Clinical trial NCT03452033
Conditions: Glaucoma, Open-Angle
Keywords: glaucoma
Sponsor: Allysta Pharmaceutical
Start date: 2018-03-15; Completion date: 2018-08-15
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will evaluate the safety, tolerability, and preliminary efficacy of three concentrations of H-1337 and vehicle administered twice daily in a parallel group, double-masked design for 28 days of dosing in patients with elevated intraocular pressure (IOP).

Detailed description:
Study ALY337-201 will be a double-masked, randomized, placebo-controlled, dose-response study assessing the safety and ocular hypotensive efficacy of H-1337 ophthalmic solution in subjects with ocular hypertension (OHT) or open angle glaucoma.

During screening, subjects who meet the preliminary inclusion/exclusion criteria will discontinue use of their ocular hypotensive therapy during the washout period. The washout duration will be dependent on the subject's pre-study ocular hypotensive therapy. Starting on Day 0, those who continue to meet the inclusions/exclusion criteria and the diurnal IOP criteria will be randomized into one of the treatments arms and dosing will be initiated, continuing for 28 days.

Arms: arm 1: H-1337 Placebo arm 2: H-1337 \[1\] arm 3: H-1337 \[2\] arm 4: H-1337 \[3\]
Interventions: intervention 1: H-1337 Placebo intervention 2: H-1337 [1] intervention 3: H-1337 [2] intervention 4: H-1337 [3]
Intervention descriptions: intervention 1: H-1337 Placebo Vehicle intervention 2: H-1337 Ophthalmic Solution Concentration 1 intervention 3: H-1337 Ophthalmic Solution Concentration 2 intervention 4: H-1337 Ophthalmic Solution Concentration 3

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Phase 1/2a Randomized, Double-masked, Placebo Controlled, Dose-ranging Study of the 
Safety and Efficacy of H-1337 in Subjects with Primary Open Angle Glaucoma (POAG) or 
Ocular Hypertension 
 
Protocol Number: 
ALY337-201 
Investigational Drug Product: 
H-1337  
IND Number: 
107,895 
Development Phase: 
Phase 2a 
Medical Monitor: 
William C. Stewart, MD 
 
Telephone: (843) 327-0316 
 
 
 
 
 
            
Sponsor Contact: 
Henry Hsu, MD 
Allysta Pharmaceuticals, Inc. 
19 Davis Drive, Suite 102 
Belmont, CA, 94002 
Telephone: (650) 515-8258 
 
Date of Protocol: 
January 8, 2018 
Version: 
1.0 
 
 
 
 
 
Confidentiality Statement 
 
The information contained herein is confidential and proprietary.  It is intended for the use of Allysta 
Pharmaceuticals, Inc’s, clinical investigators, institutional review committees and others directly involved in this 
clinical investigation.  No published information presented in this document may be reproduced or referred to in 
publications or public presentations without the expressed written consent of Allysta Pharmaceuticals, Inc.
NCT03452033


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Clinical Trial Protocol: ALY337-201 
 
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CONFIDENTIAL 
 
 
 
PROTOCOL APPROVAL SIGNATURE PAGE 
 
Protocol Number: ALY337-201 
 
Protocol Title: 
A Phase 1/2a Randomized, Double-masked, Placebo-controlled, Dose-ranging Study of the 
Safety and Efficacy of H-1337 in Subjects with Primary Open Angle Glaucoma (POAG) or 
Ocular Hypertension 
 
No party involved in the conduct of this study will modify this protocol without obtaining 
Allysta Pharmaceutical’s written agreement.  Any modification will require appropriate written 
confirmation and any protocol amendment must follow written policies as stated in this protocol.  
This trial will be conducted in accordance with current United States (US) Food and Drug 
Administration (FDA) regulations, International Conference on Harmonization (ICH) guidelines, 
Good Clinical Practice (GCP) standards, the Declaration of Helsinki, and local ethical and legal 
requirements. 
 
Allysta Pharmaceuticals, Inc. Approval: 
 
 
Signature: 
 
 
Date: 
 
Name: 
Henry Hsu, MD 
Chief Executive Officer 
Allysta Pharmaceuticals, Inc. 
 
 
 
 
 


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Clinical Trial Protocol: ALY337-201 
 
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CONFIDENTIAL 
 
INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
Protocol Number: ALY337-201 
 
Protocol Title: 
A Phase 1/2a Randomized, Double-masked, Placebo-controlled, Dose-ranging Study of the 
Safety and Efficacy of H-1337 in Subjects with Primary Open Angle Glaucoma (POAG) or 
Ocular Hypertension 
 
By signing below, the investigator agrees to adhere to the protocol as outlined and agrees that 
any changes to the protocol must be approved by Allysta Pharmaceuticals, Inc., prior to seeking 
approval from the Institutional Review Board/Ethics Committee. 
The investigator also agrees to conduct the study in accordance with current United States (US) 
Food and Drug Administration (FDA) regulations, International Conference on Harmonization 
(ICH) guidelines, Good Clinical Practice (GCP) standards, the Declaration of Helsinki, and local 
ethical and legal requirements. 
 
Investigator’s Signature:  __________________________________________ 
 
 
Printed Name:  ___________________________________________________ 
 
 
Name of Institution: ________________________________________________ 
 
 
Date:  ___________________________________________________________ 
 
 
 
 


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Clinical Trial Protocol: ALY337-201 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ............................................................................................1 
TABLE OF CONTENTS ...........................................................................................................4 
PROTOCOL SYNOPSIS ..........................................................................................................6 
SCHEDULE OF STUDY ASSESSMENTS AND PROCEDURES .......................................12 
LIST OF ABBREVIATIONS ..................................................................................................14 
1 
BACKGROUND ...................................................................................................17 
1.1 
Investigational Agent .......................................................................................18 
1.2 
Preclinical Data ................................................................................................19 
1.3 
Risk/Benefits ....................................................................................................20 
1.4 
Dose Rationale .................................................................................................20 
1.5 
Trial Conduct ...................................................................................................20 
1.6 
Population ........................................................................................................20 
2 
STUDY OBJECTIVES ..........................................................................................21 
3 
STUDY DESIGN...................................................................................................22 
3.1 
Study Design ....................................................................................................22 
3.2 
Randomization .................................................................................................22 
3.3 
Maintenance of Randomization Codes ............................................................22 
3.4 
Trial Treatment ................................................................................................23 
3.5 
Duration ...........................................................................................................23 
3.6 
Drug Packaging and Labeling ..........................................................................24 
3.7 
Drug Accountability and Storage .....................................................................25 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS .........................................26 
4.1 
Inclusion Criteria .............................................................................................26 
4.2 
Exclusion Criteria ............................................................................................27 
4.3 
Subject Withdrawal and/or Discontinuation ....................................................29 
4.4 
Medication .......................................................................................................30 
4.5 
Monitoring for Subject Compliance ................................................................31 
4.6 
Lifestyle Guidance ...........................................................................................31 
5 
STUDY VISIT PROCEDURES ............................................................................32 
5.1 
Study Visits ......................................................................................................39 
5.1.1 
Screening..............................................................................................39 
5.1.2 
Day 0/Baseline .....................................................................................39 
5.1.3 
Days 1 and 4.........................................................................................40 
5.1.4 
Days 14 and 28.....................................................................................40 
6 
ASSESSMENT OF EFFICACY ...........................................................................41 
6.1 
Efficacy Parameters .........................................................................................41 
6.2 
Method and Timing..........................................................................................41 


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7 
ASSESSMENT OF SAFETY ................................................................................42 
7.1 
Adverse Event Reporting .................................................................................42 
7.2 
Definition of Adverse Event ............................................................................42 
7.3 
Abnormal Test Findings ..................................................................................43 
7.4 
Definitions of Non-Serious Adverse Events ....................................................44 
7.5 
Definition of Serious Adverse Event ...............................................................44 
7.6 
Hospitalization .................................................................................................44 
7.7 
Pregnancy .........................................................................................................45 
7.8 
Definition of Unexpected Adverse Events ......................................................45 
7.9 
Definition of Relationship of Adverse Event to IP ..........................................45 
7.10 
Documentation of Severity of Adverse Events to IP .......................................46 
7.11 
Reporting Serious Adverse Events ..................................................................47 
7.12 
Serious Adverse Event Follow-Up ..................................................................47 
8 
STATISTICAL PLAN ...........................................................................................48 
8.1 
Sample Size ......................................................................................................48 
8.2 
Statistical Methods ...........................................................................................48 
8.3 
Subject Population(s) for Analysis ..................................................................48 
8.4 
Significance......................................................................................................49 
8.5 
Accountability Procedure .................................................................................49 
8.6 
Deviation Reporting .........................................................................................49 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION..........................50 
10 
DATA REVIEW AND ANALYSIS .....................................................................51 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................52 
12 
ETHICAL CONSIDERATIONS ...........................................................................53 
12.1 
Informed Consent.............................................................................................53 
12.2 
Institutional Review Board/Ethics Committee ................................................53 
12.3 
Confidentiality .................................................................................................53 
12.4 
Early Sponsor Discontinuation of the Trial .....................................................53 
13 
DATA HANDLING AND RECORD KEEPING .................................................54 
14 
REFERENCES ......................................................................................................55 
 


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Clinical Trial Protocol: ALY337-201 
 
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PROTOCOL SYNOPSIS 
Protocol Number: 
ALY337-201 
Title: 
A Phase 1/2a Randomized, Double-masked, Placebo-
controlled, Dose-ranging Study of the Safety and Efficacy of 
H-1337 in Subjects with Primary Open Angle Glaucoma 
(POAG) or Ocular Hypertension 
Study Objectives: 
Primary Objective:  
• Evaluate the local ocular and systemic safety of three 
concentrations of H-1337 in subjects with POAG or ocular 
hypertension treated daily for up to 28 days  
Secondary Objectives: 
• Evaluate the ocular hypotensive efficacy of H-1337  
• Evaluate the systemic pharmacokinetics of H-1337  
Study Design: 
The study will evaluate the safety, tolerability, and preliminary 
efficacy of three concentrations of H-1337 and vehicle 
administered twice daily (BID) in a parallel group, double-
masked design for 28 days of dosing.  Approximately 75-100 
subjects will be enrolled.  The study will include the following 
cohorts: 
  
H-1337 0.06% (n=20) 
H-1337 0.2% (n = 20) 
H-1337 0.6% (n = 20) 
Control (Vehicle) (n = 20) 
 
Dosing will be BID unilaterally in the study eye for the first 3 
days, then BID OU from Day 4 to Day 28.   
 
Efficacy assessments will be based upon the study eye.  The 
study eye will be the eye that meets the entry intraocular 
pressure (IOP) criteria after washout.  Should both eyes meet 
the criteria then the study eye will be defined as the eye with 
the higher 8 am IOP on Baseline (Day 0).  If both eyes have the 
same 8 am IOP on Baseline (Day 0), the study eye will be the 
right eye. 
 
Randomization will be stratified by Baseline IOP (23 to 26 
mmHg and > 26 to 32 mmHg at 8 am).  H-1337 and its vehicle 
will be packaged in identical bottles.   


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Eligibility Criteria: 
Inclusion criteria: 
1. 18 years of age or older. 
2. Diagnosis of bilateral primary open angle glaucoma or 
ocular hypertension.  
3. One qualifying IOP criteria after washout: 
• Baseline (Day 0) at T0 (T0 = 8 am ± 30 min) IOP ≥ 23 
mmHg in the study eye. 
4. IOP criteria after washout ≤ 32 mmHg OU at all time 
points. 
5. Best-corrected visual acuity (BCVA) in both eyes of 20/200 
or better on Snellen, equivalent to + 1.0 log Mar.  
6. Able and willing to sign informed consent, follow study 
instructions and complete all study visits. 
7. As applicable, must be willing to discontinue the use of all 
ocular hypotensive medication(s) in both eyes prior to 
receiving the study medication and for the entire course of 
the study. 
8. Able to self-administer or have a caretaker administer study 
eye drops. 
 
Exclusion criteria: 
Investigator will exclude any subject who in their medical 
opinion they consider unsafe for participation in this study or 
does not consider they can complete the requirement of the 
protocol for any reason. 
 
Ophthalmic: 
Exclude subjects with: 
1. Closed or very narrow angles (Grade 0-1) (see Section 5, 
gonioscopy) or those the investigator judges as occludable 
and/or with evidence of peripheral anterior synechiae 
(PAS) ≥ 180 degrees by gonioscopy within 6 months prior 
to Screening Visit in either eye.  (Patent laser iridotomy 
with Grade 1-2 angles is acceptable in either eye, providing 
the PAS criteria are still met). 
2. Previous glaucoma intraocular surgery in either eye.  Prior 
laser trabeculoplasty (ALT or SLT) in either eye is allowed 
if performed more than 6 months prior to Screening Visit. 
3. Any non-glaucoma intraocular surgery within 3 months 
prior to Screening Visit in either eye. 
4. Intraocular laser surgery such as laser capsulotomy, laser 
iridotomy, and/or retinal laser within 1 month prior to 
Screening Visit in either eye. 
5. Significant media opacity in either eye that would impede 
adequate posterior segment examination. 
6. Contraindications to pupil dilation in either eye. 
7. Other forms of glaucoma such as primary congenital, 


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juvenile onset, chronic angle closure, and secondary 
glaucoma of any type including steroid-induced, 
inflammation-induced, or exfoliation glaucoma in either 
eye. Pigment dispersion syndrome/glaucoma is permitted in 
either eye. 
8. Clinically significant corneal dystrophy, epithelial or 
endothelial disease, corneal irregularities or scarring that, in 
the investigator’s judgment, would impede an accurate 
measurement of IOP or visualization of intraocular 
anatomy in the study eye.  
9. History of refractive surgery in either eye (i.e., radial 
keratotomy, PRK, LASIK).  
10. History of corneal cross-linking procedure in either eye. 
11. Unwillingness to be contact lens free during study 
participation.  
12. Any history of uveitis, keratitis, or scleritis in either eye. 
13. Any history of penetrating ocular trauma in either eye. 
14. History within 3 months prior to Screening Visit of 
clinically significant moderate or severe chronic or active 
blepharitis, ocular dermatitis, or recent ocular conjunctivitis 
and/or ocular inflammation in either eye.  Mild blepharitis, 
hyperemia (due to prostaglandin use) and/or blepharitis, 
and/or mild inactive seasonal allergic conjunctivitis and 
non-infective dermatitis are acceptable. 
15. Corneal thickness < 480 or > 620 µm in the study eye.  
Pachymetry measurement within 6 months prior to 
Screening Visit is acceptable.  
16. Advanced or severe glaucoma with progressive visual field 
loss and/or optic nerve changes in either eye that, in the 
investigator’s best judgment, prevent safe withdrawal from 
treatment for the time periods required in this protocol. 
17. Progressive retinal (including, but not limited to worsening 
dry AMD, presence of active wet AMD, or unstable 
diabetic retinopathy) or optic nerve disease in either eye 
from any cause other than glaucoma. 
18. Any prior intravitreal steroid injection in either eye. 
19. Sub-tenon’s, sub-conjunctival or periocular steroid 
injections within the 6 months prior to Screening Visit in 
either eye. 
20. Any use of ocular topical corticosteroids in either eye 
within 7 days, or chronic (as determined by the 
investigator) topical steroids within 28 days prior to 
Baseline and ensuing trial participation. 
21. Known hypersensitivity to any component of the H-1337 
formulation, including BAK, or to topical anesthetics or 
diagnostic drops used during the study. 


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Clinical Trial Protocol: ALY337-201 
 
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22. Any ocular, condition that, in the investigator’s judgment, 
could prevent the subject from safe participation the study. 
23. Planned ocular surgery or intraocular injection procedure in 
either eye during study participation. 
 
General/Systemic: 
Exclude subjects with: 
24. Participation in a clinical study with use of any 
investigational drug or treatment within 30 days prior to 
Baseline (Day 0). 
25. Clinically significant abnormalities in: laboratory tests, 
physical examination, vital signs and/or ECG at Screening 
Visit. If in the investigator’s judgment a subject with 
clinically significant abnormalities is appropriate for 
enrollment in the study, a discussion between the 
investigator and the Medical Monitor must occur and be 
documented prior to enrollment of this subject in the study. 
26. Clinically significant systemic, psychiatric or psychological 
disease (for example, renal, hepatic, uncontrolled diabetes, 
uncontrolled blood pressure, autoimmune disorders, 
psychiatric disorders, endocrine disorders, or any other 
disorders) or dependency which, in the investigator’s 
judgment, would be unsafe and interfere with interpretation 
of the study results or the subject’s ability to comply with 
the study requirements. 
27. Anticipated changes or initiation of medications which 
might affect IOP and/or systemic blood pressure within 7 
days prior to Baseline/Day 0 (e.g., oral anti-hypertensives 
such as sympathomimetic agents, beta-adrenergic blocking 
agents, alpha agonists, alpha adrenergic blocking agents, 
calcium channel blockers, angiotensin converting enzyme 
inhibitors; [diuretics are allowed]), and 2 months prior to 
Baseline/Day 0 for corticosteroids (i.e., oral, nasal, topical 
[dermal, mucosal], and/or inhaled corticosteroids).  If there 
are no further anticipated changes in medications that could 
affect IOP and/or systemic blood pressure, then once the 
subject is stable on their new dose of medication for the 
required time period, the subject may complete the Baseline 
Visit, assuming that all other screening requirements are 
met.  Medications used on an adjustable or sliding scale 
based on testing results are allowed. 
28. Known history of Hepatitis B + C, HIV+, or AIDS and/or 
inadequate venous access.  
29. Women of childbearing potential who are pregnant, 
nursing, planning a pregnancy, or not using a medically 
acceptable form of birth control.  An adult woman is 


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considered to be of childbearing potential unless she is one 
year post-menopausal or three months post-surgical 
sterilization. All females of childbearing potential must 
have a negative serum pregnancy test result at Screening 
Visit and a negative urine and serum pregnancy test at 
Baseline (Day 0) prior to randomization in the study and 
must not intend to become pregnant during the study. 
30. History of drug or alcohol abuse within the last 5 years. 
31. Related to site study staff and/or site employees. 
 
