 for detailed timings by cohort.
Predose morning IOP assessments must be completed at least 30 minutes before dosing to allow 
the anesthetic to wear off.
Intraocular pressure will be measured at the slit lamp using Goldmann applanation tonometry. 
The procedure for measuring IOP is outlined in the ophthalmology procedures manual. Special 
care must be taken to avoid placing pressure on the globe with the fingers when moving the 
eyelids to fully expose the cornea.
Intraocular pressure must be measured after assessing the corneal epithelium for fluorescein 
staining and before pachymetry, gonioscopy, or dilation for posterior segment examination (if 
being performed).
Two consecutive IOP measurements, to the nearest mmHg, will be made in the designated study 
eye (designated study eye criteria are detailed in Section 3.1.1); if the 2 measurements differ by 
more than 2 mmHg, then a third measurement will be performed. All (2 or 3) readings will be 
used to determine the mean IOP at the given time point. The procedure will be repeated in the 
nonstudy eye. All measurements will be recorded in the source document and eCRF.
Every effort should be made to obtain an accurate IOP measurement. If the mires are irregular 
and/or an IOP reading is not obtainable, this should be noted in the source document and eCRF.
Posterior Segment Examination
The posterior segment will be visualized by a fundus examination at the following visits:

Screening – dilated

SDTP– nondilated Day -2


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
MDTP– nondilated Day -2

Day 29 – dilated
A dilated posterior segment examination of both eyes should also be performed if the BCVA in 
either eye decreases by 6 or more letters.
The following structures will be assessed (suggested technique):

Vitreous (binocular indirect examination)

Optic nerve head (slit lamp biomicroscopy)

Cup-to-disc ratio (slit lamp biomicroscopy)

Macula (slit lamp biomicroscopy)

Retina vasculature

Retina, outside of arcades, including periphery

Choroid
Observations will be described and/or will be graded as normal or abnormal. Abnormal findings 
will be described. Clinically significant abnormalities will be recorded as AEs; NCS findings 
will be recorded as AEs at the investigator’s discretion. Further details will be specified in the 
ophthalmology procedures manual.
Gonioscopy 
Gonioscopy to assess the iridocorneal angles will be performed at screening and on Day 29. 
Gonioscopy should be performed after the corneal epithelium has been evaluated for defects with 
fluorescein and after IOP has been measured but before dilated posterior segment examination 
(Day 29). The angle of each eye should be graded in all 4 quadrants using the Shaffer grading 
system.
Noncontact Specular Microscopy 
Noncontact specular microscopy will be performed to assess endothelial cell count at the 
following visits:

Screening

SDTP (Cohort A only): Day -1 and Day 2

MDTP (all cohorts): Day -1 and Days 14 and 29
Details of the procedure will be found in the ophthalmology procedures manual.


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Corneal Pachymetry 
Corneal pachymetry to assess central corneal thickness will be performed after the predose 
examination and at 1, 2, 4, and 12 hours after dosing. With the pachymeter set to perform a 
single measurement, take and record 3 consecutive measurements at each applicable time point 
at the following visits:

Screening

SDTP (Cohort A only): Day -1 and Days 1 and 2

MDTP (all cohorts): Day -1 and Days 1, 2, 7, 14, and 29
If the range of the measurements is 15 microns or less, the set of readings is acceptable; if not, 
discard all measurements and repeat until an acceptable set of 3 measurements is obtained. 
Record all 3 measures in the source document and the eCRF.
See Table 2, Table 3, Table 4, and Table 5 for detailed timings by cohort.
Full details of the procedure are provided in the ophthalmology procedures manual.
Drop Comfort Assessment
Drop comfort assessment should be performed immediately after instillation of investigational 
product and before IOP assessment (which requires topical anesthetic).
Drop comfort assessments will be performed for the first dose of the day as follows:

SDTP (Cohort A only): Day 1 

MDTP (all cohorts): Days 1, 7, 14, 21, 27, and 28
Drop comfort assessment will not be captured in the subject's daily journal.
The drop comfort assessment will be performed for each eye except for Cohort A during the 
SDTP, when only the study eye will be assessed. The assessment will be performed immediately 
and 1, 2, and 3 minutes after instillation of the investigational product. The subject will be asked 
to rate drop comfort on a scale of 0-10, where 0=very comfortable and 10=very uncomfortable.
If the score is not ≤3 at minute 3, the drop comfort assessment should be repeated at 5, 10, and 
15 minutes after dosing until the score is ≤3. If the score is >3 at 15 minutes after dosing, it 
should be recorded as an AE.
7.2.2.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed until Day 88/FU (refer to 
Section 8). Adverse events that occur after Day 33 to Day 88/FU should be captured on the AE 
eCRF page.


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7.2.2.5
Vital Signs
Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be measured at the visits specified in Table 1; the time points 
during each visit are specified in Table 2, Table 3, Table 4, and Table 5 for Cohorts A, B, C, and 
D, respectively. Additional blood pressure and pulse rate measurements may be performed, as 
determined by the investigator, in order to ensure appropriate monitoring of subject safety and 
accurate recording of vital sign measurements. Any changes from baseline that are deemed 
clinically significant by the investigator are to be recorded as an AE.
The same method for obtaining blood pressure measurement (auscultatory or oscillometric) 
should be used throughout the study for all subjects (and documented). In addition, the 
conditions of vital sign measurements should be controlled and as consistent as possible during 
the study, in order to minimize external variability of the readings. It is advised that 
measurements be collected at a comfortable room temperature with little to no background noise, 
using the same (appropriately sized) cuff placed at the same location of the same arm during the 
study. The bladder deflation rate should be deflated (calibrated for oscillometric method or 
manually by auscultatory method) at a rate of 2-3 mmHg/s (and the first and last audible sounds 
recorded as systolic and diastolic pressure) after at least 5 minutes of rest in the assumed 
position.
The cuff should have a bladder length that is 80% and a width that is at least 40% of arm 
circumference (a length-to-width ratio of 2:1). 
The subject should be asked to remove all clothing that covers the location of cuff placement. 
The subject should be instructed to relax as much as possible for at least 5 minutes before 
collection. The subject should remain quiet during this time and through the measurement.
The subject should be comfortably seated, with the legs uncrossed, with feet flat on the floor, and 
the back and arm supported, such that the middle of the cuff on the upper arm is at the level of 
the right atrium (the midpoint of the sternum).
At the screening visit, blood pressure should be compared between both arms. When there is a 
consistent interarm difference confirmed over 3 consecutive measurements (>10 mmHg), the 
arm with the higher blood pressure should be used for inclusion at screening and the last 
measurement recorded in the eCRF. The same (right or left) arm with the higher blood pressure 
will be used throughout the study.
For details on blood pressure and pulse procedures, see Figure 1.


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Figure 1
Procedures for Screening Vital Signs (Blood Pressure – Pulse)
If there is a ≤10mmHg difference between arms 
for both SBP and DBP:
Site may select to use either arm for subsequent vital 
sign assessments. 
If there is a >10mmHg difference between arms on either the SBP or DBP reading:
1.
Perform triplicate readings of SBP/DBP-pulse on both arms at intervals of at least 1 minute
2.
For each arm, calculate the mean of these 3 readings (SBP/DBP-pulse)
3.
Calculate the difference of the means between right and left arms.
If  difference >10mmHg on either arm for either SBP or DBP readings:
Identify whether the SBP or DBP has the larger mean difference. If the DBP 
has the larger mean difference (as in the example below), then use the DBP 
values to select the arm with the higher blood pressure for subsequent 
vital sign assessments.
If difference ≤10mmHg for both SBP and DBP
(or the difference between the right and left
means for both systolic and diastolic 
readings is zero):
Site may select to use either arm for subsequent 
vital sign assessments.
SBP/DBP and pulse for selected arm should 
be entered into eCRF.
The blood pressure and heart rate entered 
into the eCRF should be the last (3rd) 
triplicate on the arm with the higher mean.
Example:             Systolic       Diastolic    
Right mean  
135    /   65 
Left mean
  138   /   76
Mean difference            3       11
Use left arm
Example:               Systolic     Diastolic    
Right mean 
126  /   70 
Left mean
   120  /   75
Mean difference            6         5
Site preference on arm
Perform screening blood pressure and pulse on 
both arms after a 5-10 minute rest in sitting or 
supine position.
A single measurement is performed.
DBP=diastolic blood pressure; eCRF=electronic case report form; SBP=systolic blood pressure


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One reading (seated systolic blood pressure/diastolic blood pressure and pulse rate) should be 
taken. 
The use of automated devices for measuring pulse rate is acceptable, although, when done 
manually, pulse rate will be measured in the brachial/radial artery for at least 30 seconds. When 
the timing of these measurements coincides with a blood collection, blood pressure and pulse 
rate should be obtained before the nominal time of the blood collection.
Body Temperature
Body temperature will be measured at the visits specified in Table 1; the time points during each 
visit are specified in Table 2, Table 3, Table 4, and Table 5 for Cohorts A, B, C, and D, 
respectively.
Oral temperature should be taken by placing a digital thermometer under the tongue for at least 
30 seconds. Tympanic temperature may also be used. 
7.2.2.6
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved. Any laboratory results that are determined to be clinically significant or 
indicative of an AE, as determined by the investigator, will be captured in the clinical database.
The following clinical laboratory assessments will be performed: 
Biochemistry
Blood samples (8.5 mL) for serum biochemistry will be collected into a gel separator tube at the 
visits specified in Table 1. The following parameters will be assessed: 
Sodium
Total CO2 (Bicarbonate)
Potassium
Albumin
Glucose 
Aspartate aminotransferase
Blood urea nitrogen
Alanine aminotransferase
Creatinine
Gamma-glutamyltransferase 
Calcium
Alkaline phosphatase 
Chloride
Total bilirubin 


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Phosphorus
Uric acid
Total protein
-hCGa
a
Females only. Only females of child-bearing potential ie, not postmenopausal or surgically sterile, as defined in Section 
4.4.1, will be required to have β-hCG evaluated. Reported values of β-hCG that are >1.0 and <6.0 mIU/mL are less than the 
upper range for non-pregnant, post-menopausal female (7.0-8.3 mIU/mL) and are considered negative.
Hematology
Blood samples (4 mL) for hematology will be collected into an ethylenediaminetetraacetic acid 
tube at the visits specified in Table 1. The following parameters will be assessed:
Hemoglobin
Total neutrophils (absolute)
Hematocrit
Eosinophils (absolute)
Red blood cells
Monocytes (absolute)
Platelet count
Basophils (absolute)
White blood cell count (total and differential)
Lymphocytes (absolute)
Urinalysis
A urine sample for urinalysis will be collected at the visits specified in Table 1. The following 
parameters will be assessed:
pH
Blood
Nitrites
Glucose
Ketones
Leukocyte esterase
Protein
Bilirubin
Specific gravity
Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis. At a minimum, the microscopic examination will consist of red blood cells, white 
blood cells, casts, and bacteria.
7.2.2.7
Pregnancy Test
For all female subjects (regardless of reproductive potential status), a serum pregnancy test will 
be performed at the visits specified in Table 1; or if pregnancy is suspected; or on withdrawal of 
the subject from the study. Pregnancy test results must be confirmed as negative before 
proceeding in the study.
7.2.2.8
Drug and Alcohol Screen
A urine screen for drugs of abuse and a urine screen or breathalyzer test for alcohol will be 
performed at the visits specified in Table 1. Additional drug and alcohol screens may be 
performed at the investigator’s discretion.


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Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine. Additional drugs of abuse, eg, 
methamphetamines and tricyclic anti-depressants, which are included in currently marketed 
products for drugs of abuse screening, will also be tested in these samples. 
Results of drug and alcohol screens will be reviewed and verified by the study monitor but will 
not be collected in the eCRF database.
Any positive result for drugs of abuse or alcohol at screening or on Day -1 will exclude the 
subject from further participation in the study.
7.2.2.9
Serology Screen
At the screening visit, a blood sample of approximately 8 mL will be collected into a serum 
separator tube to test for the presence of HIV, HBsAg, and HCV antibody.
The test results must be confirmed negative before randomization. If a test result is positive, the 
subject will be excluded from entering the study. Results of the virology screen will be reviewed 
and verified by the study monitor but will not be collected in the eCRF database.
7.2.2.10
Antidrug Antibody Testing
A blood sample of approximately 6 mL will be collected to test for antidrug antibodies in serum 
at the visits specified in Table 1. On dosing days, samples will be collected before the first dose 
of the day. A full description of the ADA sample collection, handling, storage, and shipping is 
provided in the laboratory manual.
Any subject with newly developed antidrug antibodies at the Day 60 (Day 88/FU) assessment, 
which is 60 days after dosing, may require follow-up. This will be discussed as necessary by the 
principal ophthalmologist and medical monitor on a case-by-case basis.
7.2.2.11
Electrocardiogram
Twelve-lead ECGs will be performed at the visits specified in Table 1; the time points during 
each visit are specified in Table 2, Table 3, Table 4, and Table 5 for Cohorts A, B, C, and D, 
respectively.
The following parameters will be recorded on the appropriate eCRF page: heart rate, PR, RR, 
QRS, and QT intervals. The QT interval corrected for heart rate using the Bazett formula (QTcB) 
and QT interval corrected for heart rate using the Fridericia formula (QTcF) will be derived from 
the data in the database. The investigator’s assessment of the ECG tracing as normal or abnormal 
must be documented, and if abnormal, his/her determination of whether the abnormality is 
clinically significant or not will be documented on the tracing and recorded in the eCRF.
The subject should be asked to remove all clothing that covers the location of lead placement. 
The subject must be resting in the supine position for at least 5 minutes before collecting the 
ECG.


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In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings. 
One complete recording, including a 10-second rhythm strip, should be taken at each time point. 
It should be immediately assessed as a valid recording and, if not valid, it should be repeated. 
Invalid recordings will not be entered in the eCRF.
The ECG collected before dosing on Day 1 will serve as the subject’s baseline ECG.
To ensure the safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.
If the QTcF interval (calculated online on site) is increased by >45 msec from the baseline or an 
absolute QTcF value is >500 msec for any scheduled ECG, then 2 additional ECGs will be 
collected, approximately 2-4 minutes apart, to confirm the original measurement. If either of the 
QTcF values from these repeated ECGs remains above the threshold value (>45 msec from the 
baseline; or is >500 msec), then a single ECG must be repeated at least hourly until QTcF values 
from 2 successive ECGs fall below the threshold value that triggered the repeat measurement. 
When triplicate ECGs are collected, the mean of the triplicate measurements should be used to 
trigger the decision to collect follow-up ECGs.
If QTcF values remain above 500 msec (or >45 msec from the baseline) for >4 hours (or sooner 
at the discretion of the investigator) or QTcF intervals get progressively longer, the subject 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
intervals do not return to <500 msec (or to <45 msec above the baseline) after 8 hours of 
monitoring (or sooner at the discretion of the investigator). The parameters from the continuous 
ECG monitoring will be recorded in the source documents.
If a machine-read QTcF/QTcB value is prolonged, as defined above, repeat measurements may 
not be necessary if a qualified physician’s interpretation determines that the QTcF/QTcB values 
are in the acceptable range.
7.2.3
Pharmacokinetic Procedures
The name and address of the bioanalytical laboratory(ies) for this study will be maintained in the 
investigator’s files at each site and in the Trial Master File at the CRO. A laboratory manual fully 
describing the schedule and method of sample handling will be provided.
Actual PK blood (for plasma) sample collection times versus time of dosing will be monitored. 
The sponsor’s expectation is that the investigator will ensure that every effort is made to collect 
all PK samples at the precise protocol scheduled time. Pharmacokinetic sample collection must 
not deviate from the nominal collection time set forth in the protocol by more than 5 minutes 
from samples collected within 4 hours after dosing or by more than 15 minutes for samples 
collected beyond 4 hours after dosing. Samples collected outside these parameters will be 
considered protocol deviations. 


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7.2.3.1
Pharmacokinetic Sample Collection and Handling Procedures
Blood samples will be collected for determination of plasma concentrations of SHP639 at the 
visits specified in Table 1; the time points during each visit are specified in Table 2, Table 3, 
Table 4, and Table 5 for Cohorts A, B, C, and D, respectively. Potential metabolites may also be 
determined as appropriate.
A full description of the PK blood sample collection, handling, storage, and shipping is provided 
in the laboratory manual.
Polypropylene plasma sample tubes for bioanalysis must be freezer-safe and identified with 
freezer-safe labels provided by the central laboratory. The labels will contain the following 
information:

Study number (SHP639-101)

Subject identifier 

Cohort (eg, A1, A2, A3)

Treatment period (single dose or multiple dose; Cohort A only)

Nominal day

Nominal time

Matrix identifier (plasma)

Split (primary or back-up)
7.2.3.2
Shipment of Pharmacokinetic Samples
All PK samples should be double-bagged to contain leaks and packed with a sufficient quantity 
of dry ice to ensure that they remain frozen for at least 72 hours to allow for delays in shipment. 
Primary and back-up samples must be shipped separately. A courier that will track shipments 
and replenish dry ice if necessary should be used. All applicable shipping regulations must be 
followed. Shipments should be scheduled so that no samples arrive on the weekend and should 
be shipped Monday-Wednesday only. Samples should be transported to ensure that they arrive at 
the bioanalytical laboratory between the hours of 9:00 AM and 4:00 PM. The recipient and 
primary Shire contact must be notified by telephone or email when the samples are shipped and 
they must be provided with the shipment tracking number.
All PK samples, along with the corresponding documentation, should be shipped according to
the instructions provided in the laboratory manual.
Pharmacokinetic samples will be stored nominally at -70oC before and after analysis at the 
laboratory until their disposal is authorized by Shire.
7.2.3.3
Plasma Drug Assay Methodology
Plasma sample analysis will be performed according to the laboratory standard operating 
procedures.


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Plasma concentrations will be measured using a validated bioanalytical method based on liquid 
chromatography with mass spectrometry. In addition, selected plasma samples may be used to 
investigate incurred sample reproducibility (full details will be described in the bioanalytical 
study plan). The presence of other metabolites or artifacts may be monitored or quantified as 
appropriate. Raw data will be stored in the archive of the designated bioanalytical contract 
laboratory. 
7.2.4
Pharmacodynamic Assessments
Intraocular pressure (in mmHg) will be measured using Goldmann applanation tonometry at the 
visits specified in Table 1; the time points during each visit are specified in Table 2, Table 3, 
Table 4, and Table 5 for Cohorts A, B, C, and D, respectively. Refer to Section 7.2.2.3 for 
details.
7.2.5
Volume of Blood to Be Collected from Each Subject
For Cohort A, it is expected that approximately 241.5 mL of blood will be collected from all 
subjects, regardless of sex (Table 11).
For Cohorts B, C, and D, it is expected that approximately 192.5 mL of blood will be collected 
from all subjects, regardless of sex (Table 12).
Table 11
Volume of Blood to Be Collected from Each Subject in Each Treatment 
Regimen: Cohort A
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samples
4
18
72
HBsAg, HIV, HCV
8
1
8
Safety
Biochemistry and 
-hCGa
8.5
11
93.5
Hematology
4
11
44
Antidrug antibody
6
4
24
Total
241.5
-hCG=beta-human chorionic gonadotropin; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus
a
-hCG testing for females only. -hCG will be assessed in 6 of the 11 samples collected for biochemistry assessments 
(screening, SDTP [Day -2], MDTP [Day -2, Day 1, Day 26, and Day 29]) 
Cohort A: Single-dose treatment followed by multiple-dose treatment once daily.


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Table 12
Volume of Blood to Be Collected from Each Subject in Each Treatment 
Regimen: Cohorts B, C, and D
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samples
4
12
48
HBsAg, HIV, HCV
8
1
8
Safety
Biochemistry and 
-hCGa
8.5
9
76.5
Hematology
4
9
36
Antidrug antibody
6
4
24
Total
192.5
-hCG=beta-human chorionic gonadotropin; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus
a
-hCG testing for females only. -hCG will be assessed in 5 of the 9 samples collected for biochemistry assessments 
(screening and MDTP [Day -2, Day 1, Day 26, and Day 29])
Cohort B: Multiple-dose treatment twice daily; Cohort C: Multiple-dose treatment 3 times daily; Cohort D: Multiple-dose 
treatment 4 times daily.
Note: The amount of blood to be collected for each assessment is an estimate. The amount of 
blood to be collected may vary according to the instructions provided by the manufacturer or 
laboratory for an individual assessment. When more than 1 blood assessment is to be done at the 
time point/period, if they require the same type of tube, the assessments may be combined.


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guideline E2A 1995).
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. Adverse events that occur from Day 33 to Day 
88/FU should be captured on the AE eCRF page. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF 
page.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that worsens in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, or a pre-
existing medical history with worsening severity, must be recorded as new AEs (for example, if 
a subject experiences mild intermittent dyspepsia before dosing of investigational product, but 
the dyspepsia becomes severe and more frequent after first dose of investigational product has 
been administered, a new AE of severe dyspepsia [with the appropriate date of onset] is recorded 
on the appropriate eCRF page). If an AE is a recurrence, even if at a lower severity, it should be 
captured as a new AE.
The medical assessment of severity is determined by using the following definitions:


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Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his/her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document and the eCRF.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not recovered/not resolved

Recovered/resolved

Recovered/resolved with sequelae

Recovering/resolving

Unknown.


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8.1.4
Ocular and Nonocular Categorization
The investigator will categorize AEs as ocular (specified as left eye, right eye, or both eyes) or 
nonocular.
8.1.5
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.6
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values that were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.7
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Global Drug Safety Department using 
the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days post partum.


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Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Nonserious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Nonserious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.
8.1.8
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not it results in an AE/SAE as described in 
Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.


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appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this 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 inpatient 
hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be reported 
to the Shire Global Drug Safety Department and the CRO/Shire medical monitor within 24 hours 
of the first awareness of the event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the ICF, or leading 
up to the onset date of the SAE, or following the resolution date of the SAE, must be recorded as 
an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of withdrawn should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, and Site Reporting
The sponsor is responsible for notifying the relevant regulatory authorities/United States (US) 
central IRBs of related, unexpected SAEs.
In addition the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP639 program.


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The investigator is responsible for notifying the local IRB or the relevant local regulatory 
authority of all SAEs that occur at his/her site as required.


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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomly assigned, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unmask the treatment assignment (ie, investigational product blood 
concentrations, antidrug antibody, treatment allocation, and investigational product 
preparation/accountability data) will be handled with special care during the data cleaning and 
review process. These data will be handled in such a way that, before unmasking, any data that 
may unmask study team personnel will be presented as masked information or otherwise will not 
be made available. If applicable, unmasked data may be made available to quality assurance 
representatives for the purposes of conducting independent drug audits.
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the PK, PD, and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized before database lock.


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All statistical analyses will be performed using SASsoftware (SAS Institute, Inc, Cary, NC 
27513). 
9.5
Planned Interim Analysis, Adaptive Design, and Dose Escalation Committee
Shire’s Dose Escalation Committee will be convened consisting of the coordinating principal 
ophthalmologist and Shire medical monitor. Ad hoc study team members can be included such 
as biostatistics, pharmacokinetics, drug safety, and clinical operations if needed. The committee 
will review collective safety data for Cohort A and Cohort B to decide whether Part 2 in the 
same dose level and Part 1 in the next dose level (concentration) can commence.
An unmasked interim analysis (IA) will be performed after cohorts A1, A2, A3, B1, B2, and B3 
have completed through Day 29 of the B3 cohort. Data from sites will be entered into the 
database, queried, and discrepancies resolved. There is no intention to stop early based on data 
from the IA. The intent of this IA is to determine if the escalated doses have identified a 
pharmacodynamically significant safe and tolerable dose(s) for further clinical evaluation.
Team members reviewing the interim analysis will be reviewing unmasked data from cohorts 
A1, A2, A3, B1, B2, and B3. The SAP will be finalized before data are frozen for this interim 
analysis.
All cohorts conducted after B3 (ie Part 1 of the study) may be unmasked following completion of 
Day 29 to permit review of safety, tolerability and the pharmacodynamics effects of each cohort 
to better inform planning for additional cohorts and further clinical development options for 
SHP639.
A final unmasked analysis will be conducted when all subjects of the remaining cohorts have 
completed through Day 29. The Day 88/FU visit is the planned study completion for each
subject.
9.6
Sample Size Calculation and Power Considerations
A sufficient number of subjects will be screened to ensure the enrollment and completion of 
84 subjects.
The number of subjects in this study is not based on statistical power considerations because the 
statistical analyses are primarily descriptive in nature. However, if at least 7 subjects complete 
each cohort, then there will be at least 65% to 85% probability of observing at least 1 occurrence 
of any AE with a true incidence rate for a given dose group of at least 15-25%, respectively. 
It is estimated that dose escalation will occur for up to 3 dose levels (4 cohorts within each dose 
level). Each cohort will include 5 subjects randomized to active drug and 2 subjects randomized 
to placebo for an estimated total of at least 84 subjects.
For each cohort, the number of subjects will be increased as needed based on safety and IOP 
response. Any cohort can be repeated to confirm findings with regard to safety or IOP response. 


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9.7
Study Population
The safety set will consist of all subjects who have been randomized and who have received at 
least 1 dose of investigational product.
The PK set will consist of all subjects in the safety set for whom the primary PK data are 
considered sufficient and interpretable.
The PD set will consist of all subjects in the safety set for whom the primary PD data are 
evaluable.
9.8
Pharmacokinetic and Pharmacodynamic Analyses
9.8.1
Pharmacokinetic Analysis
All PK analyses will be performed using the PK set.
Plasma concentrations of SHP639 will be measured using a fully validated bioanalytical method. 
If data permit, PK parameters for SHP639 will be calculated based on plasma concentration-time 
data using a noncompartmental approach (Phoenix® WinNonlin® version 6.4 or higher, Certara 
USA, Inc, Princeton, NJ, 08540). 
9.8.1.1
Pharmacokinetic Endpoints
If data permit, PK parameters will be estimated as appropriate and may include, but are not 
limited to, the following:

Maximum observed concentration (Cmax)

Time to reach Cmax (tmax)

Area under the observed concentration vs time curve:
–
From time zero (predose) to the time of the last measurable concentration (AUC0-t)
–
Over the dosing interval (AUC0-τ) for each multiple-dose regimen including QD, BID, 
TID, and QID
–
From time zero (predose) extrapolated to infinity (AUC0-∞) for QD dosing

Apparent terminal phase elimination half-life (t½)

Apparent clearance (CL/F)

Apparent volume of distribution (Vz/F)

Accumulation ratio based on AUC for each multiple-dose regimen, calculated as AUC0-τ
(Day 27)/AUC0-τ (Day 1) (Rac[AUC])

Accumulation ratio based on Cmax for each multiple-dose regimen, calculated as Cmax
(Day 27)/Cmax (Day 1) (Rac[Cmax])
9.8.1.2
Statistical Analysis of Pharmacokinetic Parameters
Summary statistics (number of observations, mean, standard deviation [SD], coefficient of 
variation, median, maximum [max], minimum [min], and geometric mean) will be determined 


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for all plasma PK parameters and will be presented by dose, cohort, treatment period (single dose 
or multiple dose; Cohort A only), and study day. Plasma concentrations at each nominal 
sampling time will also be summarized using descriptive statistics. 
For accumulation ratios, the 95% confidence interval (CI) for the arithmetic mean of the 
difference (for example, AUC0-τ [Day 28] - AUC0-τ [Day 1]) on the logarithmic scale (natural 
base) will be calculated. The results will be back-transformed to give the ratio of geometric 
means together with the corresponding 95% CI.
Before statistical comparisons, dose-dependent parameters (Cmax, AUC0-t, AUC0-τ, and AUC0-∞) 
will be normalized to a common dose, assuming linearity. Additionally, the linear dose 
proportionality will be evaluated for Cmax, AUC0-τ, AUC0-t, and AUC0-∞using the power function 
model (eg, Cmax=α·Doseβ or equivalently log[Cmax]=log[α]+β·log[Dose], where Cmax is 
considered to increase linearly proportional to dose if β is not significantly different from 1.0) 
(Gough et al., 1995). 
9.8.2
Pharmacodynamic Analysis
All the PD analyses will be performed using the PD set. Intraocular pressure (mmHg) will be 
measured using Goldmann applanation tonometry.
9.8.2.1
Pharmacodynamic Endpoints
Pharmacodynamic parameters will be estimated as appropriate and may include, but are not 
limited to, the following:

Change from baseline in IOP

Time to the maximum change from baseline in IOP

Proportion of subjects maintaining IOP reduction after specified days of treatment
Specific endpoints in order to understand the effect of SHP639 on IOP will be defined in the 
SAP.
9.8.2.2
Statistical Analysis of Pharmacodynamic Parameters
Descriptive summary statistics for IOP (number of subjects, mean, SD, median, min, and max) 
will be calculated by dose, cohort, treatment period (single dose or multiple dose; Cohort A 
only), study day, and time point (for days with multiple assessments per day). Additionally, 95% 
CIs for each estimate and summary statistics of change from baseline and percentage change 
from baseline, along with 95% CIs, will be calculated. Pharmacodynamic parameters will be 
calculated and summarized by dose, cohort, treatment period (single dose or multiple dose; 
Cohort A only), and study day as applicable. 
All IOP data will be listed by dose, cohort, subject, treatment period (single dose or multiple 
dose; Cohort A only), and study day.


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9.8.3
Pharmacokinetic and Pharmacodynamic Analysis
The relationship between dose of SHP639 ophthalmic solution, plasma PK parameters, and 
changes in IOP may be explored using graphical and/or regression methods if the data permit.
Further details of PK, PD, and PK-PD analyses will be presented in the SAP.
9.9
Safety Analyses
9.9.1
Safety Endpoints
Safety and tolerability will be assessed by monitoring AEs, vital sign measurements, clinical 
laboratory assays, ECGs, ADA, drop comfort assessment, and ophthalmologic examinations.
9.9.2
Statistical Analysis of Safety Data
The placebo subjects will be pooled together as a pooled placebo group.
All vital sign, clinical laboratory, ECG, ADA, drop comfort assessment, and ophthalmologic 
examination data (per schedule of events) will be listed by dose, cohort, subject, treatment period 
(single dose or multiple dose; Cohort A only), visit, day, and time point (for days with multiple 
assessments per day). If the ranges are available then abnormalities will be flagged. Summary 
statistics with number of subjects, mean, SD, median, minimum, and maximum will be provided 
by dose, cohort, treatment period (single dose or multiple dose; Cohort A only), visit, day, and 
time point (for days with multiple assessments per day).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number of events, incidence, and percentage of treatment-emergent AEs will be calculated 
overall and by system organ class and preferred term by dose and cohort. Treatment-emergent 
AEs will be further summarized by severity and relationship to investigational product. Adverse 
events related to investigational product, AEs leading to withdrawal, SAEs, and deaths will be 
similarly summarized/listed. All information obtained on AEs will be displayed by dose, cohort, 
subject, treatment period (single dose or multiple dose; Cohort A only), visit, and day. A subject 
with multiple AEs within a body system will be counted only once.
9.10
Other Analyses
No other analyses are planned in this study.


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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations including ICH E6, EU 
Directive 2001/20/EC, and all updates, as well as local ethical and legal requirements.
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations and ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
international/national government regulations and guidelines. Records and data may additionally 
be reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required before release of 
investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for nonpediatric studies as per 
guidance.


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10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs are notified as appropriate. Additionally, the discontinuation of a registered 
clinical study which has been posted to a designated public website will be updated accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site before commitment to participate in this study. The investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curricula vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal ophthalmologist is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the coordinating principal ophthalmologist, in compliance with Directive 
2001/83/EC as amended by Directive 2003/63/EC and ICH Guideline E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB, and 
regulatory agency with final reports and summaries as required by international/national 
regulations.


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Communication with local IRBs to ensure accurate and timely information is provided at all 
phases during the study, may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, the coordinating principal ophthalmologist, according to national provisions, 
and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Electronic case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded into the eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly into the 
eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate/study monitor will verify the contents against the source data per 
the monitoring plan. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The clinical research associate/study monitor (and auditors, IRB, or regulatory inspectors) may 
check the eCRF entries against the source documents. The consent form includes a statement by 
which the subject agrees to the monitor/auditor from the sponsor or its representatives, national 
or local regulatory authorities, or IRB, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, and X-rays). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], European Medicines Agency (EMA), United Kingdom Medicines 
and Healthcare products Regulatory Agency) or an auditor.


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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the IRB 
for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 Code of Federal 
Regulations 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects before any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally authorized representative, as applicable, is requested to sign and date the subject 
ICF or a certified translation if applicable, after the subject has received and read (or been read) 
the written subject information and received an explanation of what the study involves, including 
but not limited to: the objectives, potential benefits and risk, inconveniences, and the subject’s 
rights and responsibilities. A copy of the informed consent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
The principal ophthalmologist provides the sponsor with a copy of the consent form that was 
reviewed by the IRB and received their favorable opinion/approval. A copy of the IRB’s written 
favorable opinion/approval of these documents must be provided to the sponsor before the start 
of the study unless it is agreed to and documented (abiding by regulatory guidelines and national 
provisions) before study start that another party (ie, sponsor or coordinating principal 
ophthalmologist) is responsible for this action. Additionally, if the IRB requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.


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10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB for review, and all must 
be approved before site initiation.
For multicenter studies, the applicant can be the coordinating principal ophthalmologist or 
sponsor, according to national provisions.
Responsibility for coordinating with IRBs is defined in the clinical trial agreement.
Before implementing changes in the study, the sponsor and the IRB must approve any revisions 
of all informed consent documents and amendments to the protocol unless there is a subject 
safety issue.
Investigational product supplies will not be released until the sponsor or CRO has received 
written IRB approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for multicenter studies, this can be done by the coordinating principal ophthalmologist, 
according to national provisions. The investigator must also keep the local IRB informed of any 
serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with Health Insurance Portability and Accountability Act (HIPAA) of 1996. 
A site that is not a covered entity as defined by HIPAA must provide documentation of this fact 
to the CRO or sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives’ 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP639; national or local regulatory authorities; and the IRB(s) which gave approval for 
the study to proceed. The sponsor and/or its representatives accessing the records and data will 
take all reasonable precautions in accordance with applicable laws, regulations, and guidelines to 
maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).


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The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred 
to, and used in, other countries which may not afford the same level of protection that 
applies within the countries where this study is conducted. The purpose of any such 
transfer would include: to support regulatory submissions, to conduct new data analyses to 
publish or present the study results, or to answer questions asked by regulatory or health 
authorities.
10.5
Study Results/Publication Policy
The term “Publication” shall mean any paper, article, manuscript, report, poster, internet posting, 
presentation slides, abstract, outline, video, instructional material, presentation (in the form of a 
written summary), or other public disclosure of the study results, in printed, electronic, oral, or 
other form. The parties understand and agree that participation in the study may involve a 
commitment to publish the data from all sites participating in the study in a cooperative 
publication with other investigators prior to publication or oral presentations of the study results 
on an individual basis. The site agrees not to publish or present the site’s study results until such 
time as either the aggregate multi-site study results are published in a cooperative publication or 
for a period of one (1) year after termination or completion of the study at all participating sites, 
whichever shall first occur. After that time, the site may publish the site’s study results in 
scientific journals or present the study results at symposia or other professional meetings in 
accordance with the following provisions:
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
At least sixty (60) days prior to submitting an abstract, manuscript, or other document for 
publication, a copy of the proposed publication will be provided to the sponsor by the site for 
review. Upon the sponsor’s request, the site agrees to remove any and all confidential 
information (expressly excluding study results) identified in the publication and to delay such 
submission or presentation for an additional sixty (60) day period in order to allow the sponsor 
time to file any patent application(s). All publications of the study results shall appropriately 
reference the multi-site study publication, if any, or the fact that the study results are a subset of 
data resulting from a larger multi-site study.
Shire is committed to transparent dissemination of all scientific, technical and medical 
manuscripts generated from Shire-supported research. Therefore, after January 1, 2018, Shire 
will require the submission of all Shire-supported research manuscripts to journals that offer 
public availability via Open Access (including publisher platforms/repositories and self-


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archiving). Open Access refers to the free at point of entry, online availability of published 
research output with, where available, rights of re-use according to an End User License.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical journals. Participation as an investigator does not confer any rights to 
authorship of publications.


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11.
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Shimmura, S., Ono, M., Shinozaki, K., Toda, I., Takamura, E., Mashima, Y.and Tsubota, K. 
1995. Sodium hyaluronate eyedrops in the treatment of dry eyes. British Journal of 
Ophthalmology, 79, 1007-11.
Stein, P. J.and Clack, J. W. 1994. Topical application of a cyclic GMP analog lowers IOP in 
normal and ocular hypertensive rabbits. Invest Ophthalmol Vis Sci, 35, 2765-8.
Vajaranant, T. S., Wu, S., Torres, M.and Varma, R. 2012. The Changing Face of Primary Open-
Angle Glaucoma in the United States: Demographic and Geographic Changes From 2011 
to 2050. American Journal of Ophthalmology, 154, 303-314.e3.
Weinreb, R. N., Aung, T.and Medeiros, F. A. 2014. The pathophysiology and treatment of 
glaucoma: a review. Jama, 311, 1901-11.
Weinreb, R. N.and Khaw, P. T. 2004. Primary open-angle glaucoma. Lancet, 363, 1711-20.


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12.
APPENDICES




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Clarification that all procedures, not only ocular procedures, performed 
within the 5 years before the first dose, should be recorded 
any ocular procedures performed within the 5 years before the date of 
the first dose of investigational product. Prior treatment information must 
be recorded on the appropriate eCRF page.
Section 5.1
Clarification that subjects should receive the single or first dose on the 
same time each day.
Subjects should receive the single or first dose (depending on cohort 
assignment) each day between 7:00am and 9:00am. This is particularly 
important for cohorts C and D as these subjects will receive 3 and 4 doses 
daily
Section 6.2.3.1
Documentation that decision was made not to enroll cohort D1.
Footnote: Cohort D1 is not to be enrolled as it was decided that the resulting 
data would not contribute to the understanding of the safety of SHP639.
Table 10
Addition of language to support not enrolling a proposed dose cohort if 
dose escalation meeting findings indicate that information from that dose 
cohort would not increase understanding of the safety of SHP639.
If, in the judgment of the coordinating principal ophthalmologist, the 
Shire medical monitor, and the Shire ophthalmic study physician, it is 
unclear whether there is a potential safety signal concern or whether 
dose escalation should occur, a dose level may be reduced, modified, or 
repeated depending on the outcome of the safety data review between 
doses or treatments. Further, based on the findings from the dose 
escalation review meetings a cohort (or cohorts) may be determined 
to not be necessary to determine the safety of SHP639. Finally, upon 
completion of all dose cohorts, additional doses may be studied based on 
emergent safety, PD, and PK data following the necessary protocol 
amendment and Institutional Review Board (IRB) reviews.
Section 6.2.3.2
Clarification that the time points of ophthalmic assessments performed 
on Day -2 and Day -1 are to be carried forward to assessments on Day 1.
Time points of ophthalmic assessments performed on Day -2 and 
Day -1 should be carried forward to assessments on Day 1. This 
ensures that the baseline IOP time points established before dosing 
begins are time-matched to the IOP assessments performed during 
dosing days for the duration of the study. 
Section 7.1.2.2
Clarification that ophthalmic assessments are considered safety 
assessments, and therefore, if their timing deviates from the scheduled 
time (and window), this will be considered a protocol deviation.
Section 7.2.2
Clarification that pregnancy testing by β-hCG is only required for 
females of childbearing potential, as defined in Section 4.4.1.
Interpretation of β-hCG results performed for post-menopausal subjects 
also added. 
Biochemistry table in Section 7.2.2.6
Clarification that urine drug screen will include drugs of abuse included 
in marketed screening products.
Additional drugs of abuse, eg, methamphetamines and tricyclic anti-
depressants, which are included in currently marketed products for 
drugs of abuse screening, will also be tested in these samples.
Section 7.2.2.8




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childbearing potential must use an acceptable form of contraception
throughout the study period and for 30 days 60 days following the last dose 
of investigational product. If hormonal contraceptives are used, they should 
be administered according to the package insert. Females of childbearing 
potential who are not currently sexually active must agree to use acceptable 
contraception, as defined below, if they become sexually active during the 
period of the study and 30 days 60 days following the last dose of 
investigational product.
Section 4.4.2 will be updated to state “Male subjects will be required to use 
a condom in conjunction with spermicidal gel, foam, cream, film, or 
suppository from the time of first dosing until 30 days 60 days after the last 
dose of investigational product. Childbearing female partners of male study 
participants will be required to follow the acceptable methods of 
contraception for this study (described in Section 4.4.1) from the time of 
first dosing until 30 days 60 days after the last dose of investigational 
product.
Male subjects must not donate sperm for at least 30 days 3 months after the 
last dose of investigational product. 
Exclusion criteria #15 updated to remove restriction on the use of 
anticholinergic medication. 
“Subject has used belladonna alkaloids (scopolamine, 
hyoscyamine, atropine) within 7 days before randomization, cannabinoids 
or, opioids, or anticholinergic drugs within 28 days before randomization, 
or B-type natriuretic peptides within the past year before randomization; or 
subject has anticipated need for any of the aforementioned drugs/drug 
categories during the study.
Synopsis 
Section 4.2
Table 8
Ophthalmologic assessments on screening and midwashout ophthalmic 
assessments (MWOA) need to be done one time during the day only. 
Ophthalmic assessments include: 
BCVA, Manifest Refraction (Screening), Slit Lamp examination of anterior 
segment, Conjunctival Redness, Corneal Haze, Corneal Epithelial integrity using 
fluorescein stain, Anterior Chamber cell and flare, Lens Opacification, IOP, 
Posterior Segment Examination, dilated (Screening and Day 29), Specular 
Microscopy (Day 29), Noncontact (Screening and Day 29), Corneal Pachymetry 
(Screening and Day 29)
Table 1, Table 2, Table 3, Table 4, 
Table 5
IOP assessments on Screening and MWOA (D-14) need to be done one 
time during the day only. 
At screening: IOP may be measured at any time during the day. 
At MWOA (D-14) IOP will be measured in the morning at 10:00am (+3 
hours). 
Additional assessments other than the “morning assessments” at screening 
and MWOA (D-14) do not need to be conducted. 
Table 1, Table 2, Table 3, Table 4, 
Table 5
Clarification of last study drug dose: 
Subjects will be administered the last dose of study drug on the morning of 
Day 28. Add a footnote to tables 2, 3, 4, and 5.
Table 2, Table 3, Table 4, Table 5


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Clarification of Corneal Pachymetry Timing: 
The timing of IOP and Corneal Pachymetry will be more closely aligned to 
allow for procedure scheduling at sites: 
Corneal Pachymetry will be performed at the following time points for all 
applicable visit days: Predose/Morning, 1 hour post dose, 2 hours post 
dose, 4 hours post dose, and 12 hours post dose. 
Table 2, Table 3, Table 4, Table 5
Section 7.2.2.3
Clarification of Baseline: 
The Baseline “BL” Column will be removed from Tables 2, 3, 4, and 5. All 
reference to “BL” will be removed from the column titles “Days 
Performed” and all reference to visits will be done by day number. 
Removed all reference to “Baseline” in Section 7.2.2.3
Table 2, Table 3, Table 4, Table 5
Section 7.2.2.3
Clarification of Antidrug antibody (Ab) sampling in Table 1: remove “X” 
from Day 26 as no sample will be collected at Day 26. 
Clarification of Antidrug Ab sampling in Tables 2, 3, 4, 5. The column 
titled “Days Performed” incorrectly identifies Antidrug Ab blood sampling 
to be collected at the screening visit. No ADA samples will be taken at 
screening. 
Clarification of Antidrug Ab sampling at Day 26: 
No ADA samples will be taken at Day 26. 
In Table 2 only: Antidrug Ab blood sampling time point was added to 
Table 2 at the predose/morning time point. Site personnel should collect the 
Antidrug Ab blood sample at the predose/morning time point.
Table 1, Table 2, Table 3, Table 4, 
Table 5
The volume of blood to be drawn per subject has changed due to the 
removal of an ADA sample at the Screening visit for all subjects. 
Table 11 and Table 12
Section 7.2.5
Clarification of Full and Abbreviated IOP exam time points: 
The schedule for abbreviated IOP exams is to be followed on Days 7, 14,
and 21. 
In tables 3, 4, and 5 update IOP, full schedule: Removed D7, D14, D21 
from “Days performed” column. 
Table 3, Table 4, Table 5 on Days 7, 
14, and 21. 
Clarification of artificial tears use: 
When subjects are at a study visit artificial tears are not to be used. 
“The use of non-preserved artificial tears is prohibited during the following 
intervals, which include study visits: 
•
Cohort A, SDTP: Day -2 -1 to Day 2, after final assessment
•
Cohort A, MDTP: Day -2 -1 to Day 29, after final assessment
•
Cohorts B, C, and D: Day -2 -1 to Day 29, after final assessment.”
Section 5.2.2
Gonioscopy Time points: 
Gonioscopy will be done at screening at any time during the day. 
Table 2, Table 3, Table 4, Table 5
Section 7.2.2.3