Number of Subjects: 
Approximately 75 – 100 subjects will be enrolled 
Number of Sites: 
Approximately 4-8 US sites 
Duration of Study: 
Screening Visit:  1 day 
Washout Period:  up to approximately 6 weeks (+ 1 week) 
depending on pre-study ocular hypotensive 
therapy and subject/site availability 
Treatment Period:  28 days   
Study Assessments: 
The following study assessments and procedures will be 
performed: 
• Medical and ophthalmic history (including prior and 
concomitant medications) 
• Adverse events 
• IP Compliance 
• Heart rate and blood pressure 
• ECG  
• Physical examination 
• Best-corrected visual acuity (ETDRS) 
• Biomicroscopy  
• Pupillary Diameter 
• Conjunctival hyperemia grading 
• Intraocular pressure (Goldmann tonometry) 
• Pachymetry  
• Gonioscopy  
• Visual field testing (automated, threshold)  
• Ophthalmoscopy (dilated)  
• Blood collection for pharmacokinetic assessments (at 
selected sites) 
• Clinical laboratories (hematology, clinical chemistry, 
pregnancy (if applicable), and urinalysis [UA]) 
Statistical 
Considerations: 
Safety:  
Adverse events: With 20 subjects per group there is a 95% 
certainty that an event that is not observed would have a true 
incidence rate of no more than 15%. 
 


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Hyperemia:  Scored on a 5-point scale from 0 to 3 (including 
0.5).  Assume the SD is 20% of the scale range or 1 unit.  Then, 
with n = 20/group there is 86% power to detect a mean 
difference of 1 unit between pairs of groups (2 group two-sided 
t-test, alpha=0.05).  If a response is defined as a hyperemia 
score ≥ 3 and the response rate in the control group is 10%, 
then with n = 20/group there is 85% power to detect a 
difference in response rates of 46% (Fisher’s exact test). 
 
In general, with 20 subjects per group there is 86% power to 
detect an effect size of 1.0. 
 
Null hypothesis:  The sample size is driven by interest in the 
IOP lowering effect of H-1337.  The study is designed to test 
whether one or more concentrations of H-1337 are superior to 
the vehicle control in the reduction of IOP.  With n = 20/group 
this stage is powered at 94% to detect a difference in IOP 
reduction of 4.0 mmHg between groups against a standard 
deviation of 3.5 mmHg (2-sided t-test, alpha=0.05). 
 
The primary efficacy measure will be the mean change in IOP 
from Baseline (Day 0) IOP (mmHg) for each group on Days 14 
and 28 at each matched time point.  IOP will be measured as 
indicated in the Schedule of Assessments and Procedures 
Table.  
 
Secondary efficacy endpoints will include: (1) the observed 
IOP, mean change and percent change from Baseline IOP at 
each matched time point at each visit and (2) the mean 
observed, mean change from Baseline and mean percent 
change from Baseline for the mean diurnal IOP at each visit, 
and (3) the proportion of subjects reaching a target IOP (< 18 
mmHg) at each time point and with the mean diurnal IOP for 
each visit.  Each concentration will be compared to vehicle and 
the difference in means between treatment arms will be 
presented.   
Investigational Drug 
Product: 
H-1337 (Topical Multi-Kinase Inhibitor), sterile and preserved 
Route of Administration: 
Topical eyedrop 


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SCHEDULE OF STUDY ASSESSMENTS AND PROCEDURES 
Assessments/Procedures1 
Screening 
(-422 to -1 
days) 
Day 0 
Baseline/ 
Randomization 
Day 1 
Day 4 
(± 1 day) 
Day 14 
(± 1 day) 
Day 28 
Exit/ET 
(± 2 days) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Informed Consent 
X 
 
 
 
 
 
Medical and Ophthalmic History  
X 
X 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
IP Administration in Office  
 
X 
Unilateral post T0 
+ 12 hrs IOP 
X 
Unilateral 
post IOP 
X 
OU post 
IOP 
X 
OU post 
T0 and T0 
+ 12 hrs 
IOP 
X 
OU post T0 
IOP 
(final dose) 
Assess IP Compliance 
 
 
 
X 
X 
X 
Heart Rate/Blood Pressure  
(± 30 min) 
X 
X 
Pre-T0 
T0 + 1 hr 
T0 + 2 hrs 
T0 + 4 hrs 
 
 
 
X 
Pre-T0 
T0 + 1 hr 
T0 + 2 hrs 
T0 + 4 hrs 
ECG 
X 
 
 
 
 
  
Physical Examination  
X 
 
 
 
 
 
Best-corrected Visual Acuity 
(ETDRS)  
X 
X 
Pre-T0 
X 
X 
Pre-T0 
X 
Pre-T0 
X 
Pre-T0 
Biomicroscopy3 
(± 30 min) 
X 
 
X 
T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 
X 
Pre-T0 
X 
Pre-T0 
X 
Pre-T0 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 
Pupillary Diameter 
(± 30 min) 
 
X 
Pre-T0 
 
 
 
 
X 
Pre-T0 
 
Conjunctival Hyperemia Grading  
(± 30 min) 
 
X 
T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 
 
X 
Pre-T0 
 
X 
Pre-T0 
 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 
                                                 
1 When possible, one examiner should conduct all ocular assessments for a subject during a single visit. If possible, 
the same examiner should conduct all ocular assessments for a subject throughout the duration of the study. 
2 +1 week permitted to accommodate scheduling considerations 
3 If any adverse findings are noted after IP administration, the subject should continue to be monitored per the 
investigator’s judgment. 


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Assessments/Procedures1 
Screening 
(-422 to -1 
days) 
Day 0 
Baseline/ 
Randomization 
Day 1 
Day 4 
(± 1 day) 
Day 14 
(± 1 day) 
Day 28 
Exit/ET 
(± 2 days) 
Intraocular Pressure4 
(Goldmann Tonometry) 
(± 30 min) 
X 
 
X 
T0 
T0 + 1 hrs 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs  
X 
T0 
X 
T0 
 
X 
T0 
T0 + 1 hr 
T0 + 2 
hrs 
T0 + 4 
hrs 
T0 + 8 
hrs 
T0 + 12 
hrs 
X 
T0 
T0 + 1 hr 
T0 + 2 hrs 
T0+ 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 
Pachymetry5  
X 
 
 
 
 
 
Gonioscopy6 
X 
 
 
 
 
 
Visual Fields (automated, threshold) 
X7 
 
 
 
 
 
Dilated ophthalmoscopy 
X 
 
 
 
 
X8 
Blood Collection for PK of H-1337 
(± 10 min at 2 & 8 hrs) 
 
X 
 
 
 
 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 8 hrs 
Clinical Laboratories 
(hematology, clinical chemistry, 
pregnancy (if applicable), and 
urinalysis)  
X9 
X10 
 
 
 
X11 
                                                 
4 Timing of IOP measurements for each subject should be consistent throughout the study. 
5 Pachymetry performed at screening will be used for inclusion/exclusion criteria only. Pachymetry within 6 months 
of Screening acceptable unless suspected change. 
6 Gonioscopy within 6 months of Screening acceptable unless suspected change. 
7 Historical VF may be used if within 6 months of screening visit unless suspected change. 
8 After T0 + 12 hrs IOP; may be deferred to following day for scheduling convenience. 
9 At Screening, if applicable, a serum pregnancy test should be performed. 
10 At Baseline, if applicable, a urine and serum pregnancy test should be conducted. Urine pregnancy test (UPT) 
must be negative to proceed to randomization; serum pregnancy test results should be reviewed as soon as available 
to confirm negative UPT result. 
11 On Day 28, if applicable, a urine pregnancy test should be conducted.  
. 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Argon Laser Trabeculoplasty 
ALT 
Alanine Aminotransferase 
AMD 
Age-related Macular Degeneration 
AP 
Alkaline Phosphatase  
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BAK 
Benzalkonium Chloride 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice Daily 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CAI 
Carbonic Anhydrase Inhibitor 
°C 
Degrees Celsius 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
Amax 
Peak Concentration   
CME 
Cystoid Macular Edema 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
ET 
Early Termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice(s) 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transferase 
GLP 
Good Laboratory Practice(s) 
GTP 
Guanosine-5'-Triphosphate 
Hg 
Mercury 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
IC 
Informed Consent Document 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 


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IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IWRS 
Interactive Web Response System 
LASIK 
Laser-Assisted In Situ Keratomileusis 
LDH 
Lactate Dehydrogenase  
LLDPE 
Linear Low Density Polyethylene 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mins 
Minutes 
mL 
Milliliter 
Mm 
Millimeter 
MOA 
Mechanism of Action 
NCS 
Not Clinically Significant 
NHP 
Non-Human Primate 
NZW 
New Zealand White Rabbit 
OD 
Right Eye 
OS 
Left Eye 
OHT 
Ocular Hypertension 
OTC 
Over The Counter 
OU 
Both Eyes 
PK 
Pharmacokinetic 
POAG 
Primary Open Angle Glaucoma 
PP 
Per Protocol 
PRK 
Photorefractive Keratectomy  
PT/PTT 
Prothrombin/Partial Thromboplastin Time 
QAM 
Every Morning 
QPM 
Every Evening 
q 12 hrs 
Every 12 Hours 
RBC 
Red Blood Cell  
RGC 
Retinal Ganglion Cells 
RhoA 
Ras Homolog Gene Family, Member A 
ROCKi 
Rho Kinase Inhibitor 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event  
Ser/Thr 
Serine/threonine 
SLT 
Selective Laser Trabeculoplasty 
SPK 
Superficial Punctate Keratitis 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TM 
Trabecular Meshwork 


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Tmax 
Time to Peak Concentration 
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
US 
United States 
VF 
Visual Fields 
WBC 
White Blood Cell 


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1 
BACKGROUND 
Glaucoma is a slowly progressive optic neuropathy characterized by a loss of retinal ganglion 
cells (RGC) and optic nerve axons resulting in vision loss.  Glaucoma is generally 
asymptomatic until advanced irreversible disease has occurred.  It is estimated that close to 
4 million Americans have glaucoma, 50% of whom are undiagnosed, and approximately 
120,000 individuals are blind from glaucoma (Prevent Blindness America 
www.preventblindness.org; National Eye Health Program/National Institutes of Health 
www.nei.nih.gov).   
Current treatments for glaucoma aim to reduce IOP, which has been shown to slow visual 
field loss in clinical trials (Musch et al., 2011).  Intraocular pressure (IOP) is the only 
modifiable risk factor, and current therapies aim to reduce IOP.  Drug therapies, classified by 
mechanism of action (MOA), include: beta-blockers, prostaglandin analogues, alpha-2 
selective agonists, carbonic anhydrase inhibitors, sympathomimetics, miotics and 
hyperosmotic agents (Vetrugno, et al.,2008).  Prostaglandins are now the most prescribed 
first-line agents to treat glaucoma worldwide and are used as a monotherapy and/or in 
conjunction with beta-blocker class agents (i.e., timolol).  Despite effective IOP lowering 
therapy, 30% of subjects still progress and lose vision and many subjects require multiple 
medications.  
An area of unmet need in glaucoma is for effective agents that act through new mechanisms, 
particularly those that can promote outflow through the trabecular meshwork.  While there 
are many classes of IOP-lowering drugs approved, no class acts to directly increase the 
conventional TM outflow other than pilocarpine.  An IOP-lowering agent that could increase 
conventional TM outflow and be used as monotherapy or in combination with current 
therapies would provide useful additional pharmacologic options for patients with glaucoma 
or ocular hypertension. 
H-1337 is a selective multi-kinase inhibitor, and the proposed mechanism of action of the 
compound is hypothesized to involve inhibition of kinases that play a role in controlling 
intracellular cytoskeletal dynamics and contractility.  While the regulation of intraocular 
pressure by the conventional (trabecular) outflow pathway is complicated, extracellular 
matrix expression and trabecular meshwork cytoskeletal shape and contractility appear to be 
important to control outflow resistance. 
The IC50 values of kinases strongly inhibited by H-1337 include 7 kinases with values less 
than 0.1 µmol/L.  Among the kinases that are potently inhibited by H-1337, LRRK2, PKA 
and PKD1 are kinases that are known to be involved in the modulation of intracellular 
cytoskeletal dynamics.  It has been hypothesized that drugs that modulate the intracellular 
cytoskeleton of cells within the trabecular meshwork may beneficially affect aqueous 
outflow dynamics.  This has been considered the primary mechanism of ROCK inhibitors 
(Rao & Epstein, 2007).  LRRK2 has been shown to affect actin polymerization in vitro and 
there is evidence for an association of LRRK2 with tubulin/actin, thus suggesting that 
cellular morphological changes may be consequences of LRRK2-modulation of cytoskeletal 
dynamics (Meixner, 2011, Gandhi, 2009).  PKA phosphorylates many cytoskeletal proteins, 
including microtubules, intermediate filaments and actin and affects cell morphology and 


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migration through its ability to directly modulate the activity of LIM kinase and cofilin, a 
crucial modulator of actin dynamics (Nadella, 2009).  Studies have also suggested an 
involvement of PKD1 in the regulation of cell shape, motility and adhesion, and 
phosphorylation of downstream substrates by PKD1 leads to altered cofilin activity and actin 
re-organization (Eiseler, et al, 2009).  Finally, while H-1337 is less potent as an inhibitor of 
ROCK I and II, it may achieve concentrations in the aqueous humor following topical 
administration that have a biologic effect (Stamer & Acott, 2012). 
In general, the most frequent adverse event seen with topical administration of rho kinase 
inhibitors is conjunctival hyperemia and H1337 administration is associated with transient 
hyperemia in preclinical studies.  The severity of this finding is variable, depending upon the 
compound, dose, and frequency of administration.  The finding is typically transient and 
resolves with cessation of therapy.  Systemic adverse drug effects are relatively uncommon 
following topical administration, and kinase inhibitors have not generally shown class-related 
adverse effects. 
1.1 
Investigational Agent 
H-1337 is a selective multi-kinase inhibitor.  The Sponsor hypothesizes that inhibition of 
kinases that control intracellular cytoskeletal dynamics at the level of the trabecular 
meshwork and other cells that regulate flow is a mechanism that will improve outflow.  As 
open-angle glaucoma is a disease of decreased trabecular outflow, the Sponsor believes that 
H-1337 beneficially enhance aqueous outflow by modulating the contractile state of TM cells 
to decrease resistance to fluid transport.  
The H-1337 investigational drug product is a preserved, isotonic, sterile ophthalmic solution 
at three concentrations (w/v) (0.06%, 0.2%, and 0.6%), buffered at pH 6.5 (range 6.3 – 6.7).  
Sodium chloride is used to adjust the osmolarity to 280 - 320 mOsm/kg.  The primary drug 
product packaging is a white, sterile low-density polyethylene (LDPE) multi-dose, 5 mL 
bottle.  A sterile LDPE nozzle/dropper insert (with nominal drop volume of 43 mm3) is used 
to dispense the ophthalmic solution.  The container closure system is closed with a sterile 
white high-density polyethylene (HDPE) cap.   
 


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Table 1 
Composition of H-1337 Drug Product 
Component 
Monograph 
Quantity, w/v 
Function 
H-1337 
N/A 
Placebo, 0.06, 
0.20, 0.60% 
Active ingredient 
WFI 
USP 
q.s. to 100% 
Diluent 
Sodium Phosphate, Dibasic, 
Anhydrous 
USP 
0.15 
Buffer 
Sodium Phosphate, Monobasic, 
Monohydrate 
USP 
0.05 
Buffer 
Sodium Chloride 
USP 
0.68-0.75 
Tonicity 
Edetate Disodium, Dihydrate 
USP 
0.10% 
Preservative 
50% Benzalkonium Chloride 
NF 
0.01% 
Preservative 
Sodium Hydroxide 
NF 
as needed 
pH adjustment 
Hydrochloric Acid 
NF 
as needed 
pH adjustment 
The placebo control (vehicle) will consist of the components of the ophthalmic formulation without H-1337.  
 
1.2 
Preclinical Data 
To support the topical ocular administration of H-1337 in humans, a series of nonclinical 
toxicology and safety pharmacology studies with topical and systemic dosing of H-1337 
were conducted.  These studies included GLP 4-week studies in rabbit and monkey using the 
topical/ocular mode of administration which evaluated the potential H-1337 to cause toxicity 
to the eye and surrounding ocular tissues as well as the potential for H-1337 to cause 
systemic toxicity.  To more comprehensively characterize the systemic safety profile of H-
1337 in the event of significant absorption from the ocular into the systemic or non- ocular 
peripheral tissue compartments, a comprehensive series of studies were conducted utilizing 
parenteral or oral routes of administration.  The core battery of safety pharmacology studies 
included a neuropharmacology study and a pulmonary function study in rats as well as a 
cardiovascular study in conscious telemetered monkeys.   
Overall, the concern for potential adverse effects is largely mitigated by the very large safety 
margins between the doses associated with systemic effects in animals and the proposed 
human clinical doses/concentrations to be administered topically. 
The effects defined in nonclinical toxicology and safety pharmacology studies conducted 
with H-1337 following topical ocular administration in the proposed formulation support the 
doses proposed for clinical evaluation.  Given the collective nonclinical data and the low 
systemic levels post topical ocular administration of H-1337, systemic effects are considered 
unlikely following topical ocular administration in humans. 
For complete information on the preclinical studies performed, please see the Investigator’s 
Brochure. 