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Gonioscopy will not be done at D-2 or D-1. 
Gonioscopy will be performed at the morning time point on Day 29. 
Gonioscopy will not be performed at the 6 hour time point on Day 29. 
Conjunctival redness assessments will be done at the following time points: 
Predose, 1 hour, 3 hours, 6 hours, and 12 hours
Table 2, Table 3, Table 4, Table 5
Footnote added to column headings of Screening, MWOA, and Day 29 to 
clarify that only one round of ophthalmic assessments will be done in the 
morning. 
Table 1
Clarify that only the following will be done at check-in: 
Physical exam
Drugs of abuse screening 
Alcohol breathalyzer 
Vital signs 
Hematology, Chemistry, Urinalysis
One ECG
Table 1
A footnote was added to refer the reader to tables 2, 3, 4, and 5 for specific 
details on assessment timing for study days. 
Table 1
Clarification on re-screening: 
Any subject who is qualified but not dosed (ie, an alternate subject) may be 
re-screened at a later date for the study. A subject who does not meet all 
eligibility criteria during screening cannot re-screen. 
Section 7.1.1.2
Clarify the study day for screening and clarify the study day window 
(days): 
Screening study day will become -28 and the study day window will be 
+14. This does not change the duration of screening (up to 42 days total).
Table 1
Remove all reference to “SDTP” in tables 3, 4, 5. There is no SDTP in 
Cohorts B, C, and D. 
Table 3, Table 4, Table 5
Clarification of IOP on Day 29: 
Day 29 only a single IOP. Day 29 removed from the full IOP schedule.
Table 3, Table 4, Table 5
Clarification of the Day 60 visit and total subject duration of participation: 
ADA sampling will be collected approximately 60 days post last dose (Day 
28). This is accurate in the synopsis, Section 3.1.4.2, and Section 3.1.5. 
The synopsis and Section 3.2 will now state: 
The subjects’ maximum duration of participation in the study is expected to 
be 146 122 days or approximately 5 4 months (Cohort A1, A2, and A3). 
The subjects’ maximum duration of participation in the study for Cohorts 
B, C, and D is expected to be 130 days or approximately 4.5 months. 
• Maximum planned duration of screening and Washout 1: 42 days
• Planned duration of treatment period: 2 days for SDTP (Cohort A only) 
and 29 days for MDTP (all cohorts)
• Planned duration of Washout 2 (Cohort A only): 3 14 days
Planned duration of follow-up: until Day 88 60±4 days
Synopsis
Section 3.2
Section 7.1
Section 7.1.1
Section 7.1.3
Table 1


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SHP639-101 Protocol Amendment 3
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11 May 2018
Anterior Chamber Cell and Flare
Anterior chamber cell and flare will be assessed and graded using the Standardization of Uveitis 
Nomenclature grading scale at the time points outlined in Table 1 (all cohorts) and specified in 
Table 2, Table 3, Table 4, and Table 5 for Cohorts A, B, C, and D, respectively.
Lens Opacification
Lens opacification will be assessed with the slit lamp during dilated examination and graded in 
the nuclear, cortical, and subcapsular layers using the Lens Opacities Classification System III 
grading scale at the time points outlined in Table 1 (all cohorts) and specified in Table 2, 
Table 3, Table 4, and Table 5, for Cohorts A, B, C, and D, respectively. The presence and 
placement of an intraocular lens and the presence of a posterior capsulotomy will be recorded.

SAP_001.pdf: 
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                                                       CONFIDENTIAL 
Page 1 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
SHP639-101 
Protocol Title: 
A Randomized, Double-masked, Placebo-controlled 
Phase 1 Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of Single 
Daily and Multiple Daily Ascending Doses of SHP639 
Topical Ophthalmic Solution in Subjects with Ocular 
Hypertension or Primary Open-angle Glaucoma 
(POAG) 
Drug: 
SHP639 
Sponsor:  
Shire HGT 
300 Shire Way, Lexington, 
MA 02421 USA 
Version No. and Date 
Final Version 1.5,  30AUG2018 
 
Version No: 
Document History 
Description of Update 
Author(s) 
Effective 
Date 
1.0 
SAP first draft 
 
 
03/23/2017 
1.1 
SAP Final Version 1.1 
 
 
06/16/2017 
1.2 
SAP Final Version 1.2 
 
 
08/04/2017 
1.3 
SAP Final Version 1.3 
 
 
09/22/2017 
1.4 
SAP Final Version 1.4 
 
 
10/11/2017 
1.5 
SAP Final Version 1.5 
 
 
08/30/2018 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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                                                       CONFIDENTIAL 
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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................ 2 
LIST OF TABLES ...................................................................................................................... 5 
ABBREVIATIONS .................................................................................................................... 6 
1. 
INTRODUCTION .......................................................................................................... 9 
2. 
STUDY DESIGN ......................................................................................................... 10 
2.1 
General Study Design ................................................................................................... 10 
2.2 
Schedule of Assessments .............................................................................................. 12 
2.3 
Determination of Sample Size ...................................................................................... 25 
2.4 
Identification of Study Eye ........................................................................................... 25 
3. 
OBJECTIVES ............................................................................................................... 26 
3.1 Study Objectives ................................................................................................................. 26 
3.1.1 Primary Objectives .................................................................................................... 26 
3.1.2 Secondary Objectives ................................................................................................ 26 
3.1.3 Exploratory Objectives .............................................................................................. 26 
4. 
SUBJECT POPULATION SETS ................................................................................. 27 
4.1 
Enrolled Set .................................................................................................................. 27 
4.2 
Randomized Set ............................................................................................................ 27 
4.3 
Safety Set ...................................................................................................................... 27 
4.4 
Pharmacokinetic Set ..................................................................................................... 27 
4.5 
Pharmacodynamic Set .................................................................................................. 27 
5. 
SUBJECT DISPOSITION ............................................................................................ 28 
6. 
PROTOCOL DEVIATIONS ........................................................................................ 29 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 30 
8. 
MEDICAL HISTORY .................................................................................................. 31 
9. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................. 32 
9.1 
Exposure to Investigational product ............................................................................. 32 
9.2 
Measurement of Treatment Compliance ...................................................................... 32 
10. 
PRIOR AND CONCOMITANT MEDICATION ........................................................ 34 


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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
11. 
SAFETY ANALYSES ................................................................................................. 35 
11.1 
Adverse Events ............................................................................................................. 35 
11.2 
Clinical Laboratory Variables ...................................................................................... 36 
11.3 
Vital Signs .................................................................................................................... 38 
11.4 
Electrocardiogram (ECG) ............................................................................................. 39 
11.5 
Antidrug Antibody Testing ........................................................................................... 40 
11.6 
Other Safety Variables .................................................................................................. 40 
11.6.1 Drop comfort assessment ....................................................................................... 40 
11.6.2 Ophthalmologic Examination ................................................................................ 41 
12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES.. 51 
12.1 
Pharmacokinetics Population and Pharmacodynamic Population ................................ 51 
12.2 
Pharmacokinetic Methods ............................................................................................ 51 
12.2.1 Concentration Data ................................................................................................ 51 
12.2.2 Handling Below the Limit of QuantificationValues .............................................. 51 
12.2.3 Pharmacokinetic Parameters .................................................................................. 52 
12.3 
Statistical Analysis of Pharmacokinetic Data ............................................................... 53 
12.4 
Pharmacodynamic Methods ......................................................................................... 53 
12.5 
Statistical Analysis of Pharmacodynamic Data ............................................................ 54 
12.6 
Analyses of Pharmacokinetic/Pharmacodynamic Relationships .................................. 54 
13. 
INTERIM ANALYSIS ................................................................................................. 56 
14. 
COMPUTER METHODS ............................................................................................ 57 
15. 
DATA HANDLING CONVENTIONS ........................................................................ 58 
15.1 
General Data Reporting Conventions ........................................................................... 58 
15.2 
Missing Date of Investigational Product ...................................................................... 58 
15.3 
Missing Date Information for Prior or Concomitant Medications ............................... 58 
15.3.1 Incomplete Start Date............................................................................................. 58 
15.3.2 Incomplete Stop Date ............................................................................................. 59 
15.4 
Missing Date Information for Adverse Events ............................................................. 59 
15.4.1 Incomplete Start Date............................................................................................. 60 
15.4.2 Incomplete Stop Date ............................................................................................. 60 
15.4.3 Incomplete Start/Stop Time ................................................................................... 60 
15.5 
Missing Severity Assessment for Adverse Events ....................................................... 60 
15.6 
Missing Relationship to Investigation Product for Adverse Events ............................. 60 
15.7 
Character Values of Clinical Laboratory Variables ..................................................... 60 


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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
15.8 
Time Ranges for Analysis of Time Points .................................................................... 61 
16. 
TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS .................... 63 


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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
LIST OF TABLES 
Table 1 
Overall Schedule of Events .................................................................................... 12 
Table 2 
Detailed Schedule of Events – Cohort A ............................................................... 16 
Table 3 
Detailed Schedule of Events – Cohort B ............................................................... 19 
Table 4 
Detailed Schedule of Events – Cohort C ............................................................... 21 
Table 5 
Detailed Schedule of Events – Cohort D ............................................................... 23 
Table 6 
Criteria Potentially Clinically Important Laboratory Tests ................................... 37 
Table 7 
Criteria for Potentially Clinically Important Vital Signs ....................................... 39 
Table 8 
Criteria for Potentially Clinically Important ECG Values ..................................... 40 
Table 9 
Examples for Coding of Special Character Values for Clinical Laboratory 
Variables ................................................................................................................ 61 
Table 10 
Visit and Time Ranges for Assessment at Every Schedule Visit and Time Point . 61 


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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
ABBREVIATIONS 
ADA 
antidrug antibody 
AE 
ALT 
ALP 
adverse event 
alanine aminotransferase 
alkaline phosphatase 
AMD 
AST 
age-related macular degeneration 
aspartate aminotransferase 
AUC0-t 
area under the observed concentration vs time curve from time zero (predose) 
to the time of the last measurable concentration 
AUC0-τ 
area under the observed concentration vs time curve over the dosing interval  
AUC0-∞ 
area under the observed concentration vs time curve from time zero (predose) 
extrapolated to infinity 
AUEC0-t 
area under the intraocular pressure values vs time curve from time zero 
(predose) to the time of the last measurable intraocular pressure 
AUEC0-τ 
area under the intraocular pressure values vs time curve over the dosing 
interval 
AUEC0-∞ 
area under the intraocular pressure values vs time curve from time zero 
(predose) extrapolated to infinity 
BCVA 
best-corrected visual acuity 
-hCG 
beta-human chorionic gonadotropin 
BID 
twice daily  
cGMP 
cyclic guanosine monophosphate 
CI 
confidence interval 
CL/F 
apparent clearance 
Cmax 
maximum observed concentration 
CNP 
C-type natriuretic peptide 
CS 
clinically significant 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
Emax 
maximum intraocular pressure reduction from baseline 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 


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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
IP 
investigator's brochure 
investigational product 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IV 
LLN 
Intravenous 
lower limit of normal 
MDTP 
MedDRA 
multiple-dose treatment period 
Medical Dictionary for Regulatory Activities 
MWOA 
midwashout ophthalmic assessment 
NCS 
not clinically significant 
NHP 
nonhuman primates 
NOAEL 
no-observed-adverse-effect level 
NPDR 
nonproliferative diabetic retinopathy 
NPR-A 
natriuretic peptide receptor A 
NPR-B 
natriuretic peptide receptor B 
OHT 
PCI 
ocular hypertension 
potentially clinically important 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
POAG 
RBC 
primary open-angle glaucoma  
red blood cell 
QD 
once daily 
QID 
4 times daily 
QTcB 
QT interval corrected for heart rate using the Bazett formula 
QTcF 
QT interval corrected for heart rate using the Fridericia formula 
Rac(AUC) 
accumulation ratio based on area under the curve 
Rac(Cmax) 
accumulation ratio based on maximum observed concentration 


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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDTP 
single-dose treatment period 
t½ 
apparent terminal phase elimination half-life 
TEmax 
time to the maximum effect (maximum intraocular pressure reduction from 
baseline) 
TID 
3 times daily 
tmax 
ULN 
time to reach maximum observed concentration 
upper limit of normal 
US 
United States 
Vz/F 
WBC 
WHO-DD 
apparent volume of distribution 
white blood cell 
World Health Organization Drug Dictionary 
 


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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
1. 
INTRODUCTION 
This is the full Statistical Analysis Plan (SAP) for Study SHP639-101. The SAP provides a 
technical and detailed elaboration of the statistical analyses of safety and PK/PD data based on 
the study protocol Amendment 3 (Version 4) dated 11 May 2018. Specifications for tables, 
figures, and listings will be provided in a separate document.  


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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
2. 
STUDY DESIGN  
2.1 
General Study Design 
This is a multicenter, randomized, double-masked, placebo-controlled, single- and multiple-dose 
escalation study. Three different SHP639 concentrations will be studied: 0.1%, 0.3%, and 0.6%. 
There will be up to 12 cohorts in total, 1 cohort for each dose level and different dosing regimen. 
Each cohort will consist of 7 subjects for a total of 84 subjects in the study. Eligible subjects will 
be randomized in a 5:2 ratio to receive either SHP639 or placebo, respectively. The anticipated 
concentrations being studied for each dosing regimen are presented in the study schema in Figure 
1. 
A sufficient number of subjects will be screened and enrolled to ensure that at least 6 of 7 
subjects complete each treatment in their assigned cohort. In the event that a sufficient number of 
subjects do not complete a cohort, replacement subjects may be enrolled. Each replacement 
subject will follow the same screening procedures and randomization sequence as the subject 
who is discontinued, regardless of when the subject discontinued. 


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Page 11 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Figure 1 
Study Schema 
 
Solid arrows are not drawn to scale and indicate both the flow of dosing regimens and the occurrence of a dose escalation 
meeting.  
BID=twice daily; MDTP=multiple-dose treatment period; QD=once daily; QID=4 times daily; SD=single dose; 
SDTP=single-dose treatment period; TID=3 times daily 
a Dose escalation meetings will convene when 6 out of 7 subjects have completed Day 14 in the previous cohort’s multiple-dose 
administration. This does not include the decision to move from Cohort B to C. Decisions will include safety, tolerability, and 
intraocular pressure data. 
 
 
 
 
 
 
 
 
 
 








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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
 
 
 
         [30 AUG 2018] 
 
 
f Subjects who are prematurely discontinued from the study will complete the Day 29/ET assessments as fully as possible. 
g A follow-up telephone call will take place 7±2 days post discharge from the clinic (Day 29 of MDTP). 
h All eligibility criteria except IOP-related criteria (inclusion criterion 4 and exclusion criterion 4) will be assessed at screening. 
i Excluding Cohort A (previously performed during the SDTP baseline). 
j Breathalyzer test for alcohol and urine screening for drugs of abuse. 
k These assessments will be performed at initial screening and may also be performed at any visit during the screening period. 
l Vital signs include blood pressure, pulse rate, and temperature. 
m Drop comfort assessments will be performed immediately and 1, 2, and 3 minutes after instillation of the investigational product; to be assessed at morning doses only. If the 
score is not ≤3 at minute 3, the drop comfort assessment should be repeated at minutes 5, 10, and 15 until the score is ≤3. If the score is >3 at minute 15, it should be recorded as 
an adverse event. 
n If BCVA decreases by 6 or more letters, then a dilated posterior segment examination should be performed. 
o Manifest refraction should be repeated if the BCVA in either eye decreases by 10 or more letters. 
p Conjunctival redness will be evaluated using the Efron scale. 
q SDTP dosing (Cohort A only): investigational product (SHP639 ophthalmic solution or placebo) will be administered once on the morning of Day 1. MDTP dosing: Cohort 
A=once daily, Cohort B=twice daily, Cohort C=3 times daily, Cohort D=4 times daily; the final dose will be administered on the morning of Day 28. Dose administration will 
occur during waking hours. 
r The Day 88 visit is 60 days post last dose (Day 28 of MDTP). 
s For Screening, MWOA, and Day 29 visits only one round of ophthalmic assessments needs to be done in the morning. 
t At check-in for overnight stays the following assessments will be performed: physical exam, drugs of abuse screening, alcohol breathalyzer, vital signs, hematology, chemistry, 
urinalysis, and a single ECG. 
u The Day 88/FU visit is labeled “Day 88” based on a subject’s duration of participation from Day 1 (1st dose) of the MDTP. Subjects in cohort A1, A2, and A3 will have been in 
the study for a longer duration due to the SDTP. 
v At screening IOP may be done at any time during the day. At MWOA (D-14), IOP should be done at 10:00am +3 hours. IOP only needs to be done at one time during screening, 
MWOA, and Day 29. 
 


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Page 16 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
 
 
 
         [30 AUG 2018] 
 
 
Table 2 
Detailed Schedule of Events – Cohort A 
Assessment 
Days Performed (Screening-D29)f 
Predose/ 
Morninga 0 m 
30 
m 1 h 2 h 3 h 4 h 6 h 8 h 12 h 
Dosing 
SDTP: D1. MDTP: D1 through D28g 
 
X 
 
 
 
 
 
 
 
 
PK blood sampling 
SDTP: D1. MDTP: D1, D27. 
X 
 
X 
X 
X 
X 
 
X 
 
 
Drop comfort assessmentb 
SDTP: D1. MDTP: D1, D7, D14, D21, D27, D28. 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
SCR. SDTP: D-2, D2. MDTP: D-2, D14, D26, D29. 
X 
 
 
 
 
 
 
 
 
 
Vital signs  
All visits except Day 88/FU 
X 
 
X 
 
 
X 
 
 
X 
 
ECG  
All visits  
X 
 
X 
 
 
X 
 
 
X 
 
BCVA  
All visits except Day 26 and Day 88/FU 
X 
 
 
X 
 
 
 
 
 
X 
Manifest refraction 
SCR. SDTP: D-2. MDTP: D-2, D29. 
X 
 
 
 
 
 
 
 
 
 
Slit lamp examination of anterior segmentc 
SCR, D-14. SDTP: D-2, D-1, D1, D2. MDTP: D-2 
and D-1, D1, D2, D7, D14, D21, D27, D28, D29. 
X 
 
 
X 
 
 
 
 
 
X 
Conjunctival redness 
SCR, D-14. SDTP: D-2, D-1, D1, D2. MDTP: D-2 
and D-1, D1, D2, D7, D14, D21, D27, D28, D29. 
X 
 
 
X 
 
X 
 
X 
 
X 
Corneal haze 
SCR, D-14. SDTP: D-2, D-1, D1, D2. MDTP: D-2 
and D-1, D1, D2, D7, D14, D21, D27, D28, D29. 
X 
 
 
X 
 
X 
 
X 
 
X 
Corneal epithelial integrity using fluorescein stain  SCR, D-14. SDTP: D-2, D-1, D1, D2. MDTP: D-2 
and D-1, D1, D2, D7, D14, D21, D27, D28, D29. 
X 
 
 
 
X 
 
X 
 
X 
X 
Anterior chamber cell and flare  
SCR, D-14. SDTP: D-2, D-1, D1, D2. MDTP: D-2 
and D-1, D1, D2, D7, D14, D21, D27, D28, D29. 
X 
 
 
X 
 
 
 
 
 
X 
Lens opacification 
SCR, D29 
X 
 
 
 
 
 
 
 
 
 
IOP, abbreviated schedule 
SCRe, D-14d. MDTP: D7, D14, D21, D29d. 
X 
 
 
 
X 
 
X 
 
X 
X 
IOP, full schedule 
SDTP: D-2, D-1, D1, D2. MDTP: D-2 and D-1, D1, 
D2, D27, D28. 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Posterior segment examination 
SCR (dilated). SDTP: D-2; nondilated. MDTP: D-2; 
nondilated, D29 (dilated). 
X 
 
 
 
 
 
 
 
 
 


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Page 17 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
 
 
 
         [30 AUG 2018] 
 
 
Table 2 
Detailed Schedule of Events – Cohort A 
Assessment 
Days Performed (Screening-D29)f 
Predose/ 
Morninga 0 m 
30 
m 1 h 2 h 3 h 4 h 6 h 8 h 12 h 
Gonioscopye 
SCR, D29. 
X 
 
 
 
 
 
 
 
 
 
Specular microscopy, noncontact 
SCR. SDTP: D-1, D2. MDTP: D-1, D14, D29. 
X 
 
 
 
 
 
 
 
 
 
Corneal pachymetry 
SCR. SDTP: D-1, D1, D2. MDTP: D-1, D1, D2, D7, 
D14, D29. 
X 
 
 
X 
X 
 
X 
 
 
X 
Antidrug Ab blood sampling 
D-2, D14, D29, D88/FU  
X 
 
 
 
 
 
 
 
 
 
Drugs of abuse 
SCR, D-14, SDTP: D-2, MDTP: D-2 and D-1, D1, 
D14, D21, D26. 
X 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
SCR (D-42), SCR (D-14). SDTP: BL (D-2), MDTP: 
BL (D-2 and D-1), D1, D14, D21, D26.  
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (female subjects) 
SCR. SDTP: BL (D-2). MDTP: BL (D-2), D1, D26, 
D29. 
X 
 
 
 
 
 
 
 
 
 
Biochemistry, hematology, and urinalysis 
SCR. SDTP: BL (D-2), D2. MDTP: BL (D-2), D1, 
D7, D14, D21, D26, D27, D29. 
X 
 
 
 
 
 
 
 
 
 
Timings relate to dose administration or the equivalent morning assessment. Refer to Protocol Section 7.1 for guidance on the priority order of assessments. Assessments on 
nondosing days 
(screening, baseline, and Day 29) will take place once in the morning only unless otherwise specified. 
Ab=antibody; BCVA=best-corrected visual acuity; D=day; ECG=electrocardiogram; FU=follow up; h=hours; IOP=intraocular pressure; m=minutes; MDTP=multiple-dose 
treatment period; PK=pharmacokinetic; SCR=screening; SDTP=single-dose treatment period. 
a Assessments will take place 60-30 minutes before dosing or in the morning on nondosing days. 
b Drop comfort assessments will be obtained immediately, 1, 2, and 3 minutes after instillation of the investigational product; to be assessed at morning doses only. If the score is 
not ≤3 at minute 3, the drop comfort assessment should be repeated at minutes 5, 10, and 15 until the score is ≤3. If the score is >3 at minute 15, it should be recorded as an 
adverse event. 
c Slit lamp examination of anterior segment will be performed only during the morning assessment on the following days: Screening, Day -14, SDTP Day -2, SDTP Day -1, 
MDTP Day -2, MDTP Day -1, and Day 29. 
d At screening IOP may be done at any time during the day. At MWOA (D-14), IOP should be done at 10:00am +3 hours. IOP only needs to be done at one time during 
screening, MWOA, and Day 29. 
e Gonioscopy at screening can be done at any time of day. Gonioscopy on Day 29 will be performed at the morning timepoint. 
f Ophthalmologic assessments on screening, MWOA (D-14), and Day 29 need to be done one time during the day only. 
These assessments include: BCVA, Manifest Refraction (Screening), Slit Lamp examination of anterior segment, Conjunctival Redness, Corneal Haze, Corneal Epithelial 
integrity using fluorescein stain, Anterior Chamber cell and flare, Lens Opacification, IOP, Posterior Segment Examination, dilated (Screening and Day 29), Specular 
Microscopy, Noncontact (Screening and Day 29), Corneal Pachymetry (Screening and Day 29) 


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Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
 
 
 
         [30 AUG 2018] 
 
 
g Subjects will be administered the last dose of study drug on the morning of Day 28 
 


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Page 19 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
 
 
 
         [30 AUG 2018] 
 
 
Table 3 
Detailed Schedule of Events – Cohort B 
Assessment 
Days Performed (Screening-D29)f 
Predose/ 
Morninga 0 m 
30 
m 1 h 2 h 3 h 4 h 
6 h 
8 h 12 h 
Dosing 
D1 through D28g 
 
X 
 
 
 
 
 
 
 
X 
PK blood sampling 
D1, D27 
X 
 
X 
X 
X 
X 
 
X 
 
 
Drop comfort assessmentb 
D1, D7, D14, D21, D27, D28 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
SCR, D-2, D14, D26, D29 
X 
 
 
 
 
 
 
 
 
 
Vital signs  
All visits except Day 88/FU 
X 
 
X 
 
 
X 
 
 
X  
ECG  
All visits 
X 
 
X 
 
 
X 
 
 
X  
BCVA 
All visits except Day 26 and Day 88/FU 
X 
 
 
X 
 
 
 
 
 
X 
Manifest refraction 
SCR, D-2, D29 
X 
 
 
 
 
 
 
 
 
 
Slit lamp examination of 
anterior segmentc 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29 
X 
 
 
X 
 
 
 
 
 
X 
Conjunctival redness 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29 
X 
 
 
X 
 
X 
 
X 
 
X 
Corneal haze 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29 
X 
 
 
X 
 
X 
 
X 
 
X 
Corneal epithelial integrity 
using fluorescein stain 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29 
X 
 
 
 
X 
 
X 
 
X X 
Anterior chamber cell and flare  SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29 
X 
 
 
X 
 
 
 
 
 
X 
Lens opacification 
SCR, D29 
X 
 
 
 
 
 
 
 
 
 
IOP, abbreviated schedule 
SCRe, D-14d, D7, D14, D21, D29d 
X 
 
 
 
X 
 
X 
 
X X 
IOP, full schedule 
D-2, D-1, D1, D2, D27, D28 
X 
 
X 
X 
X 
X 
X 
X 
X X 
Posterior segment examination SCR (dilated), D-2; nondilated, D29 (dilated) 
X 
 
 
 
 
 
 
 
 
 
Gonioscopye 
SCR, D29 
X 
 
 
 
 
 
 
 
 
 
Specular microscopy, 
noncontact 
SCR, D-1, D14, D29 
X 
 
 
 
 
 
 
 
 
 
Corneal pachymetry 
SCR, D-1, D1, D2, D7, D14, D29 
X 
 
 
X 
X 
 
X 
 
 
X 
Antidrug Ab blood sampling 
D-2, D14, D29, D88/FU  
X 
 
 
 
 
 
 
 
 
 


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Page 20 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
 
 
 
         [30 AUG 2018] 
 
 
Table 3 
Detailed Schedule of Events – Cohort B 
Assessment 
Days Performed (Screening-D29)f 
Predose/ 
Morninga 0 m 
30 
m 1 h 2 h 3 h 4 h 
6 h 
8 h 12 h 
Drugs of abuse 
SCR, D-14, D-2, D-1, D1, D14, D21, D26  
X 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
SCR, D-14, D-2, D-1, D1, D14, D21, D26  
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (female 
subjects) 
SCR, D-2, D1, D26, D29. 
X 
 
 
 
 
 
 
 
 
 
Biochemistry, hematology, and 
urinalysis 
SCR, D-2, D1, D7, D14, D21, D26, D27, D29. 
X 
 
 
 
 
 
 
 
 
 
Timings relate to the first dose of the day or the equivalent morning assessment. Assessments on nondosing days (screening, baseline, and Day 29) will take place once in the 
morning only unless otherwise specified. 
Ab=antibody; BL=baseline; BCVA=best-corrected visual acuity; D=day; ECG=electrocardiogram; FU=follow up; h=hours; IOP=intraocular pressure; m=minutes; 
MDTP=multiple-dose treatment period; PK=pharmacokinetic; SCR=screening. 
a Assessments will take place 60-30 minutes before the first dose of the day or in the morning on nondosing days. 
b Drop comfort assessments will be obtained immediately, 1, 2, and 3 minutes after instillation of the investigational product; to be assessed at morning doses only. If the score is 
not ≤3 at minute 3, the drop comfort assessment should be repeated at minutes 5, 10, and 15 until the score is ≤3. If the score is >3 at minute 15, it should be recorded as an adverse 
event. 
c Slit lamp examination of anterior segment will be performed only during the morning assessment on the following days: Screening, Day -14, Day -2, and Day -1 and Day 29. 
d  At screening IOP may be done at any time during the day.  At MWOA (D-14), IOP should be done at 10:00 am ± 3 hours. IOP only needs to be done at one time during 
screening, MWOA, and Day 29. 
e Gonioscopy at screening can be done at any time of day. Gonioscopy on Day 29 will be performed after IOP measurement but before dilation. 
f  Ophthalmologic assessments on screening, MWOA (D-14), and day 29 need to be done one time during the day only. 
    These assessments include: BCVA, Manifest Refraction (Screening), Slit Lamp examination of anterior segment, Conjunctival Redness, Corneal Haze, Corneal Epithelial 
integrity using fluorescein stain, Anterior Chamber cell and flare, Lens Opcification, IOP, Posterior Segment Examination, dilated (Screening and Day 29), Specular Microscopy, 
Noncontact (Screening and Day 29), Corneal Pachymetry (Screening and Day 29). 
g  Subjects will be administered the last dose of study drug on the morning of Day 28. 
 


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Page 21 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
 
 
 
        [30 AUG 2018] 
 
 
Table 4 
Detailed Schedule of Events – Cohort C 
Assessment 
Days Performed (Screening-D29)f 
Predose/ 
Morninga 0 m 30 m 1 h 2 h 3 h 4 h 6 h 
8 h 
12 h 
Dosing 
D1 through D28g 
 
X 
 
 
 
 
 
X 
 
X 
PK blood sampling 
D1, D27 
X 
 
X 
X 
X 
X 
 
X 
 
 
Drop comfort assessmentb 
D1, D7, D14, D21, D27, D28 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
SCR, D-2, D14, D26, D29 
X 
 
 
 
 
 
 
 
 
 
Vital signs  
All visits except Day 88/FU 
X 
 
X 
 
 
X 
 
 
X 
 
ECG  
All visits 
X 
 
X 
 
 
X 
 
 
X 
 
BCVA 
All visits except Day 26 and Day 88/FU 
X 
 
 
X 
 
 
 
 
 
X 
Manifest refraction 
SCR, D-2, D29 
X 
 
 
 
 
 
 
 
 
 
Slit lamp examination of 
anterior segmentc 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29 
X 
 
 
X 
 
 
 
 
 
X 
Conjunctival redness 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29 
X 
 
 
X 
 
X 
 
X 
 
X 
Corneal haze 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29 
X 
 
 
X 
 
X 
 
X 
 
X 
Corneal epithelial integrity 
using fluorescein stain 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29 
X 
 
 
 
X 
 
X 
 
X 
X 
Anterior chamber cell and flare  SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, D28, D29 
X 
 
 
X 
 
 
 
 
 
X 
Lens opacification 
SCR, D29 
X 
 
 
 
 
 
 
 
 
 
IOP, abbreviated schedule 
SCRe, D-14d, D7, D14, D21, D29d 
X 
 
 
 
X 
 
X 
 
X 
X 
IOP, full schedule 
D-2, D-1, D1, D2, D27, D28 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Posterior segment examination SCR (dilated), D-2; nondilated, D29 (dilated) 
X 
 
 
 
 
 
 
 
 
 
Gonioscopye 
SCR, D29 
X 
 
 
 
 
 
 
 
 
 
Specular microscopy, 
noncontact 
SCR, D-1, D14, D29 
X 
 
 
 
 
 
 
 
 
 


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Page 22 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
 
 
 
        [30 AUG 2018] 
 
 
Table 4 
Detailed Schedule of Events – Cohort C 
Assessment 
Days Performed (Screening-D29)f 
Predose/ 
Morninga 0 m 30 m 1 h 2 h 3 h 4 h 6 h 
8 h 
12 h 
Corneal pachymetry 
SCR, D-1, D1, D2, D7, D14, D29 
X 
 
 
X 
X 
 
X 
 
 
X 
Antidrug Ab blood sampling 
D-2, D14, D29, D88/FU  
X 
 
 
 
 
 
 
 
 
 
Drugs of abuse 
SCR, D-14, D-2, D-1, D1, D14, D21, D26  
X 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
SCR, D-14, D-2, D-1, D1, D14, D21, D26  
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (female 
subjects) 
SCR, D-2, D1, D26, D29. 
X 
 
 
 
 
 
 
 
 
 
Biochemistry, hematology, and 
urinalysis 
SCR, D-2, D1, D7, D14, D21, D26, D27, D29. 
X 
 
 
 
 
 
 
 
 
 
Timings relate to the first dose of the day or the equivalent morning assessment. Assessments on nondosing days (screening, baseline, and Day 29) will take place once in the 
morning only unless otherwise specified. 
Ab=antibody; BL=baseline; BCVA=best-corrected visual acuity; D=day; ECG=electrocardiogram; FU=follow up; h=hours; IOP=intraocular pressure; m=minutes; 
MDTP=multiple-dose treatment period; PK=pharmacokinetic; SCR=screening. 
a Assessments will take place 60-30 minutes before the first dose of the day or in the morning on nondosing days. 
b Drop comfort assessments will be obtained immediately, 1, 2, and 3 minutes after instillation of the investigational product; to be assessed at morning doses only. If the score is not 
≤3 at minute 3, the drop comfort assessment should be repeated at minutes 5, 10, and 15 until the score is ≤3. If the score is >3 at minute 15, it should be recorded as an adverse 
event. 
c Slit lamp examination of anterior segment will be performed only during the morning assessment on the following days: Screening, Day -14, Day -2, and Day -1 and Day 29. 
d   At screening IOP may be done at any time during the day.  At MWOA (D-14), IOP should be done at 10:00 am ± 3 hours. IOP only needs to be done at one time during screening, 
MWOA, and Day 29. 
e Gonioscopy at screening can be done at any time of day. Gonioscopy on Day 29 will be performed after IOP measurement but before dilation. 
f    Ophthalmologic assessments on screening, MWOA (D-14), and day 29 need to be done one time during the day only. 
    These assessments include: BCVA, Manifest Refraction (Screening), Slit Lamp examination of anterior segment, Conjunctival Redness, Corneal Haze, Corneal Epithelial integrity 
using fluorescein stain, Anterior Chamber cell and flare, Lens Opcification, IOP, Posterior Segment Examination, dilated (Screening and Day 29), Specular Microscopy, 
Noncontact (Screening and Day 29), Corneal Pachymetry (Screening and Day 29). 
g   Subjects will be administered the last dose of study drug on the morning of Day 28. 
 
 
 
 


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Page 23 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
 
 
 
        [30 AUG 2018] 
 
 
Table 5 
Detailed Schedule of Events – Cohort D 
Assessment 
Days Performed (Screening-D29)f 
Predose/ 
Morninga 0 m 
30 
m 
1 h 2 h 3 h 4 h 6 h 8 h 12 h 
Dosing 
D1 through D28g 
 
X 
 
 
 
 
X 
 
X 
X 
PK blood sampling 
D1, D27 
X 
 
X 
X 
X 
X 
 
X 
 
 
Drop comfort assessmentb 
D1, D7, D14, D21, D27, D28 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
SCR, D-2, D14, D26, D29 
X 
 
 
 
 
 
 
 
 
 
Vital signs  
All visits except Day 88/FU 
X 
 
X 
 
 
X 
 
 
X 
 
ECG  
All visits 
X 
 
X 
 
 
X 
 
X 
 
 
BCVA 
All visits except Day 26 and Day 88/FU 
X 
 
 
X 
 
 
 
 
 
X 
Manifest refraction 
SCR, D-2, D29 
X 
 
 
 
 
 
 
 
 
 
Slit lamp examination of anterior segmentc 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, 
D28, D29 
X 
 
 
X 
 
 
 
 
 
X 
Conjunctival redness 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, 
D28, D29 
X 
 
 
X 
 
X 
 
X 
 
X 
Corneal haze 
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, 
D28, D29 
X 
 
 
X 
 
X 
 
X 
 
X 
Corneal epithelial integrity using fluorescein stain SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, 
D28, D29 
X 
 
 
 
X 
 
X 
 
X 
X 
Anterior chamber cell and flare  
SCR, D-14, D-2, D-1, D1, D2, D7, D14, D21, D27, 
D28, D29 
X 
 
 
X 
 
 
 
 
 
X 
Lens opacification 
SCR, D29 
X 
 
 
 
 
 
 
 
 
 
IOP, abbreviated schedule 
SCRe, D-14d, D7, D14, D21, D29d 
X 
 
 
 
X 
 
X 
 
X 
X 
IOP, full schedule 
D-2, D-1, D1, D2, D27, D28 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Posterior segment examination 
SCR (dilated), D-2; nondilated, D29 (dilated) 
X 
 
 
 
 
 
 
 
 
 
Gonioscopye 
SCR, D29 
X 
 
 
 
 
 
 
 
 
 
Specular microscopy, noncontact 
SCR, D-1, D14, D29 
X 
 
 
 
 
 
 
 
 
 


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Page 24 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
 
 
 
        [30 AUG 2018] 
 
 
Table 5 
Detailed Schedule of Events – Cohort D 
Assessment 
Days Performed (Screening-D29)f 
Predose/ 
Morninga 0 m 
30 
m 
1 h 2 h 3 h 4 h 6 h 8 h 12 h 
Corneal pachymetry 
SCR, D-1, D1, D2, D7, D14, D29 
X 
 
 
X 
X 
 
X 
 
 
X 
Antidrug Ab blood sampling 
D-2, D14, D29, D88/FU  
X 
 
 
 
 
 
 
 
 
 
Drugs of abuse 
SCR, D-14, D-2, D-1, D1, D14, D21, D26  
X 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
SCR, D-14, D-2, D-1, D1, D14, D21, D26  
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (female subjects) 
SCR, D-2, D1, D26, D29. 
X 
 
 
 
 
 
 
 
 
 
Biochemistry, hematology, and urinalysis 
SCR, D-2, D1, D7, D14, D21, D26, D27, D29. 
X 
 
 
 
 
 
 
 
 
 
Timings relate to the first dose of the day or the equivalent morning assessment. Assessments on nondosing days (screening, baseline, and Day 29) will take place once in the 
morning only unless otherwise specified. 
Ab=antibody; BL=baseline; BCVA=best-corrected visual acuity; D=day; ECG=electrocardiogram; FU=follow up; h=hours; IOP=intraocular pressure; m=minutes; MDTP=multiple 
dose treatment period; PK=pharmacokinetic; SCR=screening. 
a Assessments will take place 60-30 minutes before the first dose of the day or in the morning on nondosing days. 
b Drop comfort assessments will be obtained immediately, 1, 2, and 3 minutes after instillation of the investigational product; to be assessed at morning doses only. If the score is not 
≤3 at minute 3, the drop comfort assessment should be repeated at minutes 5, 10, and 15 until the score is ≤3. If the score is >3 at minute 15, it should be recorded as an adverse 
event. 
c Slit lamp examination of anterior segment will be performed only during the morning assessment on the following days: Screening, Day -14, Day -2, and Day  1 and Day 29. 
d  At screening IOP may be done at any time during the day.  At MWOA (D-14), IOP should be done at 10:00 am ± 3 hours. IOP only needs to be done at one time during screening, 
MWOA, and Day 29. 
e Gonioscopy at screening can be done at any time of day. Gonioscopy on Day 29 will be performed after IOP measurement but before dilation. 
f Ophthalmologic assessments on screening, MWOA (D-14), and day 29 need to be done one time during the day only. 
    These assessments include: BCVA, Manifest Refraction (Screening), Slit Lamp examination of anterior segment, Conjunctival Redness, Corneal Haze, Corneal Epithelial 
integrity using fluorescein stain, Anterior Chamber cell and flare, Lens Opcification, IOP, Posterior Segment Examination, dilated (Screening and Day 29), Specular Microscopy, 
Noncontact (Screening and Day 29), Corneal Pachymetry (Screening and Day 29). 
g Subjects will be administered the last dose of study drug on the morning of Day 28. 
 
 
 
 
 
 
 


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2.3 
Determination of Sample Size 
A sufficient number of subjects will be screened to ensure the enrollment and completion of 84 
subjects. 
The number of subjects in this study is not based on statistical power considerations because the 
statistical analyses are primarily descriptive in nature. However, if at least 7 subjects complete 
each cohort, then there will be at least 65% to 85% probability of observing at least 1 occurrence 
of any AE with a true incidence rate for a given dose group of at least 15% to 25%, respectively. 
It is estimated that dose escalation will occur for up to 3 dose levels (4 cohorts within each dose 
level). Each cohort will include 5 subjects randomized to active drug (SHP639) and 2 subjects 
randomized to placebo for an estimated total of at least 84 subjects. 
For each cohort, the number of subjects will be increased as needed based on safety and IOP 
response to investigational product. Any cohort can be repeated to confirm findings with regard 
to safety or IOP response to investigational product.  
2.4 
Identification of Study Eye 
For the purpose of overall analysis, 1 eye will be designated as the primary eye for the duration 
of the subject’s participation in the study. In Cohort A single-dose treatment period (SDTP), the 
investigational product will be dosed in the designated study eye only. For all subjects 
participating in the multiple-dose treatment period (MDTP), a designated study eye will be also 
identified and the investigational product will be dosed in both eyes. For Cohort A, the study eye 
for MDTP will be the same as the study eye in SDTP. For SDTP Cohort A and MDTP Cohorts 
B, C and D, the following procedure will be used to determine the designated study eye: 
 For each subject, the mean baseline IOP at a time point will be the mean of the IOPs on 
days -2 and -1 at that time point. 
 The designated study eye will be the eye with the highest mean baseline IOP at the 
predose time point. 
 If both eyes have equal mean baseline IOPs, the eye with the highest mean IOP at the 
+2-hour time point will be the designated study eye. 
 If both eyes have equal mean IOPs at the +2-hour time point, the eye with the highest 
mean IOP at the +4-hour time point will be the designated study eye. 
 If both eyes have equal mean IOPs at the +4-hour time point, the eye with the highest 
mean IOP at the +8-hour time point will be the designated study eye. 
 If both eyes have equal mean IOPs at the +8-hour time point, the right eye will be the 
designated study eye. 


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3. 
OBJECTIVES 
SHP639 is being developed for reduction of IOP in patients with ocular hypertension and 
primary open angle glaucoma. It is expected to act through a novel mode of action (natriuretic 
peptide receptor B agonism) that leads to an increase in trabecular meshwork outflow, thus 
reducing the IOP. SHP639-101 is a first-in-human clinical study for a topical ophthalmic 
formulation of SHP639. Up to 3 different SHP639 concentrations (0.1%, 0.3%, and 0.6%) will 
be explored and safety and tolerability of SHP639 ophthalmic solution will be evaluated. As a 
secondary objective, the study will also aim to characterize the pharmacodynamics (PD) of 
SHP639, using IOP as a PD biomarker. The pharmacokinetic (PK)-PD relationship will be 
explored if the data permit. 
3.1 Study Objectives 
3.1.1 Primary Objectives 
The primary objective of this study is to investigate the safety and tolerability of single and 
multiple ascending concentrations of SHP639 ophthalmic solution in subjects with OHT or with 
POAG. 
3.1.2 Secondary Objectives 
The secondary objective of this study is to evaluate reduction of IOP, as a PD biomarker, 
following different SHP639 dosing regimens. 
3.1.3 Exploratory Objectives 
The exploratory objective for this study is to explore the PK-PD relationship of SHP639 in 
subjects with OHT or POAG.  


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4. 
SUBJECT POPULATION SETS 
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed. 
4.1 
Enrolled Set 
Enrolled set consists of all subjects who have signed informed consent.  
4.2 
Randomized Set  
Randomized set consists of all subjects in the enrolled set for whom a randomization number has 
been assigned. 
4.3 
Safety Set 
The safety set will consist of all subjects in the randomized set who had administered at least 1 
dose of investigational product. 
All safety analyses will be performed using the safety set. The placebo subjects will be pooled 
together as a pooled placebo group.  
4.4 
Pharmacokinetic Set  
The pharmacokinetic (PK) set will consist of all subjects in the safety set for whom the primary 
PK data are considered sufficient and interpretable.   
4.5 
 Pharmacodynamic Set  
The pharmacodynamic (PD) set will consist of all subjects in the safety set for whom the primary 
PD data are evaluable.  


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5. 
 SUBJECT DISPOSITION 
Subject disposition will be summarized for the enrolled set. The disposition of subjects includes 
the number and percentage of subjects for the following categories: subjects who were enrolled, 
subjects who were randomized, subjects who were in the safety set, subjects who were in the 
pharmacokinetic set, subjects who were in the pharmacodynamic set, subjects who completed the 
study, subjects who prematurely discontinued the study treatment, and subjects who did not 
complete the study. Disposition data will be summarized by treatment group and overall by 
dosing regimen. All percentages will be based on the number of subjects randomized. Reasons 
for premature discontinuation from the study treatment period as recorded on the termination 
page of the eCRF will be summarized (number and percentage) by treatment group and overall 
by dosing regimen for the randomized set. The reason for study discontinuation may include any 
of the following: adverse event, withdrawal by subject, noncompliance with investigational 
product, physician decision, study terminated by sponsor, lost to follow-up, pregnancy, protocol 
deviation, trial screen failure and other. A by-subject listing of study completion information, 
including the reason for study discontinuation, where applicable, will be presented.  
 