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1.3 
Risk/Benefits 
H-1337 is a new drug and has not yet been evaluated in humans.  While H-1337 is a new 
drug being tested for the first time in humans, other kinase inhibitors have been associated 
with conjunctival hyperemia and, in some instances, conjunctival hemorrhage.  Transient 
conjunctival hyperemia has been noted in preclinical studies of H-1337.  Additional adverse 
effects could include signs and symptoms associated with ocular irritation. 
The potential benefit to humans will be the IOP-lowering capabilities via a new mechanism 
that affects the trabecular meshwork and conventional outflow system.  Numerous studies, 
both in vitro and in vivo, have been conducted to characterize the systemic and ocular 
toxicology profile of H-1337.  For complete information on the preclinical studies performed, 
please see the Investigator’s Brochure. 
1.4 
Dose Rationale   
Ocular PK data in rabbits and monkeys confirmed that H-1337 exhibits dose-related effects 
and can reduce IOP for upwards of 8-12 hours.  The clinical doses, treatment period 
(28 days), and dosing regimen (BID) that are expected to have an acceptable safety profile 
have been selected based on preclinical toxicology data.  The total daily administered dose of 
H-1337 in human subjects will be approximately 1 mg (or 0.014 mg/kg/day, calculated 
assuming a 70-kg subject) when administered twice daily in both eyes at the maximal 
concentration of 0.6%.  
1.5 
Trial Conduct 
This study will be conducted in accordance with current US FDA regulations, International 
Conference on Harmonization (ICH) guidelines, Good Clinical Practice (GCP) standards, the 
Declaration of Helsinki, and local ethical and legal requirements. 
1.6 
Population 
Study population will include subjects of either sex and of any race/ethnicity over 18 years of 
age with a diagnosis of bilateral primary open-angle glaucoma or ocular hypertension.  


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2 
STUDY OBJECTIVES  
Primary Objective:  
• Evaluate the local ocular and systemic safety of three concentrations of H-1337 in 
subjects with POAG or ocular hypertension treated daily for up to 28 days.  
 
Secondary Objectives: 
• Evaluate the ocular hypotensive efficacy of H-1337.  
• Evaluate the systemic pharmacokinetics of H-1337. 


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3 
STUDY DESIGN 
3.1 
Study Design 
The study will evaluate the safety, tolerability, and preliminary efficacy of 3 concentrations 
of H-1337 and vehicle administered twice daily for 28 days.  Up to 100 subjects, naïve to 
H-1337, will be randomized and dosed for 28 days.  The parallel group, double-masked, 
placebo-controlled study will include the following dosing cohorts: 
• H-1337 0.06% (n=20) 
• H-1337 0.2% (n = 20 
• H-1337 0.6% (n = 20) 
• Control (Vehicle) (n = 20) 
Dosing will be BID unilaterally in the study eye for the first 3 days, then BID OU from Day 
4 to Day 28.   
3.2 
Randomization 
Randomization will be stratified by Baseline IOP (23 to 26 mmHg and > 26 to 32 mmHg at 
8 am).  H-1337 and its vehicle will be packaged in identical bottles.  An interactive web 
response system (IWRS) will be used for randomization.  
3.3 
Maintenance of Randomization Codes 
The study will be double-masked to reduce potential bias in clinical assessments.  Upon 
approval of Allysta Pharmaceuticals, Inc., and prior to initiation of the study, an unmasked 
statistician will generate and maintain the randomization codes which are consistent with the 
study design.  Other study statisticians will be masked to the identity of the treatments until 
all data have been entered into the database and locked.  
In the case of an emergency only, if it is necessary for the investigator (or a treating 
physician) to know the treatment a subject is receiving, site personnel can complete the 
subject treatment breaking code procedure in IWRS.  The mask should be broken only for 
safety purposes and only if knowing the drug allocation will have a direct impact on the 
subject’s immediate medical management.  If at all possible, the Medical Monitor should be 
contacted prior to emergency unmasking: 
William C. Stewart, MD 
william.stewart@prnorb.com 
843-327-0316 
 
If this is not possible and unmasking occurs without prior Medical Monitor approval, the 
Medical Monitor must be notified within 24 hrs.  The circumstances leading to unmasking of 
each subject are to be promptly communicated via telephone and/or in writing to the sponsor 


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(or sponsor’s designee) and the IRB.  Early termination procedures should be conducted for 
any subject for whom the randomization code is broken. 
3.4 
Trial Treatment  
Subjects will receive one of four dosing arms: H-1337 at concentrations of 0.06%, 0.2%, or 
0.6%, or a control vehicle.  IP will be administered BID unilaterally in the study eye for the 
first 3 days, then BID OU from Day 4 to Day 28. 
The IWRS will assign a number to subjects who qualify for randomization.  The first IP 
bottle will be dispensed on Day 0 (Baseline) and the second IP bottle will be dispensed to the 
subject on Day 14.  The third IP bottle will serve as a back-up if the subject needs a 
replacement IP bottle.   
3.5 
Duration 
Each subject’s participation will consist of two phases:  a screening phase (Screening and 
Baseline Visits) where subjects will wash out any current ocular hypotensive therapy and a 
dosing phase, starting on Day 0.  If a subject is not on ocular hypotensive therapy, there is no 
applicable washout period and the Baseline Visit should occur after clearance of clinical 
laboratories.   
A subject could participate in the study for a total of up to approximately 11 weeks.  Subjects 
who meet the applicable inclusion/exclusion criteria at the Screening Visit will discontinue 
use of any current ocular hypotensive therapy during the washout period.  The washout 
duration will be dependent on the subject’s pre-study ocular hypotensive therapy.  The table 
below lists the applicable washout durations for various pre-study ocular hypotensive 
medications.  (Note: This table may not be inclusive of all ocular hypotensive medications.  
The Medical Monitor should be contacted for further information regarding the washout 
period of an ocular hypotensive not included in the table.) If the Investigator assesses an 
acceptable risk, subjects may extend washout up to 49 days to accommodate scheduling. 
Table 2 
Ocular Hypotensive Medication Washout Schedule 
Ocular Hypotensive Generic/Trade Names 
Washout period* (between Screening and 
Baseline Visits) 
Muscarinic agonists (e.g., pilocarpine) and Oral 
or Topical Carbonic Anhydrase Inhibitors 
(CAI) 
≥ 5 days    
Beta-adrenoceptor antagonists 
≥ 6 weeks 
Alpha adrenoceptor agonists 
≥ 5 weeks  
Prostaglandin analogues, Combination Drugs 
(use longest wash-out period of individual 
components) * 
≥ 6 weeks   
*The washout period of longest duration should be used when the subject is taking multiple ocular hypotensive 
medications from more than one class.  Additional +1 week extended washout permitted to accommodate 
scheduling considerations. 


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Following the applicable washout period, the subject will return for applicable 
inclusion/exclusion evaluations on the Baseline Visit (Day 0).  On Day 0, a subject meeting 
all inclusion/exclusion criteria will be randomized to IP.  On Days 0 to 3, only the study eye 
will be dosed and evaluated for safety.  For the remainder of treatment, both eyes will be 
dosed and evaluated for safety.  The study eye is the eye that meets the entry IOP criteria 
after washout.  Should both eyes meet the criteria then the study eye will be defined as the 
eye with the higher 8 am IOP on Baseline (Day 0).  If both eyes have the same 8 am IOP on 
Baseline (Day 0), the study eye will be the right eye. 
Dosing will be initiated in the study eye on Day 0 in the office after the completion of all 
required examinations.  The subject will be dosed for up to 28 days during which time they 
will be monitored for safety, tolerability, and efficacy assessments according to the Schedule 
of Study Assessments and Procedures.  
The duration of participation for subjects in each stage will be as follows:  
Screening Visit: 1 day 
Washout Period: up to 6 weeks (+ 1 week) depending on pre-study ocular hypotensive 
therapy 
Treatment Period: 28 days   
 
3.6 
Drug Packaging and Labeling 
H-1337 and its vehicle will be packaged in a 5 mL low density polyethylene (LDPE) clear 
bottle with a dropper nozzle insert delivering a drop volume of 43 µL.  The bottles will be 
packaged in cartons in a format appropriate for the study; both bottles and cartons will be 
labeled in a format appropriate for the study.  Representative labels are as follows: 
Bottle label: 
 
 
Carton label: 
 


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3.7 
Drug Accountability and Storage 
All IP required for this study will be provided by Allysta Pharmaceuticals, Inc., or its 
designee.  The recipient will acknowledge receipt of IP, indicating shipment content and 
condition.  Damaged supplies may be replaced upon notification to Allysta Pharmaceuticals, 
Inc., or its designee.  Accurate records of all IP dispensed from and returned to the study site 
should be maintained and recorded.  A study monitor will periodically check the supplies of 
IP held at the site to verify accountability of all IP.  All used and unused IP (non-dispensed) 
will be returned to Allysta Pharmaceuticals, Inc., or its designee.  
IP must be kept in a safe storage area with limited access (e.g., in a locked cabinet).  The 
storage area should be temperature monitored.  IP should be stored at controlled refrigerated 
temperatures from 2°C to 8°C and protected from light.  After opening, IP bottles may be 
stored at room temperature, i.e., 15°C to 25°C.  Subjects should be instructed not to leave the 
IP in their car, near a window, or outdoors where it may be exposed to direct sunlight and/or 
heat for a prolonged period.  
The IP must not be used outside the context of this protocol.  Under no circumstances should 
the investigator or site personnel supply IP to other clinical sites, investigators or subjects, or 
allow the IP to be used other than as directed by this protocol without prior authorization 
from Allysta Pharmaceuticals, Inc.  


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects must fulfill all the inclusion and exclusion criteria and the investigator must obtain 
written approval from Allysta Pharmaceuticals, Inc., to confirm any deviation from these 
prior to randomization of the subject. 
4.1 
Inclusion Criteria 
1. 18 years of age or older. 
2. Diagnosis of bilateral primary open angle glaucoma or ocular hypertension.  
3. One qualifying IOP criteria after washout: 
- 
Baseline (Day 0) at T0 (T0 = 8 am ± 30 min) IOP ≥ 23 mmHg in the study eye. 
4. IOP criteria after washout ≤ 32 mmHg OU at all time points. 
5. Best-corrected visual acuity (BCVA) in both eyes of 20/200 or better on Snellen, 
equivalent to + 1.0 log Mar.  
6. Able and willing to sign informed consent, follow study instructions and complete all 
study visits. 
7. As applicable, must be willing to discontinue the use of all ocular hypotensive 
medication(s) in both eyes prior to receiving the study medication and for the entire 
course of the study. 
8. Able to self-administer or have a caretaker administer study eye drops. 


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4.2 
Exclusion Criteria 
Exclusion criteria: 
Investigator will exclude any subject who in their medical opinion they consider unsafe for 
participation in this study or does not consider they can complete the requirement of the 
protocol for any reason. 
Ophthalmic: 
Exclude subjects with: 
1. Closed or very narrow angles (Grade 0-1) (see Section 5, gonioscopy) or those the 
investigator judges as occludable and/or with evidence of peripheral anterior synechiae 
(PAS) ≥ 180 degrees by gonioscopy within 6 months prior to Screening Visit in either 
eye.  (Patent laser iridotomy with Grade 1-2 angles is acceptable in either eye, providing 
the PAS criteria are still met). 
2. Previous glaucoma intraocular surgery in either eye.  Prior laser trabeculoplasty (ALT or 
SLT) in either eye is allowed if performed more than 6 months prior to Screening Visit. 
3. Any non-glaucoma intraocular surgery within 3 months prior to Screening Visit in either 
eye. 
4. Intraocular laser surgery such as laser capsulotomy, laser iridotomy, and/or retinal laser 
within 1 month prior to Screening Visit in either eye. 
5. Significant media opacity in either eye that would impede adequate posterior segment 
examination. 
6. Contraindications to pupil dilation in either eye. 
7. Other forms of glaucoma such as primary congenital, juvenile onset, chronic angle 
closure, and secondary glaucoma of any type including steroid-induced, inflammation-
induced, or exfoliation glaucoma in either eye. Pigment dispersion syndrome/glaucoma is 
permitted in either eye. 
8. Clinically significant corneal dystrophy, epithelial or endothelial disease, corneal 
irregularities or scarring that, in the investigator’s judgment, would impede an accurate 
measurement of IOP or visualization of intraocular anatomy in the study eye.  
9. History of refractive surgery in either eye (i.e., radial keratotomy, PRK, LASIK).  
10. History of corneal cross-linking procedure in either eye. 
11. Unwillingness to be contact lens free during study participation.  
12. Any history of uveitis, keratitis, or scleritis in either eye. 
13. Any history of penetrating ocular trauma in either eye. 
14. History within 3 months prior to Screening Visit of clinically significant moderate or 
severe chronic or active blepharitis, ocular dermatitis, or recent ocular conjunctivitis 
and/or ocular inflammation in either eye.  Mild blepharitis, hyperemia (due to 


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prostaglandin use) and/or blepharitis, and/or mild inactive seasonal allergic conjunctivitis 
and non-infective dermatitis are acceptable. 
15. Corneal thickness < 480 or > 620 µm in the study eye.  Pachymetry measurement within 
6 months prior to Screening Visit is acceptable.  
16. Advanced or severe glaucoma with progressive visual field loss and/or optic nerve 
changes in either eye that, in the investigator’s best judgment, prevent safe withdrawal 
from treatment for the time periods required in this protocol. 
17. Progressive retinal (including, but not limited to worsening dry AMD, presence of active 
wet AMD, or unstable diabetic retinopathy) or optic nerve disease in either eye from any 
cause other than glaucoma. 
18. Any prior intravitreal steroid injection in either eye. 
19. Sub-tenon’s, sub-conjunctival or periocular steroid injections within the 6 months prior to 
Screening Visit in either eye. 
20. Any use of ocular topical corticosteroids in either eye within 7 days, or chronic (as 
determined by the investigator) topical steroids within 28 days prior to Baseline and 
ensuing trial participation. 
21. Known hypersensitivity to any component of the H-1337 formulation, including BAK, or 
to topical anesthetics or diagnostic drops used during the study. 
22. Any ocular, condition that, in the investigator’s judgment, could prevent the subject from 
safe participation the study. 
23. Planned ocular surgery or intraocular injection procedure in either eye during study 
participation. 
 
General/Systemic: 
Exclude subjects with: 
1. Participation in a clinical study with use of any investigational drug or treatment within 
30 days prior to Baseline (Day 0). 
2. Clinically significant abnormalities in: laboratory tests, physical examination, vital signs 
and/or ECG at Screening Visit.  If in the investigator’s judgment a subject with clinically 
significant abnormalities is appropriate for enrollment in the study, a discussion between 
the investigator and the Medical Monitor must occur and be documented prior to 
enrollment of this subject in the study. 
3. Clinically significant systemic, psychiatric or psychological disease (for example, renal, 
hepatic, uncontrolled diabetes, uncontrolled blood pressure, autoimmune disorders, 
psychiatric disorders, endocrine disorders, or any other disorders) or dependency which, 
in the investigator’s judgment, would be unsafe and interfere with interpretation of the 
study results or the subject’s ability to comply with the study requirements. 
4. Anticipated changes or initiation of medications which might affect IOP and/or systemic 
blood pressure within 7 days prior to Baseline/Day 0 (e.g., oral anti-hypertensives such as 


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sympathomimetic agents, beta-adrenergic blocking agents, alpha agonists, alpha 
adrenergic blocking agents, calcium channel blockers, angiotensin converting enzyme 
inhibitors; [diuretics are allowed]), and 2 months prior to Baseline/Day 0 for 
corticosteroids (i.e., oral, nasal, topical [dermal, mucosal], and/or inhaled 
corticosteroids).  If there are no further anticipated changes in medications that could 
affect IOP and/or systemic blood pressure, then once the subject is stable on their new 
dose of medication for the required time period, the subject may complete the Baseline 
Visit, assuming that all other screening requirements are met.  Medications used on an 
adjustable or sliding scale based on testing results are allowed. 
5. Known history of Hepatitis B + C, HIV+, or AIDS and/or inadequate venous access.  
6. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not 
using a medically acceptable form of birth control.  An adult woman is considered to be 
of childbearing potential unless she is one year post-menopausal or three months post-
surgical sterilization.  All females of childbearing potential must have a negative serum 
pregnancy test result at Screening Visit and a negative urine and serum pregnancy test at 
Baseline (Day 0) prior to randomization in the study and must not intend to become 
pregnant during the study. 
7. History of drug or alcohol abuse within the last 5 years. 
8. Related to site study staff and/or site employees. 
 