A listing of all Screen Failures (ie, subjects who were screened but not randomized) will be 
presented along with reasons for screen fail and details of any AEs.   
 


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6. 
PROTOCOL DEVIATIONS 
A summary of the number and percentage of subjects in the randomized set with protocol 
deviations by treatment group and overall by dosing regimen will be produced.  
All protocol deviation data will be listed for the subjects in the randomized set. 
 


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7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic variables such as age, sex, race, ethnicity, height, weight, and body mass index 
(BMI) at baseline will be summarized. Ocular assessments including Best Corrected Visual 
Acuity (BCVA) will be summarized separately for the study eye and non-study eye. Continuous 
variables, such as age (years), BMI, weight, height, and BCVA will be summarized using 
descriptive statistics for each treatment period, treatment group and overall by dosing regimen.  
Categorical variables such as sex, ethnicity, and race will be summarized by reporting the 
number and percentage of subjects in each category for each treatment group and overall by 
dosing regimen. Summaries will be performed using the randomized set. 
Demographic data will be listed using the randomized set. 


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8. 
MEDICAL HISTORY  
Medical history of subjects will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0. Recent ingestion of medication (received within 30 days or 5 half-lives 
(whichever is longer) before the date of the first dose of investigational product (see prior 
medications in section 10) and any ocular/non-ocular procedures performed within the 5 years 
before the date of the first dose of investigational product) and history of respiratory, 
cardiovascular, renal, gastrointestinal, hepatic, endocrine, hematological, neurological, 
psychiatric, and other diseases will be reviewed and recorded. The MedDRA version used for 
reporting the study will be documented in the summary table footnotes.  
The number and percentage of subjects with medical history events in each primary system 
organ class (SOC) and each preferred term (PT) will be summarized by treatment group and 
overall by dosing regimen using the randomized set.  Ocular history will be summarized for the 
study eye, the non-study eye, either eye if occurred in either eye, and both eyes if the event 
occurred in both eyes. Medical history will be counted for both eyes if a history with the same 
preferred term is present in both eyes regardless of the start date of history in each eye (e.g., the 
start date may differ between the two eyes.)  Each subject’s medical history will be listed by 
SOC and PT using the randomized set. 
 


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9. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
9.1 
Exposure to Investigational product  
Exposure to double-masked investigational product for the Safety set will be summarized in 
terms of total number of drops, and  treatment duration, which is calculated as the number of 
days from the date of first dose of double-masked investigational product taken to the date of the 
last dose of double-blind investigational product taken, inclusively for the MDTP. Descriptive 
statistics (n, mean, standard deviation, minimum, Q1, median, Q3, and maximum) will be 
presented by treatment group.  Additionally, the number and percentage of subjects who had at 
least one dose of unrefrigerated drug will be summarized.  
Exposure data including the  number of doses received by each subject, and treatment duration 
will be presented in data listings. A separate exposure listing including only subjects receiving 
unrefrigerated drug will also be presented. 
9.2 
Measurement of Treatment Compliance 
Treatment compliance will be calculated for MDTP only and will be calculated as: 
Compliance (%) = (total actual dose administered / total expected dose) × 100; 
Where,  
1. If the subject completed the treatment: total expected dose  = x × 27 + 1 (the last dose 
was taken on the morning of Day 28) 
2. If the subject discontinued the treatment, the date of treatment discontinuation will be 
used for date of expected last dose and tota expected dose will be calculated as: total 
expected dose = x × (date of expected last dose – date of first dose +1) 
 
Total actual dose = number of total doses taken between scheduled clinic visits + number of total 
drug instillations during all clinic visits, 
Number of total doses taken between scheduled clinic visits is calculated as the 
Sum of [x × (the date of last dose prior to check-in at the current visit – date of last drug 
instillation from previous visit) – number of missed doses]  
where x = 1 for Cohort A1, A2, and A3 
          x = 2 for Cohort B1, B2, and B3 
          x = 3 for Cohort C1, C2, and C3 
          x= 4 for Cohort D1, D2, and D3 


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Number of total drug instillations during all clinic visits is the sum of the numbers of drug 
instillation in all Study Drug Instillation CRFs of a subject.  
The latest date of last dose prior to check in is the date found in Study Drug Accountability CRFs 
of a subject at each scheduled visit. If a subject has terminated the study early, the date of early 
termination on the Study Completion 1 CRF will be used. Number of missed doses is the 
numbers of missed doses in Study Drug Accountability CRFs of a subject at each visit. 
Descriptive statistics for investigational product compliance during the MDTP will be presented 
by treatment group for the Safety set. Individual subject compliance information will be listed 
with treatment group indicated.  


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10. 
PRIOR AND CONCOMITANT MEDICATION  
World Health Organization-Drug Dictionary (WHODRUG) version March 2017 will be used to 
classify prior and concomitant medications by therapeutic class. Prior medication includes all 
treatments (including but not limited to prescription treatments, investigational products, 
vitamins, herbal treatments, and nondrug therapies) received within 30 days or 5 half-lives 
(whichever is longer) before the date of the first dose of investigational product and any 
procedures performed within 5 years before the date of the first dose of investigational product. 
Concomitant treatment refers to all treatment and ocular procedures received between the dates 
of the first dose of investigational product and the end of the follow-up period, inclusive.   
Both prior and concomitant medication usage will be summarized by the number and proportion 
of subjects in each treatment group and overall by dosing regimen receiving each medication 
within each preferred term for the safety set. Medications can be counted both as prior and 
concomitant medication. Multiple medication usage by a subject in the same category will be 
counted only once. Ocular medications will be summarized for the study eye, the non-study eye, 
either eye if received in either eye, and both eyes if received in both eyes. For a medication to be 
counted for both eyes, the medication start date must be the same in both eyes for a given 
preferred term. 
All prior and concomitant medication will be listed using the safety set. 


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11. 
SAFETY ANALYSES 
The safety analysis will be performed using the Safety set.  Safety and tolerability will be 
assessed by monitoring AEs, vital sign measurements, clinical laboratory test values, ECG 
readings, antidrug antibodies, drop comfort assessment, and ophthalmologic examinations. 
SDTP and MDTP outputs will be summarized separately.  For SDTP, data will be summarized 
for two periods:  
a. Dosing period only: Day 1 SDTP – Day 2 SDTP 
b. Dosing period and washout period: Day 1 SDTP up to First Dose MDTP 
For SDTP, ocular summaries will be presented for the study eye and the non-study eye.  For 
MDTP, all ocular summaries will be presented for the study eye, the non-study eye, and for 
either eye. For summarization by either eye, the eye with the less favorable response at the given 
timepoint will be summarized which may result in different eyes being summarized at different 
visits.  Adverse events and selected ocular assessments summaries will also be presented for both 
eyes. For summarization by both eyes, subjects with events or assessments occurring in both 
eyes will be included. In the MDTP, ocular summaries will be presented first by dose regimen 
then by dose level and placebo subjects will be pooled by dosing regimen. (eg, QD placebo 
subjects will be pooled together, BID placebo subjects will be pooled together, TID placebo 
subjects will be pooled together, and QID placebo subjects will be pooled together.) All subjects 
in the Safety set (including placebo-treated subjects) within a regimen will also be presented.  
(For example, all active QD doses and QD placebo patients will be combined for the QD dosing 
regimen summaries.)  
11.1 
Adverse Events  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Ocular and non-ocular AEs will be summarized separately. Ocular summaries will 
be presented separately for the study eye, the non-study eye, either eye if the event occurred in 
either eye, and both eyes if the event occurred in both eyes.  For an event to be counted for both 
eyes, the event start date must be the same in both eyes for a given preferred term. 
The number of events, incidence, and percentage of treatment-emergent AEs (TEAE) will be 
calculated overall, by system organ class and preferred term by treatment group and overall by 
dosing regimen.  AEs leading to drug withdrawal, Serious AEs (SAE), and AEs leading to death 
will be similarly summarized/listed. All information obtained on AEs will be displayed in a 
listing by treatment group, cohort, subject, treatment period (single dose or multiple dose; Cohort 
A only), visit, and day. A subject with multiple AEs within a body system will be counted only 
once. If more than 1 AE with the same preferred term is reported before the date of the first dose 
of double-blind investigational product, then the AE with the greatest severity will be used as the 
benchmark for comparison to the AEs occurring during the Double-blind Evaluation Phase under 
the preferred term.   


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Treatment-emergent AEs will be further summarized by severity and relationship to 
investigational product. An AE (classified by preferred term) that occurs during the Double-
masked Evaluation Phase will be considered a TEAE if it has a start date and time on or after the 
date and time of first dose of double-blind investigational product or if it has a start date and time 
before the date and time of the first dose of double-blind investigational product, but increases in 
severity on or after the date and time of the first dose of double-blind investigational product. An 
AE that occurs more than 7 days after the date of the last dose of double-blind investigational 
product will not be counted as a TEAE. 
The overall number of subjects having any type of TEAEs will be summarized by treatment 
group. The number and percentage of subjects reporting TEAEs will be tabulated by system 
organ class (SOC) and preferred term (PT) by treatment group; TEAEs by severity will be 
tabulated by SOC,  and maximum severity by treatment group. TEAEs considered related to 
investigational product will also be summarized by SOC and preferred term. If more than 1 AE 
occurs with the same PT for the same subject, then the subject will be counted only once for that 
PT using the most severe and most related occurrence for the summarization by severity and by 
relationship to investigational product.  For both eyes summaries of related TEAEs, the events in 
both eyes must be considered related to investigational product. For both eyes summaries of 
TEAEs by severity, the events with same preferred term starting on the same date will be 
counted by the greater severity of the events in the two eyes (eg, the eyes will not be required to 
have same severity of the event to be counted.) 
11.2 
Clinical Laboratory Variables 
Biochemistry, hematology, and urinalysis will be measured at the visits specified in Table 1; the 
time points during each visit are specified in Table 2, Table 3, Table 4, and Table 5 for Cohorts 
A, B, C, and D, respectively. Baseline for clinical laboratory for SDTP is defined as the last non-
missing scheduled assessment made prior to dosing in SDTP and baseline for MDTP is defined 
as the last non-missing scheduled assessment made prior to dosing in MDTP.  Descriptive 
statistics for clinical laboratory values (in SI units) and changes from baseline at each assessment 
time point  for quantitative variables will be presented by treatment group for the following 
clinical laboratory variables.  
Hematology 
Hematocrit, hemoglobin, red blood cells (RBC), platelet count, white blood cell 
count (WBC) – total and differential: total neutrophils (absolute), lymphocytes 
(absolute), monocytes (absolute), eosinophils (absolute), basophils (absolute) 
Biochemistry 
Sodium, potassium, glucose,  creatinine, blood urea nitrogen (BUN), calcium, 
chloride, phosphorus, total CO2 (bicarbonate), albumin, total protein, ALT, 
AST, gamma- glutamyltransferase (GGT), ALP, total bilirubin, uric acid, 
-hCG (females only). 
Urinalysis 
pH, specific gravity, blood, WBC, glucose, protein, ketones, bilirubin, nitrite, 
and  leukocyte esterase.   




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Specific Gravity 
< 0.9 × LLN 
> 1.1 × ULN 
Blood 
 
> 5 
WBC 
 
> 5 
Glucose 
 
≥ 100 mg/dL 
Protein 
 
> 20 mg/dL 
Bilirubine 
 
Other than 
negative 
Nitrite 
 
Other than 
negative 
Ketones 
 
Other than 
negative 
Leukocyte esterase 
 
Small, moderate 
and large (eg 
other than 
negative OR 
trace) 
 
11.3 
Vital Signs 
Blood pressure, pulse rate and body temperature will be measured at the visits specified in 
Table 1; the time points during each visit are specified in Table 2, Table 3, Table 4, and Table 5 
for Cohorts A, B, C, and D, respectively. Baseline for vital signs for SDTP is defined as the last 
non-missing scheduled assessment made prior to dosing in SDTP and baseline for MDTP is 
defined as the last non-missing scheduled assessment made prior to dosing in MDTP.  Additional 
blood pressure and pulse rate measurements may be performed, as determined by the 
investigator, in order to ensure appropriate monitoring of subject safety and accurate recording of 
vital sign measurements. Any changes from baseline that are deemed clinically significant by the 
investigator are to be recorded as an AE. 
Descriptive statistics for vital signs (systolic and diastolic blood pressure, pulse rate, and body 
weight) and their changes from baseline at each postbaseline visit and at the end of study will be 
presented by treatment group. Vital sign results wil be listed by individual subject. 
Vital sign values will be considered PCI if they meet both the observed value criteria and the 
change from baseline criteria listed in Table 7.  The number and percentage of subjects with PCI 
postbaseline values will be tabulated by treatment group and overall by dosing regimen in the 
Safety set. Percentages will be calculated relative to the number of subjects with baseline and at 
least 1 postbaseline assessment.  The numerator is the total number of subjects with at least 1 
PCI postbaseline vital sign value.  A supportive listing of subjects with postbaseline PCI values 
will be provided including the subject number, site, baseline, and postbaseline PCI values.   
 


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Table 7 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Flag 
Criteriaa 
Observed Value 
Change from Baseline 
Systolic blood pressure 
(mmHg) 
High 
 160 
Increase of  20 
Low 
 90 
Decrease of  20 
Diastolic blood pressure (mmHg) 
High 
 105 
Increase of  15 
Low 
 50 
Decrease of  15 
Pulse rate 
(beats per minute) 
High 
 100 
Increase of  15 
Low 
 40 
Decrease of  15 
Weight (kg) 
High 
- 
Increase of  7% 
Low 
- 
Decrease of  7% 
a A postbaseline value is considered as a PCI value if its meets both criteria for observed value and change from baseline. 
 
11.4 
Electrocardiogram (ECG) 
Twelve-lead ECGs will be performed at the visits specified in Table 1; the time points during 
each visit are specified in Table 2, Table 3, Table 4, and Table 5 for Cohorts A, B, C, and D, 
respectively. Descriptive statistics for ECG variables (heart rate, PR interval, RR interval, QRS 
interval, QT interval, and QTc interval) and their changes from baseline at each assessment time 
point will be presented by treatment group and overall by dosing regimen in the Safety set.   
Baseline for ECG for SDTP is defined as the last non-missing scheduled assessment made prior 
to dosing in SDTP and baseline for MDTP is defined as the last non-missing scheduled 
assessment made prior to dosing in MDTP.  QTc interval will be calculated using both Bazett 
(QTcB=QT/(RR)1/2) and Fridericia (QTcF=QT/(RR)1/3) corrections. ECG interpretation will be 
summarized by visit and cohort. ECG results and interpretation will be listed by individual 
subject. 
If the QTcF interval (calculated online on site) is increased by >45 msec from the baseline or an 
absolute QTcF value is >500 msec for any scheduled ECG, then 2 additional ECGs will be 
collected, approximately 2-4 minutes apart, to confirm the original measurement. If either of the 
QTcF values from these repeated ECGs remains above the threshold value (>45 msec from the 
baseline; or is >500 msec), then a single ECG must be repeated at least hourly until QTcF values 
from 2 successive ECGs fall below the threshold value that triggered the repeat measurement. 
When triplicate ECGs are collected, the mean of the triplicate measurements should be used to 
trigger the decision to collect follow-up ECGs. 
If QTcF values remain above 500 msec (or >45 msec from the baseline) for >4 hours (or sooner 
at the discretion of the investigator) or QTcF intervals get progressively longer, the subject 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
intervals do not return to <500 msec (or to <45 msec above the baseline) after 8 hours of 
monitoring (or sooner at the discretion of the investigator). 


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If a machine-read QTcF/QTcB value is prolonged, as defined above, repeat measurements may 
not be necessary if a qualified physician’s interpretation determines that the QTcF/QTcB values 
are in the acceptable range. 
Electrocardiogram variable values will be considered PCI if they meet or exceed the upper limit 
values listed in Table 8. The number and percentage of subjects with postbaseline PCI values 
will be tabulated by treatment group and overall by dosing regimen in the Safety set. The 
percentages will be calculated relative to the number of subjects with available non-PCI baseline 
and at least 1 postbaseline assessment. The numerator is the total number of subjects with at least 
1 PCI postbaseline ECG value. A listing of all subjects with postbaseline PCI value will be 
provided including the subject number, site, baseline, and postbaseline PCI values. 
Table 8 
Criteria for Potentially Clinically Important ECG Values 
ECG 
Parameter 
(unit) 
Flag 
Criteria 
Observed Value 
Change from Baseline 
Heart rate 
(bpm) 
HIGH 
 100 
Increase of  15 
LOW 
 40 
Decrease of  15 
QRS Interval 
(msec) 
HIGH 
 > 200 
 
LOW 
< 120 
 
 
PR Interval 
(msec) 
HIGH 
> 220 
Increase of > 20  
LOW 
< 100 
 
QTc Interval 
(msec)  
MEN HIGH 
> 430 
Increase of > 30 
WOMEN 
HIGH 
> 450 
Increase of > 30  
MEN LOW 
< 330 
 
WOMEN 
LOW 
< 340 
 
11.5 
Antidrug Antibody Testing 
A blood sample of approximately 6 mL will be collected to test for antidrug antibodies (ADA) in 
serum at the visits specified in Table 1. On dosing days, samples will be collected before the first 
dose of the day. Any subject with newly developed antidrug antibodies at the Day 60 assessment 
may require follow-up. Results of ADA testing will be listed by individual subject. The 
summarization format will be based on the data result type. 
11.6 
Other Safety Variables 
11.6.1 
Drop comfort assessment 
Drop comfort assessment should be performed immediately after instillation of investigational 
product and before IOP assessment (which requires topical anesthetic). Drop comfort assessment 


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will be measured at the visits specified in Table 1; the time points during each visit are specified 
in Table 2, Table 3, Table 4, and Table 5 for Cohorts A, B, C, and D, respectively. 
The drop comfort assessment will be performed for each eye (study eye, non-study eye, and 
either eye) except for Cohort A during the SDTP, when only the study eye will be assessed. For 
either eye summaries, the assessment denoting the most discomfort (e.g., greater value) will be 
summarized.  The assessment will be performed immediately and 1, 2, and 3 minutes after 
instillation of the investigational product. The subject will be asked to rate drop comfort on a 
scale of 0-10, where 0=very comfortable and 10=very uncomfortable. 
If the score is not ≤3 at minute 3, the drop comfort assessment should be repeated at 5, 10, and 
15 minutes after dosing until the score is ≤3. If the score is >3 at 15 minutes after dosing, it 
should be recorded as an AE. 
Descriptive statistics for drop comfort scores at each assessment time point during the SDTP will 
be presented for study eye by treatment group. Descriptive statistics for drop comfort scores at 
each assessment time point during the MDTP will be presented by eye (study eye, non-study eye, 
either eye) and by treatment group .  The score of drop comfort at each assessment visit and time 
point will be listed by individual subject. 
11.6.2 
Ophthalmologic Examination  
Ophthalmologic examinations of both eyes will be performed at the visits specified in Table 1; 
the time points during each visit are specified in Table 2, Table 3, Table 4, and Table 5 for 
Cohorts A, B, C, and D, respectively. Both eyes will be assessed at each examination unless 
otherwise specified. Ophthalmologic  examination results will be summarized for the study eye, 
the non-study eye, and either eye.  Summaries for either eye will be presented for MDTP only.    
11.6.2.1 Manifest Refraction 
Manifest refraction will be determined at the following visits in order to assess BCVA: 
 Screening 
 SDTP (Cohort A only): baseline (Day -2) 
 MDTP (all cohorts): baseline (Day -2) and Day 29. 
The manifest refraction will be repeated if the BCVA has decreased by 10 or more letters.  
The status of manifest refraction assessment, and the date and time of the assessment will be 
listed by individual subject. No summarization of refraction data will be performed.    
11.6.2.2 Best-Corrected Visual Acuity 
Using the manifest refraction, the BCVA will be assessed at distance before slit lamp 
examination at the following visits: 


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 Screening 
 Midwashout assessment 
 SDTP (Cohort A only): baseline (Days -2 and -1) and Days 1 and 2 
 MDTP (all cohorts): baseline (Days -2 and -1) and Days 1, 2, 7, 14, 21, 27, 28, and 29. 
See Table 2, Table 3, Table 4, and Table 5 for detailed timings by cohort. 
For each treatment period, the baseline assessments are measured on Day -2 and -1 at 
predose/morning, +1 and +12 hours.  Baseline BCVA is defined as the mean of the non-missing 
assessments at these 6 time points. A decrease in BCVA by 6 or more letters may be considered 
clinically significant (CS) or not clinically significant (NCS) and requires a dilated posterior 
segment examination. A 10 or more letter loss in BCVA is considered CS and requires a repeat 
manifest refraction and dilated posterior segment examination. Clinically significant changes 
should be recorded as AEs in the source document and eCRF.  
Descriptive statistics for BCVA letter score and changes from baseline at each assessment time 
point will be presented by eye (study eye, non-study eye, and either eye (MDTP only)) and 
treatment.  Additionally, the number and percentage of subjects with BCVA changes in  
following categories by treatment group will be presented: 
 < 6 letter decrease 
 6 to 9 letter decrease 
 >=10 letter decrease 
 
The percentages will be calculated relative to the number of subjects with available baseline 
BCVA and at the postbaseline assessment for the given timepoint. The complete results of 
BCVA will be listed by individual subject. 
For either eye summaries, at baseline the eye with the lower baseline BCVA score will be 
summarized.  For post baseline timepoints, the eye with the smaller increase from baseline will 
be summarized.  If both eyes have the same change from baseline, the eye with the lower BCVA 
score at the given visit will be summarized. 
11.6.2.3 Slit Lamp Biomicroscopy 
Slit lamp biomicroscopy will be performed at the following visits: 
 Screening 
 Midwashout assessment 
 SDTP (Cohort A only): baseline (Days -2 and -1) and Days 1 and 2 
 MDTP (all cohorts): baseline (Days -2 and -1) and Days 1, 2, 7, 14, 21, 27, 28, and 29. 


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See Table 2, Table 3, Table 4, and Table 5 for detailed timings by cohort. 
Slit lamp assessments will be performed before IOP measurement and pachymetry.  Ungraded  
slit lamp assessments will be made before  graded assessments.  
The following anterior structures will be evaluated as normal or abnormal. If abnormal, the 
findings should be described and recorded as either CS or NCS for the overall slit lamp 
biomicroscopy examination. Any CS findings should be recorded as AEs; the investigator may 
use his/her discretion to determine whether a finding considered NCS is reported as an AE. 
Findings and assessment of clinical significance should be recorded in the source documents and 
eCRF. 
The following will be examined at each visit:  
 Lids/lashes/lacrimal 
 Conjunctiva 
 Cornea 
 Anterior chamber 
 Iris 
 Lens (at Screening and Day 29 during dilated exams only) 
The findings of overall slit lamp biomicroscopy examination will be summarized for the study 
eye, the non-study eye, and if observed in either eye (MDTP only) at each visit by treatment . 
The number and percentage of subects with clinically significant abnormal results, and non-
clinically significant abnormal results for overall slit lamp biomicroscopy examination will be 
also summarized at each visit by treatment. For either eye summaries, a subject will be counted 
as normal only if both eyes are normal and as abnormal if either eye is abnormal.  The 
percentage of subjects with each findings by ocular location will be calculated relative to the 
number of subjects with available finding at specific eye and visit.   Additionally the number and 
percentage of subjects with at least one postbaseline abnormal finding for each ocular location 
will be summarized. Results of slit lamp biomicroscopy will be listed by individual subject and a 
separate listing of clinically significant findings will also be presented. 
 
11.6.2.4 Conjunctival Redness Score Assessment 
The Efron scale/conjunctival redness assessment (Efron et al. 2001) is a clinically validated, 
image-based scale that will be used to evaluate bulbar conjunctival redness during all 
ophthalmologic examinations, as outlined in Table 1 (all cohorts) and specified in Table 2, 
Table 3, Table 4, and Table 5 for Cohorts A, B, C, and D, respectively. The scale contains 
5 categories ranging from 0 (normal) to 4 (severe). 
For each treatment period, the baseline assessments are measured on Day -2 and -1 at 
predose/morning, +1, +3, +6, and +12 hours. Baseline conjunctival redness score is defined as 


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the single assessment at Day -1. A separate baseline will be derived for each scheduled time 
point. Change from baseline will be calculated comparing post treatment values to their 
respective baseline (e.g., on treatment predose assessments will be compared to baseline predose 
asessments, on treatment 1 hours assessments will be compared to baseline 1 hour assessments, 
on treatment 3 hours assessments will be compared to baseline 3 hour assessments, on treatment 
6 hours assessments will be compared to baseline 6 hour assessments and on treatment 12 hours 
assessments will be compared to baseline 12 hour assessments).  
The number and percentage of subjects in each score category at each time point will be 
summarized by eye (study eye, non-study eye, and either eye (MDTP only)), and treatment.  For 
either eye assessments, the eye with the greater score will be summariezed.   The denominator of 
the percentage is the number of subjects who have the assessment for the specified eye and visit. 
In addition, the number and percentage of subjects with clinically significant results, and non-
clinically significant results will be summarized by treatment group. Results of conjunctival 
redness score assessment will be listed by individual subject. 
Additionally, the number and percentage of subjects with conjunctival redness score changes 
from baseline in the following categories by eye (study eye, non-study eye, and either eye 
(MDTP only)) and treatment group will be presented: 
 -4 (4 points decreased from baseline) 
 -3 (3 points decreased from baseline) 
 -2 (2 points decreased from baseline) 
 -1 (1 point decreased from baseline) 
 0 (no change from baseline) 
 1 (1 point increased from baseline) 
 2 (2 point increased from baseline) 
 3 (3 point increased from baseline) 
 4 (4 point increased from baseline) 
The percentages will be calculated relative to the number of subjects with available baseline 
conjunctival redness score and at the postbaseline assessment for the given timepoint.  For either 
eye summaries, at baseline, the eye with the higher baseline redness score will be summarized.  
For post baseline timepoints, the eye with the smaller decrease from baseline will be 
summarized. If both eyes have the same change from baseline, the eye with the higher redness 
score at the given visit will be summarized.  
11.6.2.5 Corneal Haze 
Corneal haze assessments will be performed as part of the slit lamp examination at the time 
points outlined in Table 1 (all cohorts) and specified in Table 2, Table 3, Table 4, and Table 5 for 
Cohorts A, B, C, and D, respectively. 
The number and percentage of subjects for each category of corneal haze grade will be 
summarized by eye (study eye,  non-study eye, and either eye (MDTP only)) and treatment 
group at each visit and time point.   For either eye assessments, the eye with the greater score 


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will be summarized.   The denominator of the percentage is the number of subjects who have the 
assessment for the specified  eye and visit. In addition, the number and percentage of subjects 
with clinically significant results, and non-clinically significant results will be summarized by 
treatment group. Results of corneal haze assessment including corneal haze grade, epithelial 
edema, stromal thickening/haze, and Descemet’s folds will be listed by individual subject and a 
separate listing of clinically significant findings will also be presented. 
11.6.2.6 Corneal Epithelial Integrity by Fluorescein Stain 
The integrity of the corneal epithelium will be assessed using topically applied fluorescein at the 
time points outlined in Table 1 (all cohorts) and specified in Table 2, Table 3, Table 4, and 
Table 5 for Cohorts A, B, C, and D, respectively. It is important to perform the assessment 
before instillation of topical anesthetic for measurement of IOP.   
For each subject at each visit and timepoint, a total score of three components from corneal 
epithelium integrity will be calculated by adding scores across three regions: inferior, central, 
and superior for each eye. The total scores will be summarized. For each treatment period, the 
baseline assessments are measured on Day -2 and -1 at predose/morning, +2, +4, +8, and +12 
hours. Baseline corneal epithelial integrity is defined as the single assessment at Day -1 at each 
scheduled time point. Change from baseline will be calculated comparing post treatment values 
to their respective baseline (e.g., on treatment predose assessments will be compared to baseline 
predose asessments, on treatment 2 hours assessments will be compared to baseline 2 hour 
assessments, on treatment 4 hours assessments will be compared to baseline 4 hour assessments, 
on treatment 8 hours assessments will be compared to baseline 8 hour assessments and on 
treatment 12 hours assessments will be compared to baseline 12 hour assessments).   
Descriptive statistics for corneal epithelial integrity total scores and change from baseline at each 
assessment time point will be presented by eye (study eye,  non-study eye, and either eye (MDTP 
only)) and treatment group . For either eye summaries, at baseline the eye with the greater 
staining  total score will be summarized. For post baseline timepoints, the eye with the greater 
increase from baseline will be summarized.  If both eyes have the same change from baseline, 
the eye with the greater staining total score at the given visit will be summarized. In addition, the 
number and percentage of subjects with clinically significant results, and non-clinically 
significant results will be summarized by treatment group. Results of corneal epithelium integrity 
assessment including individual region scores will be listed by individual subject and clinically 
significant findings will also be presented. 
11.6.2.7 Anterior Chamber Cell and Flare 
Anterior chamber cell and flare will be assessed and graded using the Standardization of Uveitis 
Nomenclature grading scale at the time points outlined in Table 1 (all cohorts) and specified in 
Table 2, Table 3, Table 4, and Table 5 for Cohorts A, B, C, and D, respectively. 
The number and percentage of subjects for each anterior chamber cells grade and anterior 
chamber flare grade will be summarized by eye (study eye,non-study eye, and either eye (MDTP 
only)) and treatment group.  For either eye summaries, the eye with the greater score will be 


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summarized.The denominator of the percentage is the number of subjects who have the 
assessment at the specified eye and visit. In addition, the number and percentage of subjects with 
clinically significant results, and non-clinically significant results will be summarized by 
treatment group. Results of anterior chamber cell and flare assessment will be listed by 
individual subject and clinically significant findings will also be presented. 
11.6.2.8 Lens Opacification 
Lens opacification will be assessed with the slit lamp during dilated examination. Phakic eyes 
will be graded in the nuclear, cortical, and posterior  subcapsular layers using the Lens Opacities 
Classification System III grading scale at the time points outlined in Table 1 (all cohorts) and 
specified in Table 2, Table 3, Table 4, and Table 5 for Cohorts A, B, C, and D, respectively. 
Pseudophakic eyes without posterior capsulotomy will be graded in the posterior subcapsular 
layer only. Pseudophakic eyes with posterior capsulotomy will not be graded.  
The number and percentage of subjects that are phakic, the number and percentage of subjects 
that are psuedophakic, including number and percentage of subjects with and without a posterior 
capsulotomy,  and the number and percentage of subjects for each category of nuclear 
color/opalescence, cortical, and posterior subcapsular will be summarized by eye (study eye and 
non-study eye) and  treatment group at each visit and time point. The denominator of the 
percentage is the number of subjects who have the assessment for the specified eye and visit. In 
addition, the number and percentage of subjects with clinically significant results, and non-
clinically significant results will be summarized by treatment group. Results of lens opacification 
will be listed by individual subject and clinically significant findings will also be presented. 
11.6.2.9 Intraocular Pressure 
Intraocular pressure will be measured at the following visits: 
 Screening 
 Midwashout assessment 
 SDTP (Cohort A only): baseline (Days -2 and -1), Days 1and 2 
 MDTP (all cohorts): baseline (Days -2 and -1) and Days 1, 2, 7, 14, 21, 27, 28, and 29. 
See Table 2, Table 3, Table 4, and Table 5 for detailed timings by cohort. Two consecutive IOP 
measurements, to the nearest mmHg, will be made in the designated study eye; if the 2 
measurements differ by more than 2 mmHg, then a third measurement will be performed. The 
procedure will be repeated in the nonstudy eye. All measurements will be recorded in the source 
document and eCRF and the mean of the (2 or 3) readings for each eye will be used to determine 
the mean IOP at the given time point for each eye.  These mean IOP values will be used for all 
IOP analyses.    
The baseline IOP is defined as the average of  the mean IOP measurements at Day -1 and Day -2.  
A separate baseline will be derived for each scheduled timepoint.   Descriptive statistics for IOP, 
the change from baseline, and the percentage change from baseline at each assessment time point 


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will be presented by eye (study eye vs. non-study eye) and  treatment. Change from baseline will 
be calculated comparing post-treatment values to their respective baselines (e.g.,  on treatment 
pre-dose assessments will be compared to baseline pre-dose assessments, on treatment 1 hour 
assessments will be compared to baseline 1 hour assessments and on treatment 12 hour 
assessments will be compared to baseline 12 hour assessments). Line plots displaying mean IOP, 
change from baseline, and percent change from baseline at each visit and each scheduled 
timepoint will be presented by eye (study eye, non-study eye) and treatment for SDTP and 
MDTP. Line plots displaying mean IOP, at selected visits (baseline, Day 14 and Day 28) and 
selected scheduled timepoints (predose, +2h, +4h, +8h) during MDTP will be presented for study 
eye by treatment. Spaghetti plots showing the IOP values at each visit and each timepoint for all 
subjects in the Safety set will be presented by eye (study eye, non-study eye) and treatment for 
SDTP and MDTP. 
Diurnal fluctuation in IOP will be summarized as below: 
 The baseline diurnal IOP (schedule 1) is defined as the average of all IOP meansurements 
across three time points (predose, +2 h, +8 h) at Day -1 and Day -2. Postbaseline diurnal IOP 
is defined as the average of all IOP measurements across three time points (predose, +2 h, + 
8h) at each visit. Change from baseline will be calculated as the difference between 
postbaseline diurnal IOP and baseline diurnal IOP. Descriptive statistics for diurnal IOP, the 
change from baseline, and the percentage change from baseline at each visit will be presented 
by eye (study eye, non-study eye) and treatment. 
 The baseline diurnal IOP (schedule 2) is defined as the average of all IOP meansurements 
across three time points (predose, +4 h, +8 h) at Day -1 and Day -2. Postbaseline diurnal IOP 
is defined as the average of all IOP measurements across three time points (predose, +4 h, + 
8h) at each visit. Change from baseline will be calculated as the difference between 
postbaseline diurnal IOP and baseline diurnal IOP. Descriptive statistics for diurnal IOP, the 
change from baseline, and the percentage change from baseline at each visit will be presented 
by eye (study eye, non-study eye) and treatment. 
Results of intraocular pressure will be listed by individual subject. 
11.6.2.10 Posterior Segment Examination 
The posterior segment will be visualized by a fundus examination at the following visits: 
 Screening – dilated 
 SDTP baseline (Cohort A only) – nondilated (Day -2) 
 MDTP baseline – nondilated (Day -2) 
 Day 29 – dilated. 
A dilated posterior segment examination of both eyes should also be performed if the BCVA in 
either eye decreases by 6 or more letters.  
The following structures will be assessed (suggested technique): 


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 Vitreous (binocular indirect examination) 
 Optic nerve head (slit lamp biomicroscopy) 
 Cup-to-disc ratio (slit lamp biomicroscopy) 
 Macula (slit lamp biomicroscopy) 
 Retina vasculature 
 Retinal, outside of arches, including periphery 
 Choroid 
The number and percentage of subjects who have normal results and abnormal results for 
vitreous, disc, macula, retinal vasculature, retina, and choroid will be summarized by eye (study 
eye, non-study eye, and either eye (MDTP only)), treatment group and time point. For either eye 
summaries, a subject will be counted as normal only if both eyes are normal and as abnormal if 
either eye is abnormal.  The denominator of the percentage is the number of subjects who have 
assessment for the specified eye and visit. In addition, the number and percentage of subjects 
with clinically significant abnormal results, and non-clinically significant abnormal results will 
be summarized by treatment. Also, the number and percentage of subjects with at least one 
postbaseline abnormal finding  and at least one post baseline clinically significant abnormal 
finding for each assessment type will be summarized 
Descriptive statistics for the horizontal and vertical cup to disc ratios and their changes from 
baseline at each assessment time point will be presented by eye (study eye, non-study eye, and 
either eye (MDTP only)) and treatment.  Baseline disc ratio is defined as the Day -2 screening 
assessment.  For either eye summaries, the eye with the greater disc ratio will be summarized at 
baseline.  For post baseline assessment, the eye with the greater increase from baseline will be 
summarized.  If both eyes have the same change from baseline, the eye with the greater value 
will be summarized.   
The number and percentage of subjects who have no notch at baseline and a  notch present at any 
time during post baseline period will be summarized by eye (study eye, non-study eye, and either 
eye (MDTP only)) and treatment. Only subjects who have no notch at baseline will be included 
in this summary. Baseline notch presence is defined as the Day -2 baseline assessment. For either 
eye summaries, a subject will be counted as  notch absent if both eyes have no notch and as 
notch present  if either eye has a notch. The percentages will be calculated relative to the number 
of subjects with available baseline notch assessment and at the postbaseline assessment for the 
given timepoint.   
In addition, the number and percentage of subjects with changes in number of notches from 
baseline in the following categories by treatment group will be presented: 
 0 (no change) 
 1+ (increase by 1 notch) 
 2+ (increase by 2 notches) 


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 3+ (increase by 3 notches) 
 4+ (increase by 4 notches) 
The percentage will be calculated relative to the number of subjects with available baseline notch 
assessment and at the postbaseline assessment for the given timepoint.  For either eye 
summaries, the eye with greatest increase in number of notches will be summarized. 
Results of posterior segment examination will be listed by individual subject and a separate 
listing of clinically significant findings will also be presented. 
11.6.2.11 Gonioscopy  
Gonioscopy to assess the iridocorneal angles will be performed at SDTP baseline (Day -2; 
Cohort A only), MDTP baseline (Day -2; Cohorts B, C, and D), and on Day 29. Gonioscopy 
should be performed after the corneal epithelium has been evaluated for defects with fluorescein 
and after IOP has been measured but before dilated posterior segment examination (Day 29).  
The number and percentage of subjects by Shaffer grading system at position 12:00 to 3:00, 3:00 
to 6:00, 6:00 to 9:00, and 9:00 to 12:00 will be summarized by eye (study eye,. non-study eye, 
and either eye (MDTP only)) and treatment group at each visit and time point. For either eye 
summaries, the eye with the lower Shaffer grade will be summarized.  The denominator of the 
percentage is the number of subjects who have the assessment for thespecified eye and visit. 
Results of gonioscopy will be listed by individual subject. 
11.6.2.12 Noncontact Specular Microscopy  
Noncontact specular microscopy will be performed, with the subject seated, to assess endothelial 
cell count at the following visits: 
 Screening 
 SDTP (Cohort A only): baseline (Day -1) and Day 2 
 MDTP (all cohorts): baseline (Day -1) and Days 14 and 29. 
Details of the procedure will be found in the ophthalmology procedures manual. 
For each eye and timepoint assessed, three meaurements of central endothelial cell density 
(cells/mm2) will be made.  All measurements will be recorded in the source document and eCRF 
and the mean of the 3  readings for each eye will be used to determine the mean cell density at 
the given time point for each eye.  These mean density values will be used for all specular 
microscopy analyses of cell dentisty.. 
Baseline specular microscopy cell density is defined as the mean of  the 3 readings on Day -1. 
Descriptive statistics for the mean central endothelial cell density and  changes from baseline at 
each assessment time point will be presented by eye (study eye, non-study eye, and either eye 
(MDTP only)) and treatment group. For either eye summaries, the eye with the smaller cell 
density will be summarized at baseline.  For post baseline assessment, the eye with the greater 


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decrease from baseline will be summarized.  If both eyes have the same change from baseline, 
the eye with the smaller value will be summarized.    Results of noncontact specular microscopy 
will be listed by individual subject. 
11.6.2.13 Corneal Pachymetry  
Corneal pachymetry to assess central corneal thickness will be performed after the predose 
examination. With the pachymeter set to perform a single measurement, the investigator will 
take and record 3 consecutive measurements at each applicable time point at the following visits: 
 Screening 
 SDTP (Cohort A only): baseline (Day -1) and Days 1 and 2 
 MDTP (all cohorts): baseline (Day -1) and Days 1, 2, 7, 14, 28, and 29. 
If the range of the measurements is 15 microns or less, the set of readings is acceptable; if not, all 
measurements are discarded and repeated until an acceptable set of 3 measurements is obtained.  
The set of  all 3 measures are recorded in the source document.  The mean of the 3 measurements 
made at each timepoint are the values that will be used for analysis.    
See Table 2, Table 3, Table 4, and Table 5 for detailed timings by cohort. Baseline corneal 
thickness is defined as the average of the mean of measures at 5 time points (pre-dose, and hours 
1, 2, 4, 12) on Day -1. Descriptive statistics for the mean central corneal thickness and change 
from baseline at each assessment time point will be presented by eye (study eye, non-study eye, 
and either eye (MDTP only)) and  treatment group. In addition, descriptive statistics for the 
percentage change from baseline at each assessment time point will be presented by eye (study 
eye, non-study eye, and either eye) and treatment group for MDTP only. For either eye 
summaries, the eye with the smaller corneal thickness will be summarized at baseline.  For post 
baseline assessment, the eye with the greater decrease from baseline will be summarized.  If both 
eyes have the same change from baseline, the eye with the smaller value will be summarized. 
Results of corneal pachymetry will be listed by individual subject. 


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12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
12.1 
Pharmacokinetics Population and Pharmacodynamic Population 
Pharmacokinetic Set  
The PK set will consist of all subjects in the Safety set for whom the primary PK data are 
considered sufficient and interpretable.   
Pharmacodynamic Set  
The PD set will consist of all subjects in the Safety set for whom the primary PD data are 
available. 
12.2 
Pharmacokinetic Methods 
All summaries and analyses of the PK data will be based on the Pharmacokinetic Set. 
12.2.1 
Concentration Data 
Serial blood samples will be collected from each subject during this study to allow for the 
determination of the PK of SHP639 administered as SHP639 ophthalmic solution. Blood 
samples for PK analysis of SHP639 will be drawn according to the following schedule: 
SDTP (Cohort A only): Day 1 - Predose, 30 min, 1, 2, 3, and 6 h 
MDTP (all cohorts): For Days 1 and 27 - Predose, 30 min, 1, 2, 3, and 6 h 
Plasma samples will be analyzed to determine the concentrations of SHP639 using a validated 
bioanalytical method based on liquid chromatography with mass spectrometry. 
Individual plasma concentrations and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarized by scheduled time-point using the following 
descriptive statistics: number of observations (n), arithmetic mean, standard deviation (SD), 
median, geometric mean, coefficient of variation (CV), minimum, and maximum.  
The individual and mean plasma SHP639 concentration versus time profiles will be presented in 
figures on both linear and semi-logarithmic scales. Mean plasma concentration versus time 
profiles will be presented using nominal time and individual plasma concentration versus time 
profiles will be presented using actual time. 
12.2.2 
Handling Below the Limit of QuantificationValues 
All plasma concentration values below the limit of quantification (BLQ) will be set to zero when 
calculating summary statistics.  


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For the calculation of PK parameters all plasma concentrations that are BLQ prior to the first 
measurable concentration will be set to zero. The BLQ values that are between measurable 
concentrations will be set to missing. The BLQ values following the last quantifiable time-points 
will be set to missing. No concentration estimates will be imputed for missing sample values. 
Any sample with a missing value will be treated as if the sample had not been scheduled for 
collection and will be ignored when calculating mean concentrations or PK parameters. 
12.2.3 
Pharmacokinetic Parameters 
The following plasma PK parameters will be calculated for SHP639 on Day 1 for SDTP (Cohort 
A only) and on Day 1 and Day 27 for MDTP (all  cohorts) by non-compartmental method using 
Phoenix® WinNonlin® version 6.4 or higher (Certara USA, Inc., Princeton, NJ).  
Parameter  Definition  
Cmax 
Maximum observed plasma concentration 
Tmax 
Time to reach maximum observed plasma concentration 
AUC0-∞  
Area under the plasma-concentration time curve from time 0 extrapolated to 
infinity, calculated using the linear up/ log down trapezoidal rule  
AUC0-t 
Area under the plasma-concentration time curve from time 0 to the last measurable 
concentration, calculated using the linear up/ log down trapezoidal rule  
AUC0-τ  
Area under the plasma-concentration time curve over a dosing interval for each 
multiple-dose regimen, calculated using the linear up/log down trapezoidal rule 
(Day 1 and Day 27 for MDTP of all cohorts)  
t1/2  
Apparent first-order terminal elimination half-life, calculated as t1/2 = ln2/ Kel  
Kel  
Elimination rate constant estimated from the linear regression of the natural log-
transformed concentration over time at the terminal phase.  
%AUCex  
Percentage of the area extrapolated for calculation of AUC0-∞  
CL/F  
Apparent clearance, calculated as Dose/ AUC0-∞ for Day 1 for SDTP (Cohort A 
only) and Dose/ AUC0-Ԏ for Day 27 for MDTP (all cohorts) 
Vz/F  
Volume of distribution, calculated as Vz/F =(CL/F)/λz  
Rac(Cmax) 
Accumulation ratio based on Cmax for each multiple-dose regimen, calculated as 
Cmax (Day 27)/Cmax (Day 1) 
Rac(AUC) 
Accumulation ratio based on AUC for each multiple-dose regimen, calculated as 
AUC0-Ԏ (Day 27)/ AUC0-Ԏ (Day 1) 
 
All calculations for PK analysis will be based on actual sampling times. All PK analyses will be 
conducted by the Department of Clinical Pharmacology, PPD, Inc, Richmond, VA, USA.  
All PK parameters will be presented in data listings and summarized in tables by dose, cohort, 
treatment, and study day, using descriptive statistics (n, mean, SD, median, maximum, minimum, 
geometric mean, and CV%. Geometric means will be reported for AUCs and Cmax only. 
 