4.3 
Subject Withdrawal and/or Discontinuation  
Subjects are free to discontinue their participation in the study at any time without prejudice 
to further treatment.  The investigator must withdraw any subject from the study at their 
request.  Subjects should provide the reason for withdrawal and confirm whether they are 
withdrawing consent or withdrawing from IP treatment and will continue to participate in the 
study.  The investigator or Allysta Pharmaceuticals, Inc., may withdraw the subject from IP 
treatment for any reason or if the subject meets any of the following criteria. 
 
• Experiences a serious or intolerable AE that is judged by the investigator to preclude 
further study participation. 
• Develops a clinically significant laboratory or other abnormality that is judged by the 
investigator to be potentially related to IP. 
• Requires a medication that is prohibited by the protocol.  Contact the Medical Monitor to 
discuss exiting a subject due to use of a prohibited medication before exiting the subject. 
• Does not follow the protocol procedures, including noncompliance. 
• Is lost to follow-up; every effort should be made to contact the subject. 
• Administrative reasons, including termination of the trial by the Sponsor, unavailable for 
follow-up procedures. 


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• Experiences glaucomatous progression and/or unacceptable IOP elevation, per the 
discretion of the investigator. 
 
Should a subject’s medical or mental condition change or become unstable during the study, 
such that the ability of the subject to continue in this study becomes compromised or, in the 
investigator’s judgment, their health is jeopardized, or further continuation is unadvisable, 
the subject may be withdrawn from study treatment and/or withdrawn from the study. 
If a subject prematurely withdraws from the study, either at her/his request or at the 
discretion of the investigator or Allysta Pharmaceuticals, Inc. the reason for withdrawal 
should be recorded.  All subjects prematurely discontinuing study dosing, regardless of 
cause, will return within 14 days from their last dose of IP to complete Early Termination 
visit assessments; consult the Medical Monitor to determine which diurnal measurements, if 
any, are required for the ET visit.  Study subjects who withdraw from the study may be 
replaced at the Sponsor’s discretion.  
It is vital to obtain follow-up data for any subject withdrawn due to an AE or abnormal 
laboratory test.  In any case, every effort must be made to undertake safety follow-up 
procedures. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  If every effort is made to contact the subject (including two telephone calls and a 
traceable letter sent to the subject) and these attempts are unsuccessful, the subject is 
considered lost to follow-up. 
4.4 
Medication 
During the washout period from prior IOP-lowering monotherapy, topical carbonic 
anhydrase inhibitors (CAI) (i.e., Dorzolamide (Trusopt®) or Brinzolamide (Azopt®) will be 
permitted, but will not be provided by the Sponsor.  Should a topical CAI be employed 
during the washout period, the applicable washout for CAIs should be implemented and the 
CAI should be discontinued 5 days prior to Baseline (Day 0). 
Current systemic mediations which may influence intraocular pressure should be stable and 
not expected to change over the course of the trial.  Should a subject’s medical condition 
change or become unstable during the study, such that the change in non-ocular medication 
that can or may affect IOP are added or altered (i.e., steroids, systemic beta blockers, etc.), 
the subject’s condition should be reviewed with the Medical Monitor prior to possible 
withdrawal from the study.  If the subject is withdrawn, the subject will continue to be 
followed until he/she returns within 14 days from the last dose of IP to complete the Early 
Termination visit. 
If, during the study, an investigator determines the IOP is inadequately controlled such that 
the safety of the subject is compromised, the PI may withdraw the subject from study 
treatment and institute IOP treatment. 


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4.5 
Monitoring for Subject Compliance 
Subjects or their caretakers will administer study medications according to the IP dosing 
instructions and training provided.  Compliance will be assessed at each visit by asking the 
subject about any missed doses.  If the subject reports missing more than 4 doses since the 
prior visit, the subject will be counseled on IP compliance.  
4.6 
Lifestyle Guidance 
During the study, female subjects of childbearing potential (females who are menarchal) 
must use reliable precautions to prevent pregnancy.  These restrictions should be followed 
throughout the duration of the study and maintained for 30 days after trial completion.  
Acceptable contraceptive methods for females of child-bearing potential: 
• Abstinence 
• Hormonal methods of contraception (including oral and transdermal contraceptives, 
injectable progesterone, progestin sub-dermal implants, progesterone-releasing IUDs) 
• Placement of a copper-containing intrauterine device (IUD) 
• Condom with spermicidal foam/gel/film/cream/suppository 
• Male partner who has had a vasectomy for at least 4 months 
• Tubal ligation 
• Hysterectomy 


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5 
STUDY VISIT PROCEDURES 
All study visit procedures should be conducted in the order listed Section 5.1. 
Informed Consent:  Properly executed informed consent (written and verbal) is to be 
obtained prior to completion of any study-related procedures.  Subjects must review, sign, 
and date the informed consent document and receive a copy.  
Medical and Ophthalmic History:  Relevant and clinically significant medical and 
ophthalmic history must be recorded.  
Concomitant Medications:  All prescription and over-the-counter (OTC) medications and 
nutritional supplements taken during the study and 30 days prior to the Screening Visit will 
be recorded.  Diagnostic eye drops do not need to be recorded.  
Randomization:  Randomization will be accomplished using an Interactive Web Response 
System (IWRS).  Site personnel will receive instruction about IWRS access and use. 
Adverse Events:  Any events occurring after the first dose of IP will be recorded as an 
adverse event.  At each visit, the subject should be asked questions such as, “How are you 
feeling?  How are your eyes feeling today?  Have you had any changes since the last exam?” 
IP Administration and Compliance:  The first dose of study IP will be administered to the 
study eye by study staff after the IOP measurement at T0 + 12 hrs.  At Day 1/Visit 3 the AM 
dose of study IP will be administered to the study eye by study staff after the IOP 
measurement at T0.  Subjects will self-dose unilaterally until the Day 4 visit.  At 
Day 4/Visit 4 the AM dose of study IP will be administered OU by study staff after the IOP 
measurement at T0.  Subjects will self-dose OU for the remainder of the trial except on 
Day 14/Visit 5 (AM and PM doses) and Day 28/Visit 6 (AM dose) when study IP will be 
administered OU by study staff after the related IOP measurements.  Compliance will be 
assessed at applicable visits by asking the subject about any missed doses.  If the subject 
reports missing more than 4 doses since the prior visit, the subject will be counseled on IP 
compliance. 
Heart Rate and Blood Pressure (BP) Measurements:  Both systolic and diastolic blood 
pressure should be recorded.  The same type of device and cuff must be used throughout the 
study on the same subject.  An appropriate cuff size with a bladder encircling at least 80% of 
the upper arm should be used to ensure accurate measurements. 
Blood pressure will be measured using the most ideal conditions as possible given the 
subject’s medical condition and age.  If possible, the same arm should be used throughout the 
study.  Blood pressure should be measured after sitting in a seated position for 5 minutes, 
prior to the collection of blood samples for PK evaluations. 
Heart rate measurements will be measured by radial pulse.  The subject should be in a seated 
and relaxed state.  An automated blood pressure unit may be used to measure the heart rate.   


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Electrocardiogram (ECG): 12-lead ECGs should be performed according to the site’s 
standard procedures.  ECG interpretation must be documented and reviewed by the 
investigator and or another qualified medical doctor for clinically significant findings that 
might affect the subject’s safe participation in this trial. 
Physical Examination:  The following systems should be examined: cardiopulmonary, 
endocrine, gastrointestinal, musculoskeletal, rheumatic, neurologic, psychiatric, 
dermatologic, hepatic, renal, and head, ears, nose, and throat.  Other body systems may be 
deferred at the discretion of the investigator.  Abnormalities should be recorded in the 
medical history. 
Best-Corrected Visual Acuity (ETDRS):  Visual acuity will be performed before 
implementing any procedure that can affect vision (i.e., pupil dilation, tonometry, and 
gonioscopy).  The most current refraction within 6 months prior to the Screening Visit will 
be recorded unless changes in refraction are suspected.  If changes are suspected since the 
most current refraction, refraction should be repeated at the Screening Visit.  The same 
optotype should be used throughout the study for a specific subject, and the right eye should 
be tested first.  Best corrected visual acuity (BCVA) should be recorded using the ETDRS 
chart (or a modified ETDRS chart).  If a change in BCVA is noted, pinhole may be used to 
test for the BCVA, but a formal refraction prior to dilation should be performed during that 
visit and/or on the next visit.  The LogMAR scores will be calculated according to the 
standard scoring methodology. A change of ≥ 10 letters may indicate an adverse event and 
should be investigated further by the investigator and the refraction should be rechecked.  
ETDRS Scoring Methodology:  The best-corrected visual acuity will be measured using an 
ETDRS (Early Treatment Diabetic Retinopathy Study) chart.  The test distance must be at 
the distance specified on the ETDRS chart. 
Position the ETDRS chart at the approximate eye level of an average-height seated subject.  
Mark a spot on the floor (e.g., with tape) that is the appropriate test distance from the ETDRS 
chart.  The test distance for the chart must be kept constant throughout the study. 
The subject should be seated comfortably, directly in front of the chart, so that the eyes 
remain at the appropriate distance as determined by the ETDRS chart.  Testing always begins 
with the right eye, followed by the left eye.  The fellow eye should be occluded.   
Do not point to specific letters on the chart during the test.  Ask the subject to read each letter 
slowly, line by line, left to right, beginning with Line 1 at the top.  Tell the subject that the 
chart has letters only, no numbers.  If the subject reads a number, remind him/her that the 
chart contains no numbers, and request a letter in lieu of the number.  The subject should be 
told that only one chance is given to read each letter, but he/she may change his/her mind 
before moving to the next letter.  Do not allow the subject to proceed to the next letter until 
he/she has given a finite answer.  If the subject is unsure about the identity of the letter, then 
the subject should be encouraged to guess.  The subject should be encouraged to continue 
reading even if making mistakes.  When a subject reaches a level where he/she cannot guess, 
the examiner may stop the test. 


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Each letter read correctly is counted.  The examiner will total each line and the whole column 
(0 if no letters are incorrect) on the data collection form and record in the format specified. 
Slit Lamp Biomicroscopy:  This will be performed by the investigator's usual clinical 
technique.  Biomicroscopy will be performed prior to pupil dilation OU.  Changes and/or 
abnormalities of the anterior segment in the lids, conjunctiva, cornea, anterior segment, and 
lens will be graded.  Iris color will be recorded at screening. Magnification, lighting, and 
examiner should be consistent for each subject throughout the study. Findings will be graded 
according to the following scales: 
LID 
Erythema 
None (0) = 
Normal, without any redness, or less than mild 
Mild (+1) = 
A low grade flushed reddish color 
Moderate (+2) = 
Diffused redness encompassing the entire lid margin 
Severe (+3) = 
Deep diffused reddish color of lid margins and superior or inferior eyelid 
 
Edema 
None (0) = 
Normal, no swelling of the lid tissue, or less than mild 
Mild (+1) = 
Slight diffuse swelling above normal 
Moderate (+2) = 
General swelling 
Severe (+3) = 
Extensive swelling of the eyelid(s), with or without eversion of upper and/or 
lower lids. 
 
CONJUNCTIVA  
Hyperemia 
None (0) =  
Normal: few vessels of bulbar conjunctiva easily observed 
Minimal (+0.5) = 
Trace flush, reddish-pink color of the bulbar conjunctiva1 
Mild (+1) = 
Mild flush – reddish pink of the bulbar conjunctiva 
Moderate (+2) = 
Moderate, bright reddening of the bulbar conjunctiva 
Severe (+3) = 
Deep, severe, bright and diffuse reddening of the bulbar conjunctiva 
 
 
 


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CONJUNCTIVA (continued) 
Edema 
None (0) = 
Normal, no swelling of the conjunctiva or less than mild 
Mild (+1) = 
Slight diffuse or regional swelling of the conjunctiva 
Moderate (+2) = 
General swelling of the conjunctiva 
Severe (+3) = 
Extensive swelling of the conjunctiva 
 
CORNEA 
Edema 
None (0) = 
Transparent and clear or less than mild 
Mild (+1) = 
Dull glassy appearance 
Moderate (+2) = 
Dull glassy appearance of epithelium with large number of vacuoles 
Severe (+3) = 
Epithelial bullae and/or stromal edema, localized or diffuse, with or without 
stromal striae 
 
ANTERIOR CHAMBER 
Cells 
None (0) = 
No cells seen or less than mild 
Mild (+ 1) = 
1-5 cells 
Moderate (+2) = 
6-10 cells 
Severe (+3) = 
11-20 cells 
Hypopyon (+4) = 
> 20 cells, Hypopyon Formation (indicate size of hypopyon) 
 
Flare 
None (0) = 
No Tyndall effect or less than mild 
Mild (+1) = 
Tyndall beam in the anterior chamber has a mild intensity 
Moderate (+2) = 
Tyndall beam in the anterior chamber is of strong intensity 
Severe (+3) = 
Tyndall beam is very intense.  The aqueous has a white, milky appearance 
 
LENS 
Phakic 
Yes/No for each eye 
Aphakic 
Yes/No for each eye 
Pseudophakic 
Yes/No for each eye 
 
Lens Opacity (for phakic only) 
None (0) = 
None present or less than mild 
Mild (+ 1) = 
Subtle  
Moderate (+2) = 
Moderate  
Severe (+3) = 
Dense  
 
Pupillary Diameter:  Measurement of pupil size should occur under normal lighting 
conditions to the nearest 0.5 mm using a millimeter ruler or pupillary gauge while the patient 
fixates on a distant, non-accommodative target. 


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Conjunctival Hyperemia:  Hyperemia will be assessed and recorded separately from 
biomicroscopy through direct visual observation prior to fluorescein instillation and IOP 
measurement.  The hyperemia will be graded on a 0 to 3 scale using the photographic 
reference scale provided by the Sponsor for use in this protocol. 
0 Normal: few vessels of bulbar conjunctiva easily observed 
0.5 Trace flush, reddish-pink color of the bulbar conjunctiva1 
1 Mild flush – Reddish pink of the bulbar conjunctiva 
2 Moderate, Bright reddening of the bulbar conjunctiva 
3 Deep, severe, bright and diffuse reddening of the bulbar conjunctiva 
 
Intraocular Pressure:  All IOP measurements must be measured by Goldmann applanation 
tonometry.  The tonometer calibration should be checked for accuracy within one month 
before screening the first subject for the study.  A Tonometer Calibration Form must be 
completed and filed before the first subject is screened and calibration must be checked 
monthly throughout the study.  Variation within ± 2 mm Hg is acceptable.  The fluorescein 
and anesthetic agents should remain consistent throughout the study.  IOP will be measured 
following slit lamp biomicroscopy. 
Two consecutive IOP measurements should be taken for each IOP time point, with the right 
eye being measured first.  The applanation probe should be withdrawn between 
measurements.  Intraocular pressure will be measured 2 times and the average will be used 
for analysis.  If the two measurements differ by more than 4 mmHg, a third measurement will 
be taken and the median value will be used for analysis.  Mean IOP values should be rounded 
up to the next whole number if the value is equal to or greater than 0.5 mmHg, and rounded 
down if less than 0.5 mmHg (e.g., 24.5 should be rounded to 25, 24.4 should be rounded to 
24).  The same procedure will be repeated on the contralateral eye. 
In order to minimize confounding variables, every effort should be made to measure all IOP 
measurements for each subject by the same examiner using the same tonometer and 
approximately at the same time at all visits. 
Pachymetry:  Pachymetry will be performed OU at the Screening Visit; results obtained 
within the prior 6 months may be used if no change is suspected.  Central corneal thickness 
(central zone) will be measured with a calibrated ultrasound pachymeter in both eyes after 
topical anesthetic has been applied.  Three measurements will be taken, first in the right eye, 
and the average will be recorded in micrometers (μm).  The subject will be in a seated 
position and fixating on a target straight ahead.  The same procedure is then performed on the 
left eye once the measurements have been completed in the right eye.  
Gonioscopy:  The gonioscopy examination will be performed OU at the Screening Visit; 
results obtained within the prior 6 months may be used if no change is suspected.  
Gonioscopy should be performed prior to instillation of dilating or miotic drops, with high 
magnification, and with dim illumination to potentiate visualization of the angle in its natural 
configuration.  The angular width of the angle recess will be graded as an average score 
representative of all 4 quadrants using the grading criteria below.   


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Grade Description (Shaffer System, based on the angular width of the angle recess [Marsh & 
Cantor, 2005]) 
4 45 to 35° angular approach, wide open  
3 35 to 20° angular approach, wide open 
2 20° angular approach, narrow 
1 ≤ 10°angular approach, extremely narrow 
Slit 0° angle, narrowed to slit 
 
Visual Field Examination:  A visual field will be performed OU at the Screening Visit; 
reliable results obtained within the prior 6 months may be used if no change is suspected.  
Visual fields must be automated threshold visual fields (i.e., Humphrey [30-2 or 24-2] or 
Octopus equivalent).  SITA Standard (24-2 or 30-2) is preferred, SITA fast is also allowed.  
The subject’s best correction at 33 cm is to be used.  Visual fields must be reliable, defined as 
those with a) fixation losses less than or equal to 20%, b) false positives less than or equal to 
33% and c) false negatives less than or equal to 33%.  Visual fields are to be performed with 
a non-dilated pupil unless, in the opinion of the investigator, the pupil is so miotic that 
dilation is required (i.e., < 3 mm).  If the visual field examination was conducted using 
dilation at the Screening Visit, dilation should be used for any subsequent visual field 
examinations (i.e., if performed at an unscheduled visit; visual field testing should be 
performed during the trial if glaucomatous progression is suspected).  Visual field 
interpretation must be documented and reviewed by the investigator, including an assessment 
of whether the results are normal or abnormal and the clinical significance of abnormalities.   
Dilated Ophthalmoscopy:  Posterior segment exam will be performed according to the 
investigator’s preferred procedure.  Magnification, lighting, and examiner should be 
consistent for each subject throughout the study.  Ophthalmoscopy should be performed after 
pupil dilation (i.e., 1% tropicamide or cyclopentolate and 2.5% phenylephrine). The 
examination should include an evaluation of the vitreous, retina, macula, choroid, and optic 
nerve (including the absence or presence of notches and/or disc or peripapillary 
hemorrhages).  Abnormalities and pathologic findings will be graded.  Ocular structures will 
be graded according to the following scale.  
Vitreous, Retina, Macula and Choroid: Examination emphasizes the visual axis. 
0 
Normal 
1 
Abnormal, describe. 
 