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12.3 
Statistical Analysis of Pharmacokinetic Data 
For each of SD, QD, BID, TID and QID dosing regimens, if sufficient data are available across 
dose groups, dose proportionality of plasma SHP639 PK variables AUC0-∞, AUC0-t, AUC0-τ, and 
Cmax over the dose ranges tested will be investigated. For Days 1 and 27 for MDTP of all 
cohorts, the following power model will be used to assess dose proportionality. The model is 
defined as:  
ln(PK parameter) = a + b* ln(dose), 
where ‘a’ is the intercept and ‘b’ is the slope of the line. The 95% confidence interval (CI) of the 
estimate of parameter ‘b’ will be presented. A 95% CI of the slope that includes 1.0 will be 
interpreted as the absence of significant evidence of non-proportionality.  
For statistical analysis of accumulation of SHP639, a linear mixed-effect model with day, dose, 
and day and dose interaction term as fixed effects and subject as random effect will be fitted to 
the natural log-transformed Cmax and AUC0-τ  to construct 95% CIs for Day 27 compared with 
Day 1 for each of QD, BID, TID, and QID dosing regimens separately. Statistical analysis to 
assess dose proportionality and accumulation of SHP639 will be conducted using SAS for 
Windows® (Version 9.3 or higher).   
12.4 
Pharmacodynamic Methods  
All the PD analyses will be performed using the Pharmacodynamic set. Intraocular pressure 
(IOP; mmHg), a PD biomarker, will be measured using Goldmann applanation tonometry.  
Intraocular pressure will be measured according to the following schedule: 
SDTP (Cohort A only): baseline (Days -2 and -1), Days 1 and 2,  at Predose, 0.5, 1, 2, 3, 4, 6, 8, 
and 12 h 
MDTP (Cohort A only): (all cohorts): baseline (Days -2 and -1), Days 1, 2, 27, and 28,  at 
Predose, 0.5, 1, 2, 3, 4, 6, 8, and 12 h 
MDTP (all cohorts): Days 7, 14, and 21 at Predose, 2, 4, 8, and 12 h 
The individual and mean absolute IOP, IOP reduction from baseline and percentage of IOP 
reduction from baseline versus time profiles will be presented in figures. Mean plots will be 
presented using nominal time and individual plots will be presented using actual time. 
In addition, the relationship of percentage of IOP reduction from baseline and dose of SHP639 
will be presented in a Box-and-Whiskers plot. 
Percentage of IOP reduction from baseline measurements data versus time will be used to 
estimate the PD parameters using Phoenix® WinNonlin® version 6.4 (Certara USA, Inc., 
Princeton, NJ)  for each individual in each treatment by eye (study eye and non-study eye).  
Baseline is defined as the arthimetic mean of the time-matched IOP measurements on Days -2 


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and -1 for that particular subject. Potential effect of diurnal change on variation in IOP is 
accounted for by factoring time-matched baseline in the calculations of percent of IOP reduction 
from baseline measurements.   
Parameter  Definition  
IOP 
reduction 
from 
baseline 
IOP reduction from baseline is calculated as follows: Baseline IOP – IOP after 
treatment 
% of IOP 
reduction 
from 
Baseline 
Percentage of IOP reduction from baseline is calculated as follows: (Baseline IOP - 
IOP after treatment/ Baseline IOP) × 100 
Emax 
Maximum percent IOP reduction from baseline 
TEmax 
Time of Emax 
AUEC0-t 
Area under the effect curve for the percentage of IOP reduction from baseline 
versus time profile from time zero (predose) to the time of the last measurable 
percentage of IOP reduction from baseline, calculated using the linear up/log down 
interpolation rule. 
AUEC0- 
Area under the effect curve for the percentage of IOP reduction from baseline 
versus time profile over a dosing interval, calculated using the linear up/log down 
interpolation rule. 
AUEC0-∞ 
Area under the effect curve for the percentage of IOP reduction from baseline 
versus time profile from time zero (predose) extrapolated to infinity, calculated 
using the linear up/log down interpolation rule. 
 
12.5 
Statistical Analysis of Pharmacodynamic Data 
Absolute IOP, IOP reduction from baseline, and percentage of IOP reduction from baseline will 
be listed by dose, cohort, subject, treatment period (single dose or multiple dose; Cohort A only), 
eye (study eye and non-study eye), study day and sample nominal time point. Descriptive 
summary statistics for absolute IOP, IOP reduction from baseline, percentage of IOP reduction 
from baseline, Emax, TEmax, AUEC0-t, AUEC0-τ, and AUEC0-∞ (n, arithmetic mean, SD,  95% CI, 
median, maximum, minimum, geometric mean and geometric CV%) will be calculated by dose, 
cohort, treatment period, eye (study eye and non-study eye), study day, and sample nominal time 
point (for days with multiple assessments per day).   
12.6 
Analyses of Pharmacokinetic/Pharmacodynamic Relationships  
If data permit, a potential relationship between concentrations of SHP639 ophthalmic solution 
and percentage of IOP reduction from baseline will be explored graphically using box plots; the 


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relationship between the PK and PD parameters for percentage of IOP reduction from baseline 
measurement will be presented graphically using scatter plots with regression line and the 
corresponding R2 values.  
 


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13. 
INTERIM ANALYSIS 
Shire’s Dose Escalation Committee will be convened consisting of the coordinating principal 
investigator and Shire medical monitor. Ad hoc study team members can be included such as 
biostatistics, pharmacokinetics, drug safety, and clinical operations if needed. The committee 
will review collective safety data for Cohort A and Cohort B to decide whether Part 2 in the 
same dose level and Part 1 in the next dose level (concentration) can commence.An interim 
analysis is planned for November, 2017. The safety and efficacy summaries for Part 1 of the 
study will be created using clean data, for the purpose of regulatory filing in Janurary 2018. Shire 
and PPD teams will be unmasked to treatments for subjects in Cohorts A and B as of the interim 
analysis, but will remain masked to treatments for subjects in Cohorts C and D until study 
completion 
The interim analysis will consist of non period specific outputs (including but not limited to 
disposition, demographics, protocol violations, concomitant medications) and all MDTP outputs.  
Outputs to be generated for the interim analysis are denoted in the list of outputs in Section 16. 
Following changes introduced in protocol amendment 3, all cohorts conducted after B3 (eg Part 
1 of the study) may be unmasked following completion of Day 29 to permit review of safety, 
tolerability and the pharmacodynamics effects of each cohort to better inform planning for 
additional cohorts and further clinical development options for SHP639. Interim analysis of data 
from the repeat of Cohort B3 was conducted in June, 2018. Outputs for this interim analysis are 
denoted in the list of outputs in Section 16.  
A final unmasked analysis will be conducted when all patients of the remaining ochorts have 
completed through Day 29. The Day 88/FU visit is the planned study completion for each 
subject.  


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14. 
COMPUTER METHODS  
All statistical analyses will be performed using SAS Version 9.3 or higher (SAS Institute, Cary, 
NC 27513) on a suitably qualified environment. 


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15. 
DATA HANDLING CONVENTIONS 
15.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics:  n, mean, 
median, standard deviation, minimum, maximum.  Categorical and count variables will be 
summarized by the number of subjects (n) and the percent of subjects in each category.  
Percentages will be presented as whole numbers.  
15.2 
Missing Date of Investigational Product  
When the date of the last dose of investigational product is missing for a subject in the Safety set, 
all efforts should be made to obtain the date from the investigator.  If it is still missing after all 
efforts, then the last visit date when investigational product was returned will be used in the 
calculation of treatment duration.   
15.3 
Missing Date Information for Prior or Concomitant Medications  
For prior or concomitant medications, including rescue medications, incomplete (ie, partially 
missing) start date and/or stop date will be imputed.  When the start date and the stop date are 
both incomplete for a subject, impute the start date first.     
15.3.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day and month 
 
If the year of the incomplete start date is the same as the year of the date of the first dose of 
investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields 
 
If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields 
 
If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
 
If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of investigational product, then the day of the date of the first dose of 
investigational product will be assigned to the missing day 


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 
If either the year is before the year of the date of the first dose of investigational product or 
if both years are the same but the month is before the month of the date of the first dose of 
investigational product, then the last day of the month will be assigned to the missing day 
 
If either the year is after the year of the date of the first dose of investigational product or if 
both years are the same but the month is after the month of the date of the first dose of 
investigational product, then the first day of the month will be assigned to the missing day.  
15.3.2 
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields.  If the date of the last 
dose of investigational product is missing, then replace it with the last visit date.  If the imputed 
stop date is before the start date (imputed or non-imputed start date), then the imputed stop date 
will be equal to the start date. 
Missing day and month 
 
If the year of the incomplete stop date is the same as the year as of the date of the last dose 
of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields 
 
If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields 
 
If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
 
If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of investigational product, then the day of the date of the last dose of 
investigational product will be assigned to the missing day 
 
If either the year is before the year of the date of the last dose of investigational product or 
if both years are the same but the month is before the month of the date of the last dose of 
investigational product, then the last day of the month will be assigned to the missing day 
 
If either the year is after the year of the last dose of investigational product or if both years 
are the same but the month is after the month of the date of the last dose of investigational 
product, then the first day of the month will be assigned to the missing day. 
15.4 
Missing Date Information for Adverse Events  
For AEs, the default is to only impute incomplete (eg, partially missing) start dates.  Incomplete 
stop dates may also be imputed when calculation of the duration of an AE is required per the 
protocol.  If imputation of an incomplete stop date is required, and both the start date and the 
stop date are incomplete for a subject, impute the start date first. 


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15.4.1 
Incomplete Start Date  
Follow same rules as in Section 15.3.1. 
15.4.2 
Incomplete Stop Date  
When required per the protocol, follow the same rules as in 15.3.2.  
15.4.3 
Incomplete Start/Stop Time 
There is no imputation for missing start/stop time for AEs. In such cases, only the date part will 
be used to compare with the dosing date. If an AE start date is before the first dose of MDTP, it 
will be summarized in the SDTP outputs; if an AE start date is on or after the first dose of 
MDTP, it will be summarized in the MDTP outputs. 
 
15.5 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned.  If the severity is missing for an AE starting 
on or after the date of the first dose of investigational product, then a severity of “Severe” will be 
assigned.  The imputed values for severity assessment will be used for incidence summaries, 
while the actual values will be used in data listings. 
15.6 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting on or after the date of 
the first dose of investigational product, a causality of “Related” will be assigned.  The imputed 
values for relationship to double-blind investigational product will be used for incidence 
summaries, while the actual values will be presented in data listings. 
15.7 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, that a character string is reported for a numerical variable.  The appropriately 
determined coded value will be used in the statistical analysis. The following rules will be 
followed to determine the coded value: if the reported values contain character strings of “<” or 
“≤”, then coded value will be half of the original values. For example, if reported value is <5 
then coded value will be 2.5.  If the reported value contain character strings of “>” or “≥”, then 
coded value will be twice of the original values. For example, if reported value is >5 then coded 
value will be 10.  However, the actual values as reported in the database will be presented in data 
listings. 


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Table 9 
Examples for Coding of Special Character Values for Clinical Laboratory 
Variables 
 
Clinical Laboratory Test 
Possible Results (in SI units) 
Coded Value for Analysis 
Chemistry:  ALT 
< 5 
2.5 
Chemistry:  AST 
< 5 
2.5 
Chemistry:  Total Bilirubin 
< 2 
1 
Urinalysis:  Glucose 
 55 
110 
 0 
0  
Urinalysis:  pH 
> 8.0 
16 
15.8 
Time Ranges for Analysis of Time Points 
Subjects do not always adhere strictly to the visit schedule timing in the protocol. Mutually 
exclusive relative visit and time windows are defined below to provide the derived visits and 
time points that correspond to scheduled visits and time points. Assessments will be mapped to 
the corresponding visits and time points based on the visit and time window. Designation of 
visits and time points for assessments is tabulated below.   If more than one assessment falls into 
a given visit and time window, the assessment closest to the planned visit and time will be used 
for analysis.   If both assessments are equal distant from the planned assessment visit and 
timepoint, the earlier assessment will be used for analysis. 
Table 10 Visit and Time Ranges for Assessment at Every Schedule Visit and Time Point 
Protocol Scheduled Visits 
Visit Windows (Days) 
Screening 
≥ -42 - ≤ -3 
Day -2 
-2 
Day -1 
-1 
Day 1 
1 
Day 2 
2 
Day 7 
≥ 3 - ≤ 10 
Day 14 
≥ 11 - ≤ 17  
Day 21 
≥ 18 - ≤ 25  
Day 26 
26  
Day 27 
27  
Day 28 
28 


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Day 29 
29 
Follow-up 
> 29 
 
For SDTP non-dosing days including Day -2, Day -1 and Day 2, the derived timepoints will be 
the same as the scheduled timepoints. For MDTP non-dosing days including Day -2, Day -1 and 
Day 29, the derived timepoints will also be the same as the scheduled time points. For both 
SDTP and MDTP dosing days, designation of timepoints for post-dosing assessments is 
tabulated below. 
Protocol Scheduled TImepoints 
Time Windows 
Predose 
Predose 
0 m 
> 0 m - ≤ 15 m 
30 m 
> 15 m - ≤ 45 m 
1 h  
> 45 m - ≤ 90 m 
2 h 
> 90 m - ≤ 150 m 
3 h 
> 150 m - ≤ 210 m  
4 h 
> 210 m - ≤ 300 m  
6 h 
> 300 m - ≤ 420 m  
8 h 
> 420 m - ≤ 600 m  
12 h 
> 600 m - ≤ 1440 m 
 


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16. 
TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS 
Include a column on the TOC to indicate if the TFL is a Shire standard or non-standard TFL. 
Table 
Title 
Shire 
Std 
Interim 
14.1.1 
Disposition by Treatment Group (Enrolled Set) 
Y 
Y 
14.1.2 
Protocol Deviations by Treatment Group (Randomized Set) 
Y 
Y 
14.1.4.1 
Demographic and Baseline Characteristics by Treatment Period and 
Treatment Group (Randomized Set) 
Y 
Y 
14.1.4.2.1 
Baseline Characteristics by Treatment Group – SDTP (Randmized Set) 
Y 
N 
14.1.4.2.2 
Baseline Characteristics by Treatment Group – MDTP (Randmized 
Set) 
Y 
Y 
14.1.4.3.1 
Ocular Medical History by System Organ Class, Preferred Term and 
Treatment Group (Randomized Set) 
Y 
Y 
14.1.4.3.2 
Non-Ocular Medical History by System Organ Class, Preferred Term 
and Treatment Group (Randomized Set) 
Y 
Y 
14.1.4.4.1 
Ocular Prior Medications by Treatment Group (Safety set) 
Y 
Y 
14.1.4.4.2 
Non-Ocular Prior Medications by Treatment Group (Safety set) 
Y 
Y 
14.1.4.5.1 
Ocular Concomitant Medications by Treatment Group (Safety set) 
Y 
Y 
14.1.4.5.2 
Non-Ocular Concomitant Medications by Treatment Group (Safety set) Y 
Y 
14.1.5 
Investigational Product Exposure by Treatment Group (Safety set) 
Y 
Y 
14.2.3.1.1 
Summary 
of 
Plasma 
Concentrations 
(Unit) 
of 
SHP639 
(Pharmacokinetic Set) 
Y 
N 
14.2.3.1.2 
Summary of Plasma Pharmacokinetic Parameters of SHP639 – SDTP 
(Pharmacokinetic Set) 
Y 
N 
14.2.3.1.3 
Summary of Plasma Pharmacokinetic Parameters of SHP639 – MDTP 
(Pharmacokinetic Set) 
Y 
N 
14.2.3.1.4 
Dose Proportionality Analysis of SHP639 on Day 1 (Pharmacokinetic 
Set) 
Y 
N 
14.2.3.1.5 
Dose Proportionality Analysis of SHP639 on Day 27 (Pharmacokinetic 
Set) 
Y 
N 


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Table 
Title 
Shire 
Std 
Interim 
14.2.3.1.6 
Statistical Analysis of Accumulation of SHP639  (Pharmacokinetic 
Set) 
Y 
N 
14.2.3.2.1 
Summary of Absolute IOP, IOP Reduction from Baseline, and 
Percentage of IOP Reduction from Baseline by Treatment 
(Pharmacodynamic Set) 
Y 
N 
14.2.3.2.2 
Summary of Pharmacodynamic Parameters of Percentage of IOP 
Reduction from Baseline (Pharmacodynamic Set) 
Y 
N 
14.3.1.1.1 
Overall Treatment-emergent Adverse Events (TEAEs) by Treatment 
Group – SDTP Dosing Period (Safety set) 
N 
N 
14.3.1.1.2 
Overall Treatment-emergent Adverse Events (TEAEs) by Treatment 
Group – SDTP Dosing/Washout Period (Safety set) 
N 
N 
14.3.1.1.3 
Overall Treatment-emergent Adverse Events (TEAEs) by Treatment 
Group – MDTP (Safety set) 
N 
Y 
14.3.1.2.1 
Ocular Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group – SDTP Dosing Period (Safety 
set) 
Y 
N 
14.3.1.2.2 
Ocular Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group – SDTP Dosing/Washout Period 
(Safety set) 
Y 
N 
14.3.1.2.3 
Nonocular Treatment-emergent Adverse Events by System Organ 
Class, Preferred Term and Treatment Group – SDTP Dosing Period 
(Safety set) 
Y 
N 
14.3.1.2.4 
Nonocular Treatment-emergent Adverse Events by System Organ 
Class, Preferred Term and Treatment Group – SDTP Dosing/Washout 
Period (Safety set) 
Y 
N 
14.3.1.2.5 
Ocular Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group – MDTP (Safety set) 
Y 
Y 
14.3.1.2.6 
Nonocular Treatment-emergent Adverse Events by System Organ 
Class, Preferred Term and Treatment Group – MDTP (Safety set) 
Y 
Y 


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Table 
Title 
Shire 
Std 
Interim 
14.3.2.1.1 
Ocular Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group – SDTP 
Dosing Period (Safety set) 
Y 
N 
14.3.2.1.2 
Ocular Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group – SDTP 
Dosing/Washout Period (Safety set) 
Y 
N 
14.3.2.1.3 
Nonocular Treatment-emergent Adverse Events by Maximum 
Severity, System Organ Class, Preferred Term and Treatment Group – 
SDTP Dosing Period (Safety set) 
Y 
N 
14.3.2.1.4 
Nonocular Treatment-emergent Adverse Events by Maximum 
Severity, System Organ Class, Preferred Term and Treatment Group – 
SDTP Dosing/Washout Period (Safety set) 
Y 
N 
14.3.2.1.5 
Ocular Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group – MDTP 
(Safety set) 
Y 
Y 
14.3.2.1.6 
Nonocular Treatment-emergent Adverse Events by Maximum 
Severity, System Organ Class, Preferred Term and Treatment Group – 
MDTP (Safety set) 
Y 
Y 
14.3.2.2.1 
Ocular Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group – SDTP Dosing Period (Safety set) 
Y 
N 
14.3.2.2.2 
Ocular Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group – SDTP Dosing/Washout Period (Safety set) 
Y 
N 
14.3.2.2.3 
Nonocular Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group – SDTP Dosing Period (Safety set) 
Y 
N 
14.3.2.2.4 
Nonocular Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group – SDTP Dosing/Washout Period (Safety set) 
Y 
N 


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Table 
Title 
Shire 
Std 
Interim 
14.3.2.2.5 
Ocular Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group – MDTP (Safety set) 
Y 
N 
14.3.2.2.6 
Nonocular Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group – MDTP (Safety set) 
Y 
N 
14.3.3.1.1 
Ocular Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class and Preferred Term and Treatment Group – SDTP 
Dosing Period (Safety set) 
Y 
N 
14.3.3.1.2 
Ocular Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class and Preferred Term and Treatment Group – SDTP 
Dosing/Washout Period (Safety set) 
Y 
N 
14.3.3.1.3 
Nonocular Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class and Preferred Term and Treatment Group – SDTP 
Dosing Period (Safety set) 
Y 
N 
14.3.3.1.4 
Nonocular Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class and Preferred Term and Treatment Group – SDTP 
Dosing/Washout Period (Safety set) 
Y 
N 
14.3.3.1.5 
Ocular Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class and Preferred Term and Treatment Group – 
MDTP (Safety set) 
Y 
N 
14.3.3.1.6 
Nonocular Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class and Preferred Term and Treatment Group – 
MDTP  (Safety set) 
Y 
N 
14.3.3.2.1 
Ocular Treatment-Emergent Adverse Events Leading to Withdrawal by 
System Organ Class and Preferred Term and Treatment Group – SDTP 
Dosing Period (Safety set) 
Y 
N 
14.3.3.2.2 
Ocular Treatment-Emergent Adverse Events Leading to Withdrawal by 
System Organ Class and Preferred Term and Treatment Group – SDTP 
Dosing/Washout Period (Safety set) 
Y 
N 