Optic Nerve 
0 
Normal. No damage 
1 
Mild Optic nerve damage, secondary to glaucoma including any rim loss (sloping or 
thinning) 
2 
Moderate Optic nerve damage, including cupping to disc margin at one or more 
points 
3 
Severe Optic nerve damage, nearly total cupping, only nasal rim or less present 
 


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Any new findings (i.e., notch and/or peripapillary hemorrhage) or deterioration from 
Screening Visit findings will be reported as an adverse event.  The cup/disc ratio will be 
recorded horizontally and vertically for each examination, and reported in 0.1 increments. 
Blood Collection for PK assessment: Will be conducted at selected sites.  See separate blood 
collection manual. 
Frequency 
Day 0 and Day 28. 
 
Time Points 
Pre-dose at Days 0 and 28 and approximately 2 and 8 hours (± 10 min) 
post- AM dose on Day 28  
Analysis 
Plasma analysis for the test article and/or metabolites, if applicable, will be 
conducted.  Some collected samples may not be assayed if the expected 
concentration of test article and/or metabolites, based on initial assay 
results, is below the lower quantitation limit of the assay. 
 
Pharmacokinetic analysis will be conducted and will include (if 
appropriate), but not be limited to, peak concentration (Cmax), time to peak 
concentration (Tmax), and area under the concentration-time curve (AUC). 
Reporting 
Plasma analysis (including principle investigator compliance statements and 
Quality Assurance statements) and pharmacokinetic determination reports 
will be provided for inclusion in the clinical study report. 
 
Clinical Laboratories:  See separate blood collection manual. 
Hematology:  White blood cells (WBC) (neutrophils, eosinophils, basophils, lymphocytes, 
monocytes), red blood cells (RBC), hematocrit, hemoglobin, platelets, MCV, MCH, MCHC, 
RDW   
Clinical Chemistry:  Total protein, albumin, blood urea nitrogen (BUN), total bilirubin, 
creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate 
dehydrogenase (LDH), alkaline phosphatase (AP), gamma-glutamyl transferase (GGT), total 
cholesterol, calcium, sodium, potassium, chloride, glucose, uric acid, triglycerides, direct 
bilirubin, creatine phosphokinase (CPK), and GFR estimate. 
Urinalysis:  Specific gravity, pH, ketones, protein, glucose, bilirubin, urobilinogen, blood, 
leukocyte esterase (urinalysis abnormalities in protein, blood, and leukocyte esterase will 
reflex a microscopic examination including white blood count, red blood count, epithelial 
cells, bacteria, mucus, casts, and crystals). 
Lab results must be reviewed by the investigator or another medical doctor (with 
documentation) to assure the subject’s safety. 
Pregnancy Test: 
Serum pregnancy will be required at the Screening Visit for women of child bearing 
potential.  Urine pregnancy and serum pregnancy tests will be performed in women of child 


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bearing potential at Baseline (Day 0).  Pregnancy test results must be negative for subjects to 
continue in the study.  On Day 28, a urine pregnancy test will be administered. 
5.1 
Study Visits 
Perform study procedures as referenced in the Schedule of Study Assessments and 
Procedures (see protocol synopsis) in the order specified below. 
5.1.1 
Screening 
• Informed consent 
• Medical/ophthalmic and concomitant medication history, with review of 
inclusion/exclusion criteria 
• BCVA 
• Biomicroscopy 
• Goldmann tonometry 
• Gonioscopy 
• Pachymetry 
• Visual field testing 
• Dilated ophthalmoscopy  
• At any time during the visit after informed consent: 
◦ 
Heart rate/blood pressure 
◦ 
ECG 
◦ 
Physical examination 
◦ 
Phlebotomy and urine sample for clinical laboratories 
5.1.2 
Day 0/Baseline 
• Medical/ophthalmic and concomitant medication history, with review of 
inclusion/exclusion criteria 
• BCVA 
• Biomicroscopy at all required timepoints 
• Pupillary diameter 
• Conjunctival hyperemia grading 
• Goldmann tonometry at all required timepoints 


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• Phlebotomy for pK (any time prior to IP dosing) 
• IP administration 
5.1.3 
Days 1 and 4 
• Concomitant medications 
• Adverse events 
• IP compliance (Day 4 only) 
• BCVA 
• Biomicroscopy  
• Conjunctival hyperemia grading (Day 4 only) 
• Goldmann tonometry 
• IP administration 
5.1.4 
Days 14 and 28 
• Phlebotomy and urine sample for clinical laboratories (Day 28 only at any time during 
the visit) 
• Concomitant medications 
• Adverse events 
• IP compliance 
• Heart rate/blood pressure at all required timepoints 
• BCVA 
• Biomicroscopy at all required timepoints  
• Pupillary diameter (Day 28 only) 
• Conjunctival hyperemia grading at all required timepoints 
• Goldmann tonometry 
• Phlebotomy for pK at all required timepoints (Day 28 only) 
• IP administration (Day 14 AM and PM, Day 28 AM only) 
• Dilated ophthalmoscopy after final Goldmann tonometry (Day 28 only) – may be 
performed on following day for scheduling convenience. 


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6 
ASSESSMENT OF EFFICACY 
6.1 
Efficacy Parameters 
Primary Efficacy Endpoints: 
The primary efficacy measure will be the mean change in IOP from Baseline (Day 0) IOP 
(mmHg) for each group on Days 14 and 28 at each matched time point as compared to 
vehicle.  IOP will be measured according to the Schedule of Assessments and Procedures 
Table.   
Secondary efficacy endpoints:  
1. The observed IOP, mean change from Baseline, and % change from Baseline IOP at each 
matched time point at each visit, and  
2. The mean observed, mean change from Baseline and mean % change from Baseline for 
the mean diurnal IOP at each visit, and  
3. The proportion of subjects reaching a target IOP (< 18 mmHg) at each time point and 
with the mean diurnal IOP for each visit.  Each concentration will be compared to vehicle 
and the difference in means between treatment arms will be presented.   
6.2 
Method and Timing 
The efficacy parameter for this study is IOP as measured by Goldman applanation tonometry 
and recorded on the CRF.  The timing of the IOP measurements are based on preclinical IOP 
data that was observed both in NHP and rabbits.  The time points of diurnal IOP 
measurements are based on the expected peak and trough of H-1337 efficacy, the timing and 
frequency of dosing of H-1337 during 24 hours, and the circadian IOP diurnal curve.  


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7 
ASSESSMENT OF SAFETY 
7.1 
Adverse Event Reporting 
The investigator is responsible for monitoring the safety of subjects who have entered the 
study.  Subjects should be asked at each visit about any changes in their health status.  Any 
changes in health status after informed consent has been obtained, but prior to the first dose 
of IP, will be reported as medical history.  AEs will be reported after the subject receives the 
first dose of IP (Day 0).  Ongoing AEs at early termination or study completion (Day 28) will 
be followed until the event resolves, stabilizes, or for 30 days, whichever comes first.  
All adverse events (serious and non-serious) must be documented regardless of the causal 
relationship to the study medication.  The severity, frequency, seriousness, duration, 
relationship to IP(s), treatment of event, action taken with IP, and outcome for every adverse 
event should be documented in the source documents and CRFs. 
Non-clinically significant incremental < 2 grade changes in conjunctival hyperemia 
(according to the photographic reference scale provided for the trial) are not required to be 
reported as adverse events. 
To capture the most potentially relevant safety information during a clinical study, it is 
important that investigators record accurate AE terms on CRFs.  Wherever possible, a 
specific disease or syndrome rather than individual associated signs and symptoms should be 
identified by the investigator and recorded on the CRF.  However, if an observed or reported 
sign or symptom is not considered a component of a specific disease or syndrome by the 
investigator, it should be recorded as a separate AE on the CRF. 
Investigators are required to report to Allysta Pharmaceuticals, Inc. or its representative all 
observed and/or volunteered AEs occurring during the clinical trial (21 CFR §312.64[b]) 
regardless of treatment group or suspected causality to the investigational drug. 
7.2 
Definition of Adverse Event 
An AE is any unfavorable medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have to have a causal 
relationship with this treatment.  An AE can, therefore, be any unfavorable and unintended 
sign, symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product.  All 
AEs, including observed or volunteered problems, complaints, or symptoms, must be 
recorded.  This definition also includes AEs which are reported up to 30 days after a subject 
has completed a clinical study.  Therapeutic failures during clinical trials are not considered 
to be AEs. 
Examples of adverse events include, but are not limited to: 
• Abnormal test finding 
• Clinically significant symptoms and signs 


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• Changes in physical examination findings 
• Hypersensitivity 
• Progression/worsening of underlying disease 
• Change in BCVA > 10 letters  
• Clinically significant change in pachymetry 
 
Additionally, they may include the signs and symptoms resulting from: 
• Drug overdose 
• Drug withdrawal 
• Drug abuse 
• Drug misuse 
• Drug interactions 
• Exposure in utero (i.e., pregnancy within 30 days of study completion) 
 
7.3 
Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 
• Test result is associated with accompanying symptoms 
 and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention 
 and/or 
• Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy 
and/or 
• Test result is considered to be an adverse event by the investigator or Allysta 
Pharmaceuticals, Inc. 
 
Reporting an abnormal test, in absence of any of the above conditions, does not constitute an 
adverse event.  Any abnormal test result that is determined to be an error or is felt to be not 
clinically significant (NCS) by the investigator does not require reporting as an adverse 
event. 


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Abnormal laboratory test results reported to the investigator from the time the subject has 
taken at least one dose of the study treatment through last subject visit should be recorded as 
an adverse event if the above criteria are met. 
7.4 
Definitions of Non-Serious Adverse Events 
Adverse events that do not meet the definitions for serious adverse events (SAEs) are non-
serious AEs.  Subjects should be instructed to report any AE that they experience to the 
investigator.   
7.5 
Definition of Serious Adverse Event 
An SAE is any experience that suggests a significant hazard, contraindication, side effect, or 
precaution.  This includes any experience that: 
• Results in death 
• Is acutely life-threatening 
• Requires in-subject hospitalization or prolongs the existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Requires medical or surgical intervention to prevent one of the outcomes listed above  
 
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 in-subject hospitalization, or the development of drug dependency or drug abuse.  
This definition includes concurrent illness or injuries, exacerbation of pre-existing conditions 
and AEs occurring as a result of drug withdrawal, abuse or overdose.  Serious adverse events 
observed during all periods of a clinical study are to be recorded, including those occurring 
during a period without study medication and whether or not the AE is judged to be related to 
the study medication. 
7.6 
Hospitalization 
Reported adverse events associated with hospitalization or prolonged hospitalizations are 
considered serious.  Any initial admission (even if less than 24 hours) to a healthcare facility 
meets these criteria.  Admission also includes transfer within the hospital to an 
acute/intensive care facility.  
Hospitalization does not include the following: 
• Rehabilitation facility 
• Hospice facility 


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• Respite care (caregiver relief) 
• Skilled nursing facility 
• Nursing homes 
• Routine emergency admission  
• Same day surgeries 
 
Hospitalization or prolongation in the absence of a precipitating, clinical adverse event (e.g., 
for work-up of persistent pre-treatment lab abnormality) is not in itself a serious adverse 
event.  
Diagnostic and therapeutic noninvasive procedures, such as surgery, should not be reported 
as adverse events.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an adverse event.  For example, an acute 
appendicitis that begins during the adverse event reporting period should be reported as an 
adverse event and the resulting surgical intervention should be recorded as a treatment of that 
adverse event.  
7.7 
Pregnancy 
If a subject becomes pregnant during the study or up until 30 days after the last dose of IP, 
the Investigator must notify Allysta Pharmaceuticals, Inc. or its representative immediately 
and within 24 hours of learning of its occurrence by completing a Pregnancy Report Form 
and forwarding to Allysta Pharmaceuticals, Inc. or its representative.  The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications.  Any complications during 
pregnancy should be recorded as an AE and may constitute an SAE if they fulfill any of the 
specified criteria for an SAE.  If upon outcome, the pregnancy meets one of the serious 
criteria (e.g. spontaneous miscarriage, congenital anomaly, or birth defect), it will then be 
considered an SAE and full details will be requested.  These events will not be included in 
the clinical study report, but will be maintained in the clinical study files.   
7.8 
Definition of Unexpected Adverse Events 
An AE is considered an unexpected AE if it is not mentioned in the Investigator’s Brochure 
(IB), or if it is of greater frequency and/or severity than that mentioned in the IB, in the 
judgment of the Medical Monitor. 
7.9 
Definition of Relationship of Adverse Event to IP 
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious).  The investigator must record the relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious AE reporting requirements, if 


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applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to the 
adverse event.  If the investigator does not know whether or not the investigational product 
caused the event, then the event will be handled as “related to investigational product” for 
reporting purposes, as defined by Allysta Pharmaceuticals, Inc.  If the investigator’s causality 
assessment is “unknown but not related to investigational product,” this should be clearly 
documented in study records. 
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable.  The categories are as follows: 
0=Unrelated: 
No temporal association, or the cause of the event has been 
identified, or the drug, biological, or device cannot be implicated. 
 
1=Possibly Related: 
Temporal association, but other etiologies are likely to be the 
cause; however, involvement of the drug, biological, or device 
cannot be excluded. 
 
2=Probably Related: 
Temporal association, other etiologies are possible, but unlikely. 
 
3=Definitely Related: 
Temporal association and no other etiologies possible. 
 
 
7.10 
Documentation of Severity of Adverse Events to IP 
All adverse events will be examined to determine severity.  The categories are as follows: 
Mild: 
Awareness of sign, symptom, or event, but easily tolerated. Does 
not interfere with subject’s usual function.  
 
Moderate: 
Discomfort enough to cause some interference with usual activity 
and may warrant intervention. 
 
Severe: 
Incapacitating with inability to do usual activities or significantly 
affects clinical status, and warrants intervention. 
 
Life-threatening: 
Immediate risk of death. 
 


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7.11 
Reporting Serious Adverse Events 
SAEs (this refers to any AE that meets one or more of the aforementioned serious criteria) 
occurring after the subject receives the first dose of IP (Day 0) will be reported to Allysta 
Pharmaceuticals or its representative, followed until the event resolves or stabilizes, the 
subject’s early termination or study completion (Day 28), or within 30 days of the last 
administration of IP, whichever comes first.   
SAEs, and all deaths occurring within the study population, whether considered to be 
drug-related or not, will be reported on the SAE Report Form within 24 hours of knowledge 
of the occurrence to Allysta Pharmaceuticals, Inc. or its representative.  
This can be done by emailing a completed SAE Report Form to: 
 
Name:  
Ashley Hehr 
Title:   
Drug Safety Specialist Consultant 
Company:  Safety Sphere, LLC (www.safety-sphere.com) 
Email:  
aly337-201sae@safety-sphere.com 
Office Phone: 844-965-1070 
Office Fax: 
855-805-2406 
 
Where the initial report is made verbally or by telephone to Allysta Pharmaceuticals, Inc. or 
the study monitor, the SAE Report Form must be emailed within 24 hours according to the 
instructions above.  
The investigator will be requested to supply detailed information regarding the event at the 
time of the initial contact.  All SAEs (initial and follow-up information) must be reported to 
the reviewing Institutional Review Board/Ethics Committee, according to their reporting 
requirements, and a copy of that report must be forwarded to Allysta Pharmaceuticals, Inc. or 
its representative. Allysta Pharmaceuticals (or designee) will report all Suspected 
Unexpected Serious Adverse Reactions (SUSARs) to Regulatory Authorities within 
7/15 days of receipt depending on reporting requirements. 
7.12 
Serious Adverse Event Follow-Up  
For all SAEs, the investigator must submit follow-up reports to Allysta Pharmaceuticals, Inc., 
regarding the subject’s subsequent course until the SAE has subsided, or until the condition 
stabilizes (in the case of persistent impairment), the subject dies, or within 30 days of the last 
administration of IP, whichever comes first.  
SAEs that come to the attention of the investigator within 30 days following early 
termination or Day 28 will be reported to Allysta Pharmaceuticals, Inc. or its representative 
within 24 hours of knowledge of the occurrence.   


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8 
STATISTICAL PLAN 
8.1 
Sample Size 
The sample size is driven by interest in the IOP lowering effect of H-1337.  The study is 
designed to test whether one or more concentrations of H-1337 are superior to the vehicle 
control in the reduction of IOP.  With n = 20/group this stage is powered at 94% to detect a 
difference in IOP reduction of 4.0 mmHg between groups against a standard deviation of 
3.5 mmHg (2-sided t-test, alpha=0.05). 
Adverse events:  With 20 subjects per group there is a 95% certainty that an event that is not 
observed would have a true incidence rate of no more than 15%. 
Hyperemia:  Scored on a 5-point scale from 0 to 3.  Assume the SD is 20% of the scale range 
or 1 unit.  Then, with n = 20/group there is 86% power to detect a mean difference of 1 unit 
between pairs of groups (2 group two-sided t-test, alpha=0.05).  If a response is defined as a 
hyperemia score ≥ 3 and the response rate in the control group is 10%, then with n = 
20/group there is 85% power to detect a difference in response rates of 46% (Fisher’s exact 
test). 
In general, with 20 subjects per group there is 86% power to detect an effect size of 1.0. 
If a concentration is chosen that is less than the maximum, the safety data from the higher 
doses can be combined to increase power. 
8.2 
Statistical Methods 
Continuous and ordinal measures will be summarized by descriptive statistics (n, mean, 
standard deviation, median, minimum and maximum values).  Qualitative measures will be 
tabulated by counts and percentages.  Selected safety measures may be summarized by the 
use of shift tables.  Summary tables will show the data for each time point (visit and/or time 
of day as appropriate) and will display the observed and change (and for IOP the % change) 
from baseline value. 
A statistical analysis plan will be prepared prior to unmasking the treatment assignments. 
An analysis of results will be conducted when the database for each stage has been locked 
and the treatment assignments have been revealed.  No within-stage interim analyses are 
planned. 
8.3 
Subject Population(s) for Analysis 
Up to approximately 4 to 8 US sites will be active. 
All subjects who receive IP and at least one dose will be evaluable for the safety analysis.  
For efficacy considerations, the primary analysis population will be the intent-to-treat (ITT) 
population.  All subjects who receive study medication and who complete at least one on-
therapy study visit will be evaluable for the ITT analyses.  Subjects who receive study 


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medication, satisfy pre-randomization inclusion/exclusion criteria, and who complete at least 
one on-therapy study visit will be evaluable for a per protocol population analysis.  
Individual subject visits and data points that do not satisfy protocol criteria may be excluded 
from per protocol analyses.  Evaluability will be determined prior to breaking the code for 
masked treatment assignment. 
8.4 
Significance 
For superiority testing, a 2-sided test with a significance level of p ≤ 0.05 will be used.   
8.5 
Accountability Procedure 
It is expected that in this small trial of brief duration, the incidence of missing data will be 
kept to a minimum.  Sites, subjects and Allysta Pharmaceuticals, Inc., or its representative 
will be trained in methods to encourage continued participation to maximize the completion 
rate and overall quality of the trial.  As this is a small Phase 1/2a exploratory trial, there are 
no plans to impute values for missing data.  With regard to the primary efficacy variable, 
IOP, there are steps taken in the procedure for collecting these data that minimize the 
likelihood of spurious data. 
8.6 
Deviation Reporting 
Any deviations from the statistical plan enumerated in the protocol or final statistical plan 
will be described and justified in the clinical study report. 


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9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Study visits will be conducted by an authorized Allysta Pharmaceuticals, Inc., representative 
to inspect study data, subjects’ medical records, and CRFs in accordance with current US 
Good Clinical Practices (GCP) and the respective local, national government and 
international regulations and guidelines. 
The investigator will permit authorized representatives of Allysta Pharmaceuticals, Inc., or its 
representative, the Food and Drug Administration (FDA), and the appropriate health 
authorities to inspect facilities and records relevant to this study. 


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10 
DATA REVIEW AND ANALYSIS 
There will be no formal external Data Monitoring Committee.  The masked data will be 
continually monitored on an ongoing basis, according to the safety plan, as subjects are 
enrolled and complete the study.  During the study, investigators, site personnel, and Allysta 
Pharmaceuticals personnel responsible for the daily conduct of the study will remained 
masked to the results to maintain the scientific rigor and credibility of the trial.  Allysta 
Pharmaceuticals personnel and selected external consultants will be unmasked once data is 
locked.  Data will then be reviewed, the safety and efficacy for each dose determined. 


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11 
QUALITY CONTROL AND QUALITY ASSURANCE 
Each investigator must adhere to the protocol as detailed in this document and agrees that 
any changes to the protocol must be approved by Allysta Pharmaceuticals, Inc., prior to 
seeking approval from the IRB/Ethics Committee.  Each investigator will be responsible for 
enrolling only those subjects who have met protocol eligibility criteria.  During study 
conduct, Allysta Pharmaceuticals and/or its representative will conduct periodic monitoring 
visits to ensure that the protocol and Good Clinical Practices (GCPs) are being followed.  
The monitors may review source documents to confirm that the data recorded on CRFs is 
accurate.  The investigator and institution will allow Allysta Pharmaceuticals, Inc., monitors 
or its agents and appropriate regulatory authorities direct access to source documents and 
CRFs to perform this verification. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 


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12 
ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with current US FDA regulations, International 
Conference on Harmonization (ICH) guidelines, Good Clinical Practice (GCP) standards, the 
Declaration of Helsinki, and local ethical and legal requirements.  The Principal Investigator 
must sign the protocol signature page to indicate acceptance of the protocol. 
12.1 
Informed Consent 
The subject must sign the Informed Consent Document before his or her participation in the 
study.  A copy of the Informed Consent Document must be provided to the subject or the 
subject's legal guardian.  If applicable, it will be provided in a certified translation of the 
subject’s first or native language.  The original signed informed consent document for each 
participating subject shall be filed with records kept by the investigator and must be available 
for verification by study monitors at any time, and a copy will be given to each subject. 
12.2 
Institutional Review Board/Ethics Committee 
This protocol, the informed consent document, relevant supporting information and all types 
of subject recruitment or advertisement information must be submitted to the IRB/Ethics 
Committee for review and must be approved before the study is initiated.  Any amendments 
to the protocol must also be approved by the IRB/Ethics Committee prior to implementing 
changes in the study.  The investigator is responsible for keeping the IRB/Ethics Committee 
apprised of the progress of the study, any SAEs, and any changes made to the protocol 
according to the requirements of the site’s IRB. 
12.3 
Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and 
disclosure to third parties other than those noted below is strictly prohibited. Information 
obtained during the conduct of this study will be used by Allysta Pharmaceuticals, Inc., in 
connection with the development of the IP.  The study investigator is obliged to provide 
Allysta Pharmaceuticals, Inc., or designee with complete test results and all data developed in 
this study.  This information may be disclosed to other physicians who are conducting similar 
studies and to the FDA as deemed necessary by Allysta Pharmaceuticals, Inc.  Subject-
specific information may be provided to other appropriate medical personnel only with the 
subject’s permission. 
12.4 
Early Sponsor Discontinuation of the Trial 
All clinical investigational data will be reviewed by the Medical Monitor on a regular basis.  
Reports of all data will be made available to the appropriate IRB/Ethics Committee and to 
the FDA.  The clinical investigation may be suspended if the Medical Monitor, upon review 
and evaluation of the clinical data, finds the severity or incidence of single or total 
complications unacceptable for continuation of the investigation. 


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13 
DATA HANDLING AND RECORD KEEPING 
The investigator must retain all study records according to ICH guidelines and according to 
the record retention policies of the country where the study is being conducted.  FDA 
requires that records are retained for at least 2 years after a marketing application is approved 
for the drug, or if an application is not approved, until 2 years after FDA has been notified of 
the discontinuation of the investigational use of the drug (21CFR312.57).   


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14 
REFERENCES 
Eiseler T, et al. Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell 
motility through slingshot. Nat Cell Biol 2009; 11(5): 545-556. 
Gandhi PN. Leucine-rich repeat kinase 2 (LRRK2): a key player in the pathogenesis of 
Parkinson's disease. J Neurosci Res 2009; 87(6): 1283-1295. 
Marsch BC, Cantor LB. The Spaeth Gonioscopic Grading System. Glaucoma Today 2005; 
May/June: 22-25. 
Meixner A. A QUICK screen for Lrrk2 interaction partners--leucine-rich repeat kinase 2 is 
involved in actin cytoskeleton dynamics. Mol Cell Proteomics 2011;10(1): M110 001172. 
Musch DC, Gillespie BW, Niziol LM, Lichter PR, Varma R; CIGTS Study Group. 
Intraocular Pressure Control and Long-term Visual Field Loss in the Collaborative Initial 
Glaucoma Treatment Study. Ophthalmology. 2011 Sep;118(9):1766-73. 
Nadella KS. Regulation of actin function by protein kinase A-mediated phosphorylation of 
Limk1. EMBO Rep 2009;10(6): 599-605. 
Rao VP, Epstein DL: Rho GTPase/Rho kinase inhibition as a novel target for the treatment of 
glaucoma. BioDrugs. 2007; 21(3): 167-177 
Stamer WD, Acott TS: Current understanding of conventional outflow dysfunction in 
glaucoma. Curr Opin Ophthalmol 2012; 23(2): 135-143. 
Vetrugno M, Cantatore F, Ruggeri G, Ferreri P, Montepara A, Quinto A, Sborgia C. Primary 
open angle glaucoma: an overview on medical therapy.  Progress in Brain Research.  2008; 
173: 181-93. 
 

SAP_001.pdf: 
ALY337-201 
    Statistical Analysis Plan 
Allysta Pharmaceuticals, Inc. 
CONFIDENTIAL 
6 SEP 2018 
 
Page 1 of 28 
 
STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL TITLE: 
A Phase 1/2a Randomized, Double-masked, Placebo 
Controlled, Dose-ranging Study of the Safety and Efficacy of 
H-1337 in Subjects with Primary Open Angle Glaucoma 
(POAG) or Ocular Hypertension 
PROTOCOL NUMBER: 
ALY337-201 
STUDY DRUG: 
H-1337 
IND NUMBER: 
131440 
DEVELOPMENT PHASE: 
Phase 2a 
 
SPONSOR: 
Allysta Pharmaceuticals, Inc. 
 
19 Davis Drive, Suite 102 
 
Belmont, CA, 94002 
 
DATE: 
September 6, 2018 
 
 
 
 
 
 
Confidentiality Statement 
 
The information contained herein is confidential and proprietary.  It is intended for the use of Allysta 
Pharmaceuticals, Inc’s, clinical investigators, institutional review committees and others directly involved in this 
clinical investigation.  No published information presented in this document may be reproduced or referred to in 
publications or public presentations without the expressed written consent of Allysta Pharmaceuticals, Inc.
 
NCT03452033


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    Statistical Analysis Plan 
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CONFIDENTIAL 
6 SEP 2018 
 
Page 2 of 28 
PREPARED BY: 
 
 
 
06SEP2018 
 
Steve Crockett, PhD 
Biostatistician 
Date 
 
 
 
 
APPROVAL(S): 
 
 
 
 
 
Henry Hsu, MD 
Allysta Pharmaceuticals, Inc. 
Date 
 
 
September 7, 2018
07SEP2018


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Page 9 of 32 
TABLE OF CONTENTS 
 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................4 
1. 
INTRODUCTION ................................................................................ 6 
2. 
STUDY DESCRIPTION ....................................................................... 7 
2.1 
Study Objectives .........................................................................................................7 
2.2 
Study Subjects .............................................................................................................7 
2.3 
Study Design/ Procedures .........................................................................................10 
2.4 
Randomization ..........................................................................................................10 
2.5 
Study Treatments ......................................................................................................10 
2.6 
Duration ....................................................................................................................10 
2.7 
Maintenance of Randomization Codes .....................................................................11 
3. 
STUDY ASSESSMENTS/ENDPOINTS ............................................... 11 
4. 
SAMPLE SIZE AND POWER CONSIDERATIONS .............................. 18 
5. 
ANALYSIS POPULATIONS ............................................................... 18 
6. 
HANDLING OF MISSING DATA ....................................................... 18 
7. 
STATISTICAL ANALYSIS ................................................................. 19 
7.1 
Subject Disposition ...................................................................................................19 
7.2 
Demographic and Baseline Characteristics ..............................................................20 
7.3 
Treatment Compliance and Exposure .......................................................................20 
7.4 
Intraocular pressure ...................................................................................................21 
7.5 
Adverse Events .........................................................................................................22 
7.6 
Concomitant Medications .........................................................................................22 
7.7 
Ocular and Other Medical History ............................................................................22 
7.8 
Clinical Laboratory Assessment ...............................................................................23 
7.9 
Physical examination ................................................................................................23 
7.10 
Vital Signs .................................................................................................................23 
7.11 
Electrocardiogram .....................................................................................................23 
7.12 
Best-Corrected Visual Acuity ...................................................................................23 
7.13 
Ocular Hyperemia, Biomicroscopy, Ophthalmoscopy and Ocular Symptoms ........23 
7.14 
Pupil Diameter ..........................................................................................................23 
7.15 
Pachymetry ...............................................................................................................23 
7.16 
Gonioscopy at Screening Visit ..................................................................................24 
7.17 
Visual field ................................................................................................................24 
8. 
INTERIM ANALYSIS ........................................................................ 24 
9. 
APPENDICES ................................................................................... 25 
9.1 
Appendix 1: Schedule of Study Assessments and Procedures .................................25 
9.2 
Appendix 2. Efficacy Endpoints and Time Points ....................................................27 
 


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Page 9 of 32 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Argon Laser Trabeculoplasty 
ALT 
Alanine Aminotransferase 
Amax 
Peak Concentration   
AMD 
Age-related Macular Degeneration 
ANCOVA 
Analysis of Covariance 
AP 
Alkaline Phosphatase  
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BAK 
Benzalkonium Chloride 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice Daily 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CFB 
Change From Baseline 
CPK 
Creatine Phosphokinase 
ECG 
Electrocardiogram 
ET 
Early Termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transferase 
Hg 
Mercury 
HIV 
Human Immunodeficiency Virus 
Hrs 
Hours 
IC 
Informed Consent Document 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IWRS 
Interactive Web Response System 
LASIK 
Laser-Assisted In Situ Keratomileusis 
LDH 
Lactate Dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
Mm 
Millimeter 
OTC 
Over The Counter 
OU 
Both Eyes 
PAS 
Peripheral Anterior Synechiae 
PK 
Pharmacokinetic 


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POAG 
Primary Open Angle Glaucoma 
PRK 
Photorefractive Keratectomy  
PT 
Preferred Term 
RBC 
Red Blood Cell  
RGC 
Retinal Ganglion Cells 
ROCK 
Rho Kinase  
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SLT 
Selective Laser Trabeculoplasty 
TEAE 
Treatment Emergent Adverse Event 
TM 
Trabecular Meshwork 
Tmax 
Time to Peak Concentration 
US 
United States 
VF 
Visual Fields 
WBC 
White Blood Cell 


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Page 6 of 28 
This is version 1 of the statistical analysis plan (SAP) for study ALY337-201. If revisions are 
needed, the document will be amended. The SAP should be finalized prior to the database lock 
and final unmasking. All deviations from the analyses described in the final SAP will be noted in 
the clinical study report (CSR). 
 
1. 
INTRODUCTION 
Glaucoma is a slowly progressive optic neuropathy characterized by a loss of retinal ganglion 
cells (RGC) and optic nerve axons resulting in vision loss.  Glaucoma is generally asymptomatic 
until advanced irreversible disease has occurred.  It is estimated that close to 4 million 
Americans have glaucoma, 50% of whom are undiagnosed, and approximately 
120,000 individuals are blind from glaucoma.   
Current treatments for glaucoma aim to reduce IOP, which has been shown to slow visual field 
loss in clinical trials.  Intraocular pressure (IOP) is the only modifiable risk factor, and current 
therapies aim to reduce IOP.  Despite effective IOP lowering therapy, 30% of subjects still 
progress and lose vision and many subjects require multiple medications.  
An area of unmet need in glaucoma is for effective agents that act through new mechanisms, 
particularly those that can promote outflow through the trabecular meshwork.  While there are 
many classes of IOP-lowering drugs approved, no class acts to directly increase the conventional 
TM outflow other than pilocarpine.  An IOP-lowering agent that could increase conventional TM 
outflow and be used as monotherapy or in combination with current therapies would provide 
useful additional pharmacologic options for patients with glaucoma or ocular hypertension. 
H-1337 is a selective multi-kinase inhibitor, and the proposed mechanism of action of the 
compound is hypothesized to involve inhibition of kinases that play a role in controlling 
intracellular cytoskeletal dynamics and contractility. 
It has been hypothesized that drugs that modulate the intracellular cytoskeleton of cells within 
the trabecular meshwork may beneficially affect aqueous outflow dynamics.  This has been 
considered the primary mechanism of ROCK inhibitors.  While H-1337 is less potent as an 
inhibitor of ROCK I and II, it may achieve concentrations in the aqueous humor following 
topical administration that have a biologic effect. 
In general, the most frequent adverse event seen with topical administration of rho kinase 
inhibitors is conjunctival hyperemia and H1337 administration is associated with transient 
hyperemia in preclinical studies.  The severity of this finding is variable, depending upon the 
compound, dose, and frequency of administration.  The finding is typically transient and resolves 
with cessation of therapy.  Systemic adverse drug effects are relatively uncommon following 


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topical administration, and kinase inhibitors have not generally shown class-related adverse 
effects. 
2. 
STUDY DESCRIPTION 
2.1 
Study Objectives 
Primary Objective:  
Evaluate the local ocular and systemic safety of three concentrations of H-1337 in subjects 
with POAG or ocular hypertension treated daily for up to 28 days.  
Secondary Objectives: 
Evaluate the ocular hypotensive efficacy of H-1337.  
Evaluate the systemic pharmacokinetics of H-1337. 
2.2 
Study Subjects 
INCLUSION CRITERIA: 
1. 18 years of age or older. 
2. Diagnosis of bilateral primary open angle glaucoma or ocular hypertension.  
3. One qualifying IOP criteria after washout: 
4. Baseline (Day 0) at T0 (T0 = 8 am ± 30 min) IOP ≥ 23 mmHg in the study eye. 
5. IOP criteria after washout ≤ 32 mmHg OU at all time points. 
6. Best-corrected visual acuity (BCVA) in both eyes of 20/200 or better on Snellen, equivalent 
to + 1.0 log Mar.  
7. Able and willing to sign informed consent, follow study instructions and complete all study 
visits. 
8. As applicable, must be willing to discontinue the use of all ocular hypotensive medication(s) 
in both eyes prior to receiving the study medication and for the entire course of the study. 
9. Able to self-administer or have a caretaker administer study eye drops. 
EXCLUSION CRITERIA: 
Ophthalmic: 
Exclude subjects with: 
1. Closed or very narrow angles (Grade 0-1) (see Section 5, gonioscopy) or those the 
investigator judges as occludable and/or with evidence of peripheral anterior synechiae 
(PAS) ≥ 180 degrees by gonioscopy within 6 months prior to Screening Visit in either eye.  
(Patent laser iridotomy with Grade 1-2 angles is acceptable in either eye, providing the PAS 
criteria are still met). 