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Table 
Title 
Shire 
Std 
Interim 
14.3.3.2.3 
Nonocular 
Treatment-Emergent 
Adverse 
Events 
Leading 
to 
Withdrawal by System Organ Class and Preferred Term and Treatment 
Group – SDTP Dosing Period (Safety set) 
Y 
N 
14.3.3.2.4 
Nonocular 
Treatment-Emergent 
Adverse 
Events 
Leading 
to 
Withdrawal by System Organ Class and Preferred Term and Treatment 
Group – SDTP Dosing/Washout Period (Safety set) 
Y 
N 
14.3.3.2.5 
Ocular Treatment-Emergent Adverse Events Leading to Withdrawal by 
System Organ Class and Preferred Term and Treatment Group – 
MDTP (Safety set) 
Y 
N 
14.3.3.2.6 
Nonocular 
Treatment-Emergent 
Adverse 
Events 
Leading 
to 
Withdrawal by System Organ Class and Preferred Term and Treatment 
Group – MDTP (Safety set) 
Y 
N 
14.3.3.4.1 
Ocular Treatment-Emergent Serious Adverse Events by System Organ 
Class and Preferred Term and Treatment Group – SDTP Dosing Period 
(Safety set) 
Y 
N 
14.3.3.4.2 
Ocular Treatment-Emergent Serious Adverse Events by System Organ 
Class and Preferred Term and Treatment Group – SDTP 
Dosing/Washout Period (Safety set) 
Y 
N 
14.3.3.4.3 
Nonocular Treatment-Emergent Serious Adverse Events by System 
Organ Class and Preferred Term and Treatment Group – SDTP Dosing 
Period (Safety set) 
Y 
N 
14.3.3.4.4 
Nonocular Treatment-Emergent Serious Adverse Events by System 
Organ Class and Preferred Term and Treatment Group – SDTP 
Dosing/Washout Period (Safety set) 
Y 
N 
14.3.3.4.5 
Ocular Treatment-Emergent Serious Adverse Events by System Organ 
Class and Preferred Term and Treatment Group – MDTP (Safety set) 
Y 
N 
14.3.3.4.6 
Nonocular Treatment-Emergent Serious Adverse Events by System 
Organ Class and Preferred Term and Treatment Group – MDTP 
(Safety set) 
Y 
N 
14.3.4.1.1 
Quantitative Clinical Laboratory Results by Visit and Treatment Group 
during SDTP Period: Hematology (Safety set) 
Y 
N 


Shire  
                                                       CONFIDENTIAL 
Page 68 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Table 
Title 
Shire 
Std 
Interim 
14.3.4.1.2 
Quantitative Clinical Laboratory Results by Visit and Treatment Group 
during MDTP Period: Hematology (Safety set) 
Y 
Y 
14.3.4.1.3 
Quantitative Clinical Laboratory Results by Visit and Treatment Group 
during SDTP Period:  Biochemistry (Safety set) 
Y 
N 
14.3.4.1.4 
Quantitative Clinical Laboratory Results by Visit and Treatment Group 
during MDTP Period:  Biochemistry (Safety set) 
Y 
Y 
14.3.4.1.5 
Qualitative Clinical Laboratory Results by Visit and Treatment Group 
during SDTP Period: Urinalysis (Safety set) 
Y 
N 
14.3.4.1.6 
Qualitative Clinical Laboratory Results by Visit and Treatment Group 
during MDTP Period: Urinalysis (Safety set) 
Y 
Y 
14.3.4.2.1 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in SDTP Period: Hematology (Safety set) 
Y 
N 
14.3.4.2.2 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in MDTP Period: Hematology (Safety set) 
Y 
Y 
14.3.4.2.3 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in SDTP Period: Biochemistry (Safety set) 
Y 
N 
14.3.4.2.4 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in MDTP Period: Biochemistry (Safety set) 
Y 
Y 
14.3.4.2.5 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in SDTP Period: Urinalysis (Safety set) 
Y 
N 
14.3.4.2.6 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in MDTP Period: Urinalysis (Safety set) 
Y 
Y 
14.3.5.1.1 
Actual Values and Change from Baseline in Vital Signs by Visit and 
by Treatment Group – SDTP (Safety set) 
Y 
N 
14.3.5.1.2 
Actual Values and Change from Baseline in Vital Signs by Visit and 
by Treatment Group – MDTP (Safety set) 
Y 
Y 
14.3.5.2.1 
Potentially Clinically Important (PCI) Vital Signs Results by 
Treatment Group – SDTP (Safety set) 
Y 
N 


Shire  
                                                       CONFIDENTIAL 
Page 69 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Table 
Title 
Shire 
Std 
Interim 
14.3.5.2.2 
Potentially Clinically Important (PCI) Vital Signs Results by 
Treatment Group – MDTP (Safety set) 
Y 
N 
14.3.6.1.1 
Actual Values and Change from Baseline in ECG by Visit and 
Treatment Group - SDTP (Safety set) 
Y 
N 
14.3.6.1.2 
Actual Values and Change from Baseline in ECG by Visit and 
Treatment Group - MDTP (Safety set) 
Y 
Y 
14.3.6.2.1 
ECG Interpretation by Visit and Treatment Group – SDTP (Safety set) 
Y 
N 
14.3.6.2.2 
ECG Interpretation by Visit and Treatment Group – MDTP (Safety set) Y 
Y 
14.3.6.3.1 
Potentially Clinically Important (PCI) ECG Results by Treatment 
Group - SDTP (Safety set) 
Y 
N 
14.3.6.3.2 
Potentially Clinically Important (PCI) ECG Results by Treatment 
Group – MDTP (Safety set) 
Y 
Y 
14.3.7.1.1 
Drop comfort Assessment Results by Treatment Group – SDTP (Safety 
set) 
N 
N 
14.3.7.1.2 
Drop comfort Assessment Results by Treatment Group – MDTP 
(Safety set) 
N 
Y 
14.3.7.2.1 
Actual Values and Change from Baseline in Best-Corrected Visual 
Acuity (BCVA) by Visit and Treatment Group – SDTP (Safety set) 
N 
N 
14.3.7.2.2 
Actual Values and Change from Baseline in Best-Corrected Visual 
Acuity (BCVA) by Visit and Treatment Group – MDTP (Safety set) 
N 
Y 
14.3.7.2.3 
BCVA Categorical Change from Baseline by Visit and Treatment 
Group – SDTP (Safety set) 
N 
N 
14.3.7.2.4 
BCVA Categorical Change from Baseline by Visit and Treatment 
Group – MDTP (Safety set) 
N 
Y 
14.3.7.3.1 
Slit Lamp Biomicroscopy Findings by Visit and Treatment Group – 
SDTP (Safety set) 
N 
N 


Shire  
                                                       CONFIDENTIAL 
Page 70 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Table 
Title 
Shire 
Std 
Interim 
14.3.7.3.2 
Slit Lamp Biomicroscopy Findings by Visit and Treatment Group – 
MDTP (Safety set) 
N 
Y 
14.3.7.3.3 
Slit Lamp Examination Interpretation by Visit and Treatment Group – 
SDTP (Safety set) 
N 
N 
14.3.7.3.4 
Slit Lamp Examination Interpretation by Visit and Treatment Group – 
MDTP (Safety set) 
N 
Y 
14.3.7.4.1 
Conjunctival Redness Results by Visit and Treatment Group – SDTP 
(Safety set) 
N 
N 
14.3.7.4.2 
Conjunctival Redness Results by Visit and Treatment Group – MDTP 
(Safety set) 
N 
Y 
14.3.7.4.3 
Conjunctival Redness Interpretation by Visit and Treatment Group - 
SDTP (Safety set) 
N 
N 
14.3.7.4.4 
Conjunctival Redness Interpretation by Visit and Treatment Group - 
MDTP (Safety set) 
N 
Y 
14.3.7.4.5 
Conjunctival Redness Categorical Change from Baseline by Visit and 
Treatment Group - SDTP  (Safety set) 
 
N 
Y 
14.3.7.4.6 
Conjunctival Redness Categorical Change from Baseline by Visit and 
Treatment Group - MDTP  (Safety set) 
 
N 
Y 
14.3.7.5.1 
Corneal Haze Results by Visit and Treatment Group – SDTP (Safety 
set) 
N 
N 
14.3.7.5.2 
Corneal Haze Results by Visit and Treatment Group – MDTP (Safety 
set) 
N 
Y 
14.3.7.5.3 
Corneal Haze Assessment Interpretation by Visit and Treatment Group 
– SDTP (Safety set) 
N 
N 
14.3.7.5.4 
Corneal Haze Assessment Interpretation by Visit and Treatment Group 
– MDTP (Safety set) 
N 
Y 


Shire  
                                                       CONFIDENTIAL 
Page 71 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Table 
Title 
Shire 
Std 
Interim 
14.3.7.6.1 
Actual Values and Change from Baseline in Corneal Epithelial 
Integrity Total Scores by Visit and Treatment Group – SDTP (Safety 
set) 
N 
N 
14.3.7.6.2 
Actual Values and Change from Baseline in Corneal Epithelial 
Integrity Total Scores by Visit and Treatment Group – MDTP (Safety 
set) 
N 
Y 
14.3.7.6.3 
Corneal Epithelium Integrity (Fluorescein Staining) Interpretation by 
Visit and Treatment Group - SDTP (Safety set) 
N 
N 
14.3.7.6.4 
Corneal Epithelium Integrity (Fluorescein Staining) Interpretation by 
Visit and Treatment Group - MDTP (Safety set) 
N 
Y 
14.3.7.7.1 
Anterior Chamber Cell and Flare Results by Visit and Treatment 
Group – SDTP (Safety set) 
N 
N 
14.3.7.7.2 
Anterior Chamber Cell and Flare Results by Visit and Treatment 
Group – MDTP (Safety set) 
N 
Y 
14.3.7.7.3 
Anterior Chamber Cell and Flare Interpretation by Visit and Treatment 
Group – SDTP (Safety set) 
N 
N 
14.3.7.7.4 
Anterior Chamber Cell and Flare Interpretation by Visit and Treatment 
Group – MDTP (Safety set) 
N 
N 
14.3.7.8.1 
Lens Opacification Results by Visit and Treatment Group – SDTP 
(Safety set) 
N 
N 
14.3.7.8.2 
Lens Opacification Results by Visit and Treatment Group – MDTP 
(Safety set) 
N 
Y 
14.3.7.8.3 
Lens Opacification Interpretation by Visit and Treatment Group – 
SDTP (Safety set) 
N 
N 
14.3.7.8.4 
Lens Opacification Interpretation by Visit and Treatment Group – 
MDTP (Safety set) 
N 
Y 
14.3.7.9.1 
Actual Values and Change from Baseline in Intraocular Pressure 
(mmHg) by Treatment Group – SDTP (Safety set) 
N 
N 


Shire  
                                                       CONFIDENTIAL 
Page 72 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Table 
Title 
Shire 
Std 
Interim 
14.3.7.9.2 
Actual Values and Percentage Change from Baseline in Intraocular 
Pressure (mmHg) by Treatment Group – SDTP (Safety set) 
N 
N 
14.3.7.9.3 
Actual Values and Change from Baseline in Diurnal (Schedule 1) 
Intraocular Pressure (mmHg) by Treatment Group – SDTP (Safety set) 
N 
N 
14.3.7.9.4 
Actual Values and Percentage Change from Baseline in Diurnal 
(Schedule 1) Intraocular Pressure (mmHg) by Treatment Group – 
SDTP (Safety set) 
N 
N 
14.3.7.9.5 
Actual Values and Change from Baseline in Diurnal (Schedule 2) 
Intraocular Pressure (mmHg) by Treatment Group – SDTP (Safety set) 
N 
N 
14.3.7.9.6 
Actual Values and Percentage Change from Baseline in Diurnal 
(Schedule 2) Intraocular Pressure (mmHg) by Treatment Group – 
SDTP (Safety set) 
N 
N 
14.3.7.9.7 
Actual Values and Change from Baseline in Intraocular Pressure 
(mmHg) by Treatment Group – MDTP (Safety set) 
N 
Y 
14.3.7.9.8 
Actual Values and Percentage Change from Baseline in Intraocular 
Pressure (mmHg) by Treatment Group – MDTP (Safety set) 
N 
Y 
14.3.7.9.9 
Actual Values and Change from Baseline in Diurnal (Schedule 1) 
Intraocular Pressure (mmHg) by Treatment Group – MDTP (Safety 
set) 
N 
Y 
14.3.7.9.10 Actual Values and Percentage Change from Baseline in Diurnal 
(Schedule 1) Intraocular Pressure (mmHg) by Treatment Group – 
MDTP (Safety set) 
N 
Y 
14.3.7.9.11 Actual Values and Change from Baseline in Diurnal (Schedule 2) 
Intraocular Pressure (mmHg) by Treatment Group – MDTP (Safety 
set) 
N 
Y 
14.3.7.9.12 Actual Values and Percentage Change from Baseline in Diurnal 
(Schedule 2) Intraocular Pressure (mmHg) by Treatment Group – 
MDTP (Safety set) 
N 
Y 
14.3.7.10.1 Posterior Segment Examination Results by Visit and Treatment Group 
– SDTP (Safety set) 
N 
N 


Shire  
                                                       CONFIDENTIAL 
Page 73 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Table 
Title 
Shire 
Std 
Interim 
14.3.7.10.2 Posterior Segment Examination Results by Visit and Treatment Group 
– MDTP (Safety set) 
N 
Y 
14.3.7.10.3 Actual Values and Change from Baseline Cup to Disc Ratios by Visit 
and Treatment Group – SDTP (Safety set) 
N 
N 
14.3.7.10.4 Actual Values and Change from Baseline Cup to Disc Ratios by Visit 
and Treatment Group – MDTP (Safety set) 
N 
Y 
14.3.7.10.5 Posterior Segment Examination Notch Assessment by Treatment 
Group – SDTP (Safety set) 
N 
N 
14.3.7.10.6 Posterior Segment Examination Notch Assessment by Treatment 
Group – MDTP (Safety set) 
N 
Y 
14.3.7.10.8 Categorical Change in Number of Notches by Treatment Group – 
MDTP (Safety set) 
N 
N 
14.3.7.11.1 Gonioscopy Results by Visit and Treatment Group – SDTP (Safety set) N 
N 
14.3.7.11.2 Gonioscopy Results by Visit and Treatment Group – MDTP (Safety 
set) 
N 
Y 
14.3.7.12.1 Actual Values and Change from Baseline in Noncontact Specular 
Microscopy (cells/mm^2) by Treatment Group – SDTP (Safety set) 
N 
N 
14.3.7.12.2 Actual Values and Change from Baseline in Noncontact Specular 
Microscopy (cells/mm^2) by Treatment Group – MDTP (Safety set) 
N 
Y 
14.3.7.13.1 Actual Values and Change from Baseline in Corneal Pachymetry (um) 
by Treatment Group – SDTP (Safety set) 
N 
N 
14.3.7.13.2 Actual Values and Change from Baseline in Corneal Pachymetry (um) 
by Treatment Group – MDTP (Safety set) 
N 
Y 
14.3.7.13.3 Actual Values and Percentage Change from Baseline in Corneal 
Pachymetry (um) by Treatment Group – MDTP (Safety set) 
N 
Y 
 
Figure 
Title 
Shire 
Std 
Interim 


Shire  
                                                       CONFIDENTIAL 
Page 74 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Figure 
Title 
Shire 
Std 
Interim 
14.2.3.1.1 
Mean (+SD) Plasma Concentrations of SHP639 
versus Time (Linear and  Semilogarithmic Scales) 
(Pharmacokinetic Set) 
Y 
N 
14.2.3.1.2 
Individual Plasma Concentrations of SHP639 
versus 
Time 
by 
Treatment 
(Linear 
and 
Semilogarithmic Scales) (Pharmacokinetic Set) 
Y 
N 
14.2.3.2.1 
Mean (+SD) Absolute IOP versus Time by 
Treatment (Pharmacodynamic Set) 
Y 
N 
14.2.3.2.2 
Mean (+SD) IOP Reduction from Baseline versus 
Time by Treatment (Pharmacodynamic Set) 
Y 
N 
14.2.3.2.3 
Mean (+SD) Percentage of IOP Reduction from 
Baseline 
versus 
Time 
by 
Treatment 
(Pharmacodynamic Set) 
Y 
N 
14.2.3.2.4 
Individual Absolute IOP versus Time by Treatment 
(Pharmacodynamic Set) 
Y 
N 
14.2.3.2.5 
Individual IOP Reduction from Baseline versus 
Time by Treatment (Pharmacodynamic Set) 
Y 
N 
14.2.3.2.6 
Individual Percentage of IOP Reduction from 
Baseline 
 
versus 
Time 
by 
Treatment 
(Pharmacodynamic Set) 
Y 
N 
14.2.3.2.7 
Relationship  of Percentage of IOP Reduction from 
Baseline and Dose of SHP639 (Pharmacodynamic 
Set) 
N 
N 
14.2.3.2.8 
Relationship between Emax of  Percentage of IOP 
Reduction from Baseline and Cmax for SHP639 
(Pharmacokinetic and Pharmacodynamic Set) 
N 
N 
14.3.7.9.13 Line Plots of Mean Intraocular Pressure (mmHg) 
by Treatment Group – SDTP (Safety set) 
N 
N 
14.3.7.9.14 Line Plots of Change from Baseline in Intraocular 
Pressure (mmHg) by Treatment Group – SDTP 
(Safety set) 
N 
N 
14.3.7.9.15 Line Plots of Percentage Change from Baseline in 
Intraocular Pressure (mmHg) by Treatment Group 
– SDTP (Safety set) 
N 
N 
14.3.7.9.16 Line Plots of Mean Intraocular Pressure (mmHg) 
by Treatment Group – MDTP (Safety set) 
N 
Y 
14.3.7.9.17 Line Plots of Change from Baseline in Intraocular 
Pressure (mmHg) by Treatment Group – MDTP 
(Safety set) 
N 
Y 


Shire  
                                                       CONFIDENTIAL 
Page 75 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Figure 
Title 
Shire 
Std 
Interim 
14.3.7.9.18 Line Plots of Percentage Change from Baseline in 
Intraocular Pressure (mmHg) by Treatment Group 
– MDTP (Safety set) 
N 
Y 
14.3.7.9.19 Line Plots of Mean Intraocular Pressure (mmHg) 
for Study Eye by Treatment Group – MDTP 
(Safety set) 
N 
Y 
14.3.7.9.20 Spaghetti Plots of Intraocular Pressure (mmHg) by 
Treatment Group – SDTP (Safety set) 
N 
N 
14.3.7.9.21 Spaghetti Plots of Intraocular Pressure (mmHg) by 
Treatment Group – MDTP (Safety set) 
N 
Y 
 
 
Listing 
Title 
Shire 
Std 
Interim 
16.2.1.1.1 Subject Disposition (Enrolled Set) 
Y 
Y 
16.2.1.1.2 Screen Failure Subject Disposition (Enrolled Set) 
Y 
Y 
16.2.2.2 
Protocol Deviations (Randomized Set) 
Y 
Y 
16.2.4.1 
Subject Demographics (Randomized Set) 
Y 
Y 
16.2.4.3 
Medical History (Randomized Set) 
Y 
Y 
16.2.4.4.1 Prior Medications (Safety set) 
Y 
Y 
16.2.4.4.2 Concomitant Medications (Safety set) 
Y 
Y 
16.2.5.2.1 Treatment Exposure (Safety set) 
N 
Y 
16.2.5.2.2 Treatment Exposure – Subjects Who Received Unrefrigerated Drug 
Only (Safety set) 
N 
Y 
16.2.5.3.1 Individual Plasma Concentrations (unit) of SHP639 (Safety set) 
Y 
N 
16.2.5.3.2 Individual Plasma Pharmacokinetic Parameters of SHP639  
(Pharmacokinetic Set) 
Y 
N 
16.2.5.3.3 Listing of Absolute IOP, IOP Reduction from Baseline, and Percentage 
of IOP Reduction from Baseline  (Safety set) 
Y 
N 


Shire  
                                                       CONFIDENTIAL 
Page 76 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Listing 
Title 
Shire 
Std 
Interim 
16.2.5.3.4 Listing of Pharmacodynamic Parameters of Percentage of IOP 
Reduction from Baseline (Pharmacodynamic Set) 
Y 
N 
16.2.6.1 
Drop Comfort Assessment Results (Safety set) 
N 
Y 
16.2.6.2 
Manifest Refraction Results (Safety set) 
N 
Y 
16.2.6.3 
Best Corrected Visual Acuity (BCVA) Results (Safety set) 
N 
Y 
16.2.6.4 
Slit Lamp Biomicroscopy Results (Safety set) 
N 
Y 
16.2.6.5 
Clinically Significant Slit Lamp Biomicroscopy Results (Safety set) 
N 
Y 
16.2.6.6 
Conjunctival Redness Score Assessment Results and Interpretation 
(Safety set) 
N 
Y 
16.2.6.7 
Corneal Haze Score Assessment Results and Interpretation (Safety set) 
N 
Y 
16.2.6.8 
Corneal Epithelium Integrity Results and Interpretation (Safety set) 
N 
Y 
16.2.6.9 
Anterior Chamber Cell and Flare Results and Interpretation (Safety 
set) 
N 
Y 
16.2.6.10 
Lens Opacification Results and Interpretation (Safety set) 
N 
Y 
16.2.6.11 
Intraocular Pressure Results and Interpreation (Safety set) 
N 
Y 
16.2.6.12 
Posterior Segment Examination Results and Interpretation (Safety set) 
N 
Y 
16.2.6.13 
Gonioscopy Results and Interpretation (Safety set) 
N 
Y 
16.2.6.14 
Noncontact Specular Microscopy Results and Interpretation (Safety 
set) 
N 
Y 
16.2.6.15 
Corneal Pachymetry Results and Interpreation (Safety set) 
N 
Y 
16.2.7.1 
Adverse Events (Safety set) 
Y 
Y 
16.2.7.2 
Serious Adverse Events (SAE) (Safety set) 
Y 
Y 
16.2.7.3 
Adverse Events Leading to Withdrawal (Safety set) 
Y 
Y 
16.2.7.5 
Adverse Events Leading to Death (Safety set) 
Y 
Y 


Shire  
                                                       CONFIDENTIAL 
Page 77 of 77 
Statistical Analysis Plan v1.5 
Protocol Number: SHP639-101 
[30 AUG 2018] 
 
 
Listing 
Title 
Shire 
Std 
Interim 
16.2.8.1.2 Clinical Laboratory Test Results (Safety set) 
Y 
Y 
16.2.8.1.3 Subjects with Potentially Clinically Important Laboratory Test Results 
(Safety set) 
Y 
Y 
16.2.8.1.4 Listing of Antidrug Antibody Results (Safety set) 
N 
N 
16.2.8.2.1 Vital Signs (Safety set) 
Y 
Y 
16.2.8.2.2 Subjects with Potentially Clinically Important Vital Signs (Safety set) 
Y 
Y 
16.2.8.3.1 Lead ECG Results and Interpretation by Central Reader (Safety set) 
Y 
Y 
16.2.8.3.2 Subjects with Potentially Clinically Important ECG Results (Safety 
set) 
Y 
Y