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2. Previous glaucoma intraocular surgery in either eye.  Prior laser trabeculoplasty (ALT or 
SLT) in either eye is allowed if performed more than 6 months prior to Screening Visit. 
3. Any non-glaucoma intraocular surgery within 3 months prior to Screening Visit in either eye. 
4. Intraocular laser surgery such as laser capsulotomy, laser iridotomy, and/or retinal laser 
within 1 month prior to Screening Visit in either eye. 
5. Significant media opacity in either eye that would impede adequate posterior segment 
examination. 
6. Contraindications to pupil dilation in either eye. 
7. Other forms of glaucoma such as primary congenital, juvenile onset, chronic angle closure, 
and secondary glaucoma of any type including steroid-induced, inflammation-induced, or 
exfoliation glaucoma in either eye. Pigment dispersion syndrome/glaucoma is permitted in 
either eye. 
8. Clinically significant corneal dystrophy, epithelial or endothelial disease, corneal 
irregularities or scarring that, in the investigator’s judgment, would impede an accurate 
measurement of IOP or visualization of intraocular anatomy in the study eye.  
9. History of refractive surgery in either eye (i.e., radial keratotomy, PRK, LASIK).  
10. History of corneal cross-linking procedure in either eye. 
11. Unwillingness to be contact lens free during study participation.  
12. Any history of uveitis, keratitis, or scleritis in either eye. 
13. Any history of penetrating ocular trauma in either eye. 
14. History within 3 months prior to Screening Visit of clinically significant moderate or severe 
chronic or active blepharitis, ocular dermatitis, or recent ocular conjunctivitis and/or ocular 
inflammation in either eye.  Mild blepharitis, hyperemia (due to prostaglandin use) and/or 
blepharitis, and/or mild inactive seasonal allergic conjunctivitis and non-infective dermatitis 
are acceptable. 
15. Corneal thickness < 480 or > 620 µm in the study eye.  Pachymetry measurement within 
6 months prior to Screening Visit is acceptable.  
16. Advanced or severe glaucoma with progressive visual field loss and/or optic nerve changes 
in either eye that, in the investigator’s best judgment, prevent safe withdrawal from treatment 
for the time periods required in this protocol. 
17. Progressive retinal (including, but not limited to worsening dry AMD, presence of active wet 
AMD, or unstable diabetic retinopathy) or optic nerve disease in either eye from any cause 
other than glaucoma. 
18. Any prior intravitreal steroid injection in either eye. 
19. Sub-tenon’s, sub-conjunctival or periocular steroid injections within the 6 months prior to 
Screening Visit in either eye. 


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20. Any use of ocular topical corticosteroids in either eye within 7 days, or chronic (as 
determined by the investigator) topical steroids within 28 days prior to Baseline and ensuing 
trial participation. 
21. Known hypersensitivity to any component of the H-1337 formulation, including BAK, or to 
topical anesthetics or diagnostic drops used during the study. 
22. Any ocular, condition that, in the investigator’s judgment, could prevent the subject from 
safe participation the study. 
23. Planned ocular surgery or intraocular injection procedure in either eye during study 
participation. 
General/Systemic: 
Exclude subjects with: 
1. Participation in a clinical study with use of any investigational drug or treatment within 30 
days prior to Baseline (Day 0). 
2. Clinically significant abnormalities in: laboratory tests, physical examination, vital signs 
and/or ECG at Screening Visit.  If in the investigator’s judgment a subject with clinically 
significant abnormalities is appropriate for enrollment in the study, a discussion between the 
investigator and the Medical Monitor must occur and be documented prior to enrollment of 
this subject in the study. 
3. Clinically significant systemic, psychiatric or psychological disease (for example, renal, 
hepatic, uncontrolled diabetes, uncontrolled blood pressure, autoimmune disorders, 
psychiatric disorders, endocrine disorders, or any other disorders) or dependency which, in 
the investigator’s judgment, would be unsafe and interfere with interpretation of the study 
results or the subject’s ability to comply with the study requirements. 
4. Anticipated changes or initiation of medications which might affect IOP and/or systemic 
blood pressure within 7 days prior to Baseline/Day 0 (e.g., oral anti-hypertensives such as 
sympathomimetic agents, beta-adrenergic blocking agents, alpha agonists, alpha adrenergic 
blocking agents, calcium channel blockers, angiotensin converting enzyme inhibitors; 
[diuretics are allowed]), and 2 months prior to Baseline/Day 0 for corticosteroids (i.e., oral, 
nasal, topical [dermal, mucosal], and/or inhaled corticosteroids).  If there are no further 
anticipated changes in medications that could affect IOP and/or systemic blood pressure, then 
once the subject is stable on their new dose of medication for the required time period, the 
subject may complete the Baseline Visit, assuming that all other screening requirements are 
met.  Medications used on an adjustable or sliding scale based on testing results are allowed. 
5. Known history of Hepatitis B + C, HIV+, or AIDS and/or inadequate venous access.  
6. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not 
using a medically acceptable form of birth control.  An adult woman is considered to be of 
childbearing potential unless she is one year post-menopausal or three months post-surgical 
sterilization.  All females of childbearing potential must have a negative serum pregnancy 
test result at Screening Visit and a negative urine and serum pregnancy test at Baseline (Day 
0) prior to randomization in the study and must not intend to become pregnant during the 
study. 


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7. History of drug or alcohol abuse within the last 5 years. 
8. Related to site study staff and/or site employees. 
 
2.3 
Study Design/ Procedures 
The study will evaluate the safety, tolerability, and preliminary efficacy of 3 concentrations of H-
1337 and vehicle administered twice daily for 28 days.  Up to 100 subjects, naïve to H-1337, will 
be randomized and dosed for 28 days.  The parallel group, double-masked, placebo-controlled 
study will include the following dosing cohorts: 
H-1337 0.06% (n=20) 
H-1337 0.2% (n = 20 
H-1337 0.6% (n = 20) 
Control (Vehicle) (n = 20) 
Dosing will be BID unilaterally in the study eye for the first 3 days, then BID OU from Day 4 to 
Day 28. 
 
2.4 
Randomization 
Randomization will be stratified by Baseline IOP (23 to 26 mmHg and > 26 to 32 mmHg at 
8 am).  H-1337 and its vehicle will be packaged in identical bottles.  An interactive web response 
system (IWRS) will be used for randomization. 
 
2.5 
Study Treatments 
Subjects will receive one of four dosing arms: H-1337 at concentrations of 0.06%, 0.2%, or 
0.6%, or a control vehicle.  IP will be administered BID unilaterally in the study eye for the first 
3 days, then BID OU from Day 4 to Day 28. 
The IWRS will assign a number to subjects who qualify for randomization.  The first IP bottle 
will be dispensed on Day 0 (Baseline) and the second IP bottle will be dispensed to the subject 
on Day 14.  The third IP bottle will serve as a back-up if the subject needs a replacement IP 
bottle. 
 
2.6 
Duration 
Each subject’s participation will consist of two phases:  a screening phase (Screening and 
Baseline Visits) where subjects will wash out any current ocular hypotensive therapy and a 
dosing phase, starting on Day 0.  If a subject is not on ocular hypotensive therapy, there is no 


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applicable washout period and the Baseline Visit should occur after clearance of clinical 
laboratories.   
A subject could participate in the study for a total of up to approximately 11 weeks.  Subjects 
who meet the applicable inclusion/exclusion criteria at the Screening Visit will discontinue use 
of any current ocular hypotensive therapy during the washout period.  The washout duration will 
be dependent on the subject’s pre-study ocular hypotensive therapy.   
 
2.7 
Maintenance of Randomization Codes 
The study will be double-masked to reduce potential bias in clinical assessments.  Upon approval 
of Allysta Pharmaceuticals, Inc., and prior to initiation of the study, an unmasked statistician will 
generate and maintain the randomization codes which are consistent with the study design.  
Other study statisticians will be masked to the identity of the treatments until all data have been 
entered into the database and locked.  
In the case of an emergency only, if it is necessary for the investigator (or a treating physician) to 
know the treatment a subject is receiving, site personnel can complete the subject treatment 
breaking code procedure in IWRS. 
 
3. 
STUDY ASSESSMENTS/ENDPOINTS 
Informed Consent:  Properly executed informed consent (written and verbal) is to be obtained 
prior to completion of any study-related procedures.  Subjects must review, sign, and date the 
informed consent document and receive a copy.  
Medical and Ophthalmic History:  Relevant and clinically significant medical and ophthalmic 
history must be recorded.  
Concomitant Medications:  All prescription and over-the-counter (OTC) medications and 
nutritional supplements taken during the study and 30 days prior to the Screening Visit will be 
recorded.  Diagnostic eye drops do not need to be recorded.  
Randomization:  Randomization will be accomplished using an Interactive Web Response 
System (IWRS).  Site personnel will receive instruction about IWRS access and use. 
Adverse Events:  Any events occurring after the first dose of IP will be recorded as an adverse 
event.  At each visit, the subject should be asked questions such as, “How are you feeling?  How 
are your eyes feeling today?  Have you had any changes since the last exam?” 
IP Administration and Compliance:  The first dose of study IP will be administered to the study 
eye by study staff after the IOP measurement at T0 + 12 hrs.  At Day 1/Visit 3 the AM dose of 


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study IP will be administered to the study eye by study staff after the IOP measurement at T0.  
Subjects will self-dose unilaterally until the Day 4 visit.  At Day 4/Visit 4 the AM dose of study 
IP will be administered OU by study staff after the IOP measurement at T0.  Subjects will self-
dose OU for the remainder of the trial except on Day 14/Visit 5 (AM and PM doses) and Day 
28/Visit 6 (AM dose) when study IP will be administered OU by study staff after the related IOP 
measurements.  Compliance will be assessed at applicable visits by asking the subject about any 
missed doses.  If the subject reports missing more than 4 doses since the prior visit, the subject 
will be counseled on IP compliance. 
Heart Rate and Blood Pressure (BP) Measurements:  Both systolic and diastolic blood pressure 
should be recorded. 
Heart rate measurements will be measured by radial pulse.  The subject should be in a seated and 
relaxed state.  An automated blood pressure unit may be used to measure the heart rate.   
Electrocardiogram (ECG): 12-lead ECGs should be performed according to the site’s standard 
procedures.  ECG interpretation must be documented and reviewed by the investigator and or 
another qualified medical doctor for clinically significant findings that might affect the subject’s 
safe participation in this trial. 
Physical Examination:  The following systems should be examined: cardiopulmonary, endocrine, 
gastrointestinal, musculoskeletal, rheumatic, neurologic, psychiatric, dermatologic, hepatic, 
renal, and head, ears, nose, and throat.  Other body systems may be deferred at the discretion of 
the investigator.  Abnormalities should be recorded in the medical history. 
Best-Corrected Visual Acuity (ETDRS):  Visual acuity will be performed before implementing 
any procedure that can affect vision (i.e., pupil dilation, tonometry, and gonioscopy).  The most 
current refraction within 6 months prior to the Screening Visit will be recorded unless changes in 
refraction are suspected.  If changes are suspected since the most current refraction, refraction 
should be repeated at the Screening Visit.  The same optotype should be used throughout the 
study for a specific subject, and the right eye should be tested first.  Best corrected visual acuity 
(BCVA) should be recorded using the ETDRS chart (or a modified ETDRS chart).  If a change 
in BCVA is noted, pinhole may be used to test for the BCVA, but a formal refraction prior to 
dilation should be performed during that visit and/or on the next visit.  The LogMAR scores will 
be calculated according to the standard scoring methodology. A change of ≥ 10 letters may 
indicate an adverse event and should be investigated further by the investigator and the refraction 
should be rechecked.  
Slit Lamp Biomicroscopy:  This will be performed by the investigator's usual clinical technique.  
Biomicroscopy will be performed prior to pupil dilation OU.  Changes and/or abnormalities of 
the anterior segment in the lids, conjunctiva, cornea, anterior segment, and lens will be graded.  


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Iris color will be recorded at screening. Findings will be graded according to the following 
scales: 
LID 
Erythema 
None (0) = 
Normal, without any redness, or less than mild 
Mild (+1) = 
A low grade flushed reddish color 
Moderate (+2) = 
Diffused redness encompassing the entire lid margin 
Severe (+3) = 
Deep diffused reddish color of lid margins and superior or inferior eyelid 
Edema 
None (0) = 
Normal, no swelling of the lid tissue, or less than mild 
Mild (+1) = 
Slight diffuse swelling above normal 
Moderate (+2) = 
General swelling 
Severe (+3) = 
Extensive swelling of the eyelid(s), with or without eversion of upper and/or 
lower lids. 
 
CONJUNCTIVA  
Hyperemia 
None (0) =  
Normal: few vessels of bulbar conjunctiva easily observed 
Minimal (+0.5) = 
Trace flush, reddish-pink color of the bulbar conjunctiva 
Mild (+1) = 
Mild flush – reddish pink of the bulbar conjunctiva 
Moderate (+2) = 
Moderate, bright reddening of the bulbar conjunctiva 
Severe (+3) = 
Deep, severe, bright and diffuse reddening of the bulbar conjunctiva 
Edema 
None (0) = 
Normal, no swelling of the conjunctiva or less than mild 
Mild (+1) = 
Slight diffuse or regional swelling of the conjunctiva 
Moderate (+2) = 
General swelling of the conjunctiva 
Severe (+3) = 
Extensive swelling of the conjunctiva 
 
CORNEA 
Edema 
None (0) = 
Transparent and clear or less than mild 
Mild (+1) = 
Dull glassy appearance 
Moderate (+2) = 
Dull glassy appearance of epithelium with large number of vacuoles 
Severe (+3) = 
Epithelial bullae and/or stromal edema, localized or diffuse, with or without 
stromal striae 


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ANTERIOR CHAMBER 
Cells 
None (0) = 
No cells seen or less than mild 
Mild (+ 1) = 
1-5 cells 
Moderate (+2) = 
6-10 cells 
Severe (+3) = 
11-20 cells 
Hypopyon (+4) = 
> 20 cells, Hypopyon Formation (indicate size of hypopyon) 
Flare 
None (0) = 
No Tyndall effect or less than mild 
Mild (+1) = 
Tyndall beam in the anterior chamber has a mild intensity 
Moderate (+2) = 
Tyndall beam in the anterior chamber is of strong intensity 
Severe (+3) = 
Tyndall beam is very intense.  The aqueous has a white, milky appearance 
 
LENS 
Phakic 
Yes/No for each eye 
Aphakic 
Yes/No for each eye 
Pseudophakic 
Yes/No for each eye 
Lens Opacity (for phakic only) 
None (0) = 
None present or less than mild 
Mild (+ 1) = 
Subtle  
Moderate (+2) = 
Moderate  
Severe (+3) = 
Dense  
 
Pupillary Diameter:  Measurement of pupil size should occur under normal lighting conditions to 
the nearest 0.5 mm using a millimeter ruler or pupillary gauge while the patient fixates on a 
distant, non-accommodative target. 
Conjunctival Hyperemia:  Hyperemia will be assessed and recorded separately from 
biomicroscopy through direct visual observation prior to fluorescein instillation and IOP 
measurement.  The hyperemia will be graded on a 0 to 3 scale using the photographic reference 
scale provided by the Sponsor for use in this protocol. 
0 
Normal: few vessels of bulbar conjunctiva easily observed 
0.5 
Trace flush, reddish-pink color of the bulbar conjunctiva 
1 
Mild flush – Reddish pink of the bulbar conjunctiva 
2 
Moderate, Bright reddening of the bulbar conjunctiva 


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3 
Deep, severe, bright and diffuse reddening of the bulbar conjunctiva 
Intraocular Pressure:  All IOP measurements must be measured by Goldmann applanation 
tonometry.   
Two consecutive IOP measurements should be taken for each IOP time point, with the right eye 
being measured first.  The applanation probe should be withdrawn between measurements.  
Intraocular pressure will be measured 2 times and the average will be used for analysis.  If the 
two measurements differ by more than 4 mmHg, a third measurement will be taken and the 
median value will be used for analysis. The same procedure will be repeated on the contralateral 
eye. 
Pachymetry:  Pachymetry will be performed OU at the Screening Visit; results obtained within 
the prior 6 months may be used if no change is suspected.  Central corneal thickness (central 
zone) will be measured with a calibrated ultrasound pachymeter in both eyes after topical 
anesthetic has been applied.  Three measurements will be taken, first in the right eye, and the 
average will be recorded in micrometers (μm).  The subject will be in a seated position and 
fixating on a target straight ahead.  The same procedure is then performed on the left eye once 
the measurements have been completed in the right eye.  
Gonioscopy:  The gonioscopy examination will be performed OU at the Screening Visit; results 
obtained within the prior 6 months may be used if no change is suspected.  Gonioscopy should 
be performed prior to instillation of dilating or miotic drops, with high magnification, and with 
dim illumination to potentiate visualization of the angle in its natural configuration.  The angular 
width of the angle recess will be graded as an average score representative of all 4 quadrants 
using the grading criteria below.   
Grade Description (Shaffer System, based on the angular width of the angle recess [Marsh & 
Cantor, 2005]) 
4 
45 to 35° angular approach, wide open  
3 
35 to 20° angular approach, wide open 
2 
20° angular approach, narrow 
1 
≤ 10° angular approach, extremely narrow 
Slit 
0° angle, narrowed to slit 
Visual Field Examination:  A visual field will be performed OU at the Screening Visit; reliable 
results obtained within the prior 6 months may be used if no change is suspected.  Visual fields 
must be automated threshold visual fields (i.e., Humphrey [30-2 or 24-2] or Octopus equivalent).  
SITA Standard (24-2 or 30-2) is preferred, SITA fast is also allowed.  The subject’s best 


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correction at 33 cm is to be used.  Visual fields must be reliable, defined as those with a) fixation 
losses less than or equal to 20%, b) false positives less than or equal to 33% and c) false 
negatives less than or equal to 33%.     
Dilated Ophthalmoscopy:  Posterior segment exam will be performed according to the 
investigator’s preferred procedure.  Magnification, lighting, and examiner should be consistent 
for each subject throughout the study.  Ophthalmoscopy should be performed after pupil dilation 
(i.e., 1% tropicamide or cyclopentolate and 2.5% phenylephrine). The examination should 
include an evaluation of the vitreous, retina, macula, choroid, and optic nerve (including the 
absence or presence of notches and/or disc or peripapillary hemorrhages).  Abnormalities and 
pathologic findings will be graded.  Ocular structures will be graded according to the following 
scale.  
Vitreous, Retina, Macula and Choroid: Examination emphasizes the visual axis. 
0 
Normal 
1 
Abnormal, describe. 
Optic Nerve 
0 
Normal. No damage 
1 
Mild Optic nerve damage, secondary to glaucoma including any rim loss (sloping or 
thinning) 
2 
Moderate Optic nerve damage, including cupping to disc margin at one or more points 
3 
Severe Optic nerve damage, nearly total cupping, only nasal rim or less present 
Any new findings (i.e., notch and/or peripapillary hemorrhage) or deterioration from Screening 
Visit findings will be reported as an adverse event.  The cup/disc ratio will be recorded 
horizontally and vertically for each examination, and reported in 0.1 increments. 
Blood Collection for PK assessment: Will be conducted at selected sites.  See separate blood 
collection manual. 
Frequency 
Day 0 and Day 28. 
 
Time Points 
Pre-dose at Days 0 and 28 and approximately 2 and 8 hours (± 10 min) 
post- AM dose on Day 28  


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Analysis 
Plasma analysis for the test article and/or metabolites, if applicable, will be 
conducted.  Some collected samples may not be assayed if the expected 
concentration of test article and/or metabolites, based on initial assay 
results, is below the lower quantitation limit of the assay. 
 
Pharmacokinetic analysis will be conducted and will include (if 
appropriate), but not be limited to, peak concentration (Cmax), time to peak 
concentration (Tmax), and area under the concentration-time curve (AUC). 
Reporting 
Plasma analysis (including principle investigator compliance statements and 
Quality Assurance statements) and pharmacokinetic determination reports 
will be provided for inclusion in the clinical study report. 
 
Clinical Laboratories:  See separate blood collection manual. 
Hematology:  White blood cells (WBC) (neutrophils, eosinophils, basophils, lymphocytes, 
monocytes), red blood cells (RBC), hematocrit, hemoglobin, platelets, MCV, MCH, MCHC, 
RDW   
Clinical Chemistry:  Total protein, albumin, blood urea nitrogen (BUN), total bilirubin, 
creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate 
dehydrogenase (LDH), alkaline phosphatase (AP), gamma-glutamyl transferase (GGT), total 
cholesterol, calcium, sodium, potassium, chloride, glucose, uric acid, triglycerides, direct 
bilirubin, creatine phosphokinase (CPK), and GFR estimate. 
Urinalysis:  Specific gravity, pH, ketones, protein, glucose, bilirubin, urobilinogen, blood, 
leukocyte esterase (urinalysis abnormalities in protein, blood, and leukocyte esterase will reflex a 
microscopic examination including white blood count, red blood count, epithelial cells, bacteria, 
mucus, casts, and crystals). 
Lab results must be reviewed by the investigator or another medical doctor (with documentation) 
to assure the subject’s safety. 
Pregnancy Test: 
Serum pregnancy will be required at the Screening Visit for women of child bearing potential.   
Urine pregnancy and serum pregnancy tests will be performed in women of child bearing 
potential at Baseline (Day 0).  Pregnancy test results must be negative for subjects to continue in 
the study.  On Day 28, a urine pregnancy test will be administered. 
  


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4. 
SAMPLE SIZE AND POWER CONSIDERATIONS 
The sample size is driven by interest in the IOP lowering effect of H-1337.  The study is 
designed to test whether one or more concentrations of H-1337 are superior to the vehicle control 
in the reduction of IOP.  With n = 20/group this protocol is powered at 94% to detect a difference 
in IOP reduction of 4.0 mmHg between groups against a standard deviation of 3.5 mmHg (2-
sided t-test, alpha=0.05). 
Adverse events:  With 20 subjects per group there is a 95% certainty that an event that is not 
observed would have a true incidence rate of no more than 15%. 
Hyperemia:  Scored on a 5-point scale from 0 to 3.  Assume the SD is 20% of the scale range or 
1 unit.  Then, with n = 20/group there is 86% power to detect a mean difference of 1 unit 
between pairs of groups (2 group two-sided t-test, alpha=0.05).  If a response is defined as a 
hyperemia score ≥ 3 and the response rate in the control group is 10%, then with n = 20/group 
there is 85% power to detect a difference in response rates of 46% (Fisher’s exact test). 
In general, with 20 subjects per group there is 86% power to detect an effect size of 1.0. 
If a concentration is chosen that is less than the maximum, the safety data from the higher doses 
can be combined to increase power. 
 
5. 
ANALYSIS POPULATIONS 
The Safety Population will include all randomized subjects who receive at least one dose of 
study medication. 
All subjects who receive study medication and who complete at least one on-therapy study visit 
will comprise the Intent to Treat Population.  
Subjects who receive study medication, satisfy pre-randomization inclusion/exclusion criteria, 
and who complete at least one on-therapy study visit will be evaluable for a Per Protocol 
Population analysis.  Individual subject visits and data points that do not satisfy protocol criteria 
may be excluded from per protocol analyses.  Evaluability will be determined prior to breaking 
the code for masked treatment assignment. 
All analyses will be based on the actual treatment each subject received. 
 
6. 
HANDLING OF MISSING DATA 
Missing data will not be imputed for efficacy assessments.  
If intensity of an adverse event is missing the event will be considered severe. If relationship of 
adverse event to study drug is missing the event will be counted as related.  


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Adverse events will be considered treatment emergent unless it can be determined from the onset 
or end date information that the event cannot have been treatment emergent. 
Other adverse events will be assumed to occur during the screening period. 
 
7. 
STATISTICAL ANALYSIS 
All statistical analyses and reporting will be performed using the SAS® System Version 9.3 or 
later.  
Unless otherwise specified, continuous variables will be summarized with descriptive statistics 
(n, mean, median, standard deviation, standard error, minimum, and maximum), and categorical 
variables will be summarized with counts and percentages. 
All data collected in the study database will be presented in the listings. 
 
Definition of Study Eye: The study eye will be the eye that meets the entry intraocular pressure 
(IOP) criteria after washout. Should both eyes meet the criteria, then the study eye will be 
defined as the eye with the higher 8 am IOP on Baseline (Day 0). If both eyes have the same 8 
am IOP on Baseline (Day 0), the study eye will be the right eye.  The study eye will be 
designated by the investigator.  The designation may take into account ocular history as well as 
IOP criteria. 
Definition of Baseline:  
For vital signs, PK, BCVA and biomicroscopy baseline is the pre-T0 time point on Day 1. For 
clinical laboratories and pupil diameter  baseline is the Day 0 collection. For IOP and hyperemia 
baseline is the set of repeated measures at different times during the Day 0 visit. For 
ophthalmoscopy baseline is the Screening Day. 
7.1 
Subject Disposition 
Subject disposition, including the number of subjects randomized, treated, and completing the 
study (and completing each study visit), will be tabulated by treatment group. The percentage of 
subjects treated and completing the study will be based on the total number randomized.  
Eligibility criteria exemptions and major protocol deviations will be summarized by treatment 
group and presented in a listing. Major protocol deviations may include the following: violation 
of inclusion or exclusion criteria, using prohibited medications, non-adherence to study treatment 
schedule.  


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The total number and percentage of subjects included in each of the analysis datasets described 
in Section 5 will be summarized by treatment group, with percentages based on the total number 
randomized subjects. 
Discontinuations and the reasons for discontinuation will be summarized for all randomized 
subjects. Summaries will include the number and percentage of subjects within each treatment 
group. Reasons for discontinuation following the receipt of study drug will include the 
following: 
1. 
Protocol violation 
2. 
Lost to follow-up 
3. 
Adverse event 
4. 
Non-compliance 
5. 
Subject withdrew consent 
6. 
Investigator decision 
7. 
Uncontrolled IOP 
8. 
Other 
 
7.2 
Demographic and Baseline Characteristics 
The demographic and baseline characteristics will be summarized for all randomized subjects by 
treatment group.  
Continuous variables such as age will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum, and maximum), and categorical variables such as gender, 
race, and ethnicity will be summarized using counts and percentages of subjects. 
Age will be determined as the whole integer number of years from the date of birth (DOB) to the 
date of the screening visit, i.e., the truncated integer difference between the DOB and Visit 1. 
Baseline comparability between treatment groups will be assessed via descriptive statistics. 
Prior medications will be tabulated by preferred term (WHO drug dictionary).  
Medical and surgical history classified using MedDRA dictionary will be presented in a listing.  
 
7.3 
Treatment Compliance and Exposure 
The number of subjects by number of doses missed will be summarized by eye, visit and 
treatment group. 


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Duration of drug exposure will be calculated for each subject as the number of days they 
received any study drug. The number and percentage of subjects by treatment group will be 
summarized according to the following duration-of-exposure categories: ‘<7 days’, ‘7 to <14 
days’, ’14 to <21 days’, ’21 to <31 days’, and ‘31 days’. 
 
7.4 
Intraocular pressure 
The comparisons among treatment groups in IOP will be done for the various endpoints and time 
points. The outline of the analyses and groups is presented in Appendix 2. 
For each visit in which IOP is measured descriptive statistics at each time point will be presented 
for the observed, change from baseline and % change from baseline values. In addition, at visits 
where five assessments are made descriptive statistics will be presented for the average of the 
observed values and the change from baseline and percent change from baseline where the 
values will be computed using average of five corresponding values at Day 0 as a baseline. 
Descriptive statistics of IOP measures described above will be presented for the study eye, non-
study eye and average of both eyes by time point and treatment group.  
The 95% confidence intervals of the mean IOP by treatment group and time point and for diurnal 
IOP as well as for corresponding change from baseline will be presented.  
For the IOP, diurnal IOP, and their change from baseline, each of the active treatment groups 
will be compared to the placebo group using the analysis of covariance (ANCOVA) model, 
separately for each time point. Baseline value will be used as a covariate. The difference between 
treatment groups in adjusted least-square means will be presented. Mean diurnal IOP will be 
presented as the mean of all values (including the 8 pm IOP value) (12-hour diurnal) and mean 
of all values up to the 4 pm IOP value (8 hour diurnal).  If a subject is missing any time point for 
the calculation of the diurnal IOP, that subject will be excluded from the affected diurnal IOP 
analysis in the per protocol population. 
The proportion of subjects reaching a target IOP (< 18 mmHg) at each time point and with the 
mean diurnal IOP for each visit will be presented by treatment group. 
Within each dose level the change from baseline IOP will also be compared (a within subject 
comparison) with descriptive statistics. 
Exploratory summaries may be presented to examine if treatment effects differ depending on iris 
color, age and baseline IOP. 
Each comparison will be tested at the significance level of 0.05. No adjustments for multiple 
comparisons will be made. 


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CONFIDENTIAL 
6 SEP 2018 
 
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7.5 
Adverse Events 
Treatment emergent adverse events (TEAE) are those with onset after randomization or if 
occurring prior to randomization worsened after randomization. Only treatment emergent events 
will be summarized. All events in the clinical database regardless of when they occurred will be 
provided in data listings. Adverse events will be classified according to the MedDRA system to 
the levels of System Organ Class (SOC) and primary Preferred Term (PT). 
An overall summary will be presented which gives the number and percentage of subjects within 
each treatment group that experienced any TEAE, experienced any treatment related TEAE, 
permanently discontinued treatment due to a TEAE, experienced a treatment emergent SAE, and 
that died. 
In summary tables, AEs occurring in both eyes will be counted once at the greater intensity and 
relationship to study drug.  
Events that are possibly, probably or definitely related will be counted as an event related to 
study drug.  
The number and percentage of subjects experiencing one or more events within a MedDRA 
system organ class and preferred term class without regard to intensity, relationship, or 
seriousness will be tabulated by treatment group. In addition, tables will display events by SOC, 
PT, and maximum intensity or closest relationship to treatment. 
The number of deaths and SAEs will also be presented, and AEs leading to premature 
discontinuation from the study will be listed and tabulated. 
A glossary listing that shows the verbatim terms assigned to each SOC and PT will be provided.  
A listing of TEAEs by treatment group ordered by subject, SOC, PT, and onset date will be 
provided. 
A listing of serious TEAEs by treatment group ordered by subject, SOC, PT, and onset date will 
be provided. 
7.6 
 Concomitant Medications 
All concomitant medications listed on the case report form will be provided in data listings in the 
clinical study report. Each medication will be mapped to their corresponding Preferred Term 
from the WHO Drug Dictionary. A frequency distribution of all concomitant medications used 
during the study sorted by Preferred Term will be provided for each treatment group.  
7.7 
Ocular and Other Medical History 
Ocular and other medical history reported at the Screening Visit and on Day 0 prior to the first 
dose of study drug, will be summarized by System Organ Class and Preferred Term. 


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CONFIDENTIAL 
6 SEP 2018 
 
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7.8 
Clinical Laboratory Assessment 
Clinical laboratory data (hematology, serum chemistry, and urine) at each scheduled visit will be 
summarized with descriptive statistics by treatment group, as will the change from baseline to 
each post-baseline visit. Each subject’s data will also be classified to low, normal, and high 
according to the normal ranges. These data will be summarized in shift tables comparing each 
post-baseline visit to baseline.  
7.9 
Physical examination 
Physical examination findings at the Screening Visit will be summarized by System Organ Class 
and Preferred Term. 
7.10 
Vital Signs 
Descriptive statistics of vital signs and their change from baseline will be tabulated by time point 
and treatment group. 
7.11 
Electrocardiogram  
The interpretation of the ECG with respect to normal/abnormal will be tabulated. 
7.12 
Best-Corrected Visual Acuity 
Descriptive statistics of the observed and change from baseline BCVA will be tabulated for each 
eye by visit and treatment group. 
7.13 
Ocular Hyperemia, Biomicroscopy, Ophthalmoscopy and Ocular 
Symptoms 
The observations of ocular hyperemia, biomicroscopy, ophthalmoscopy, and ocular symptoms 
will be summarized in frequency tables based on the ordinal scales for each measure for each eye 
by time point and treatment group.  In addition, the photographic assessment of ocular hyperemia 
will be summarized by descriptive statistics (See Appendix 2).  
7.14 
Pupil Diameter 
Descriptive statistics of pupil diameter and its CFB will be tabulated for each eye by time point 
and treatment group. 
7.15 
Pachymetry 
Descriptive statistics of the observed corneal thickness will be tabulated for each eye by 
treatment group. 


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CONFIDENTIAL 
6 SEP 2018 
 
Page 24 of 28 
7.16 
Gonioscopy at Screening Visit 
Anterior chamber angle classified by the Shaffer’s classification will be summarized in 
frequency tables for each eye by treatment group. 
7.17 
Visual field 
The observation of visual field examination will be summarized in a frequency table for each eye 
by treatment group.  
8. 
INTERIM ANALYSIS 
No interim analyses are planned. 


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CONFIDENTIAL 
6 SEP 2018 
 
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9. 
 APPENDICES  
9.1 
Appendix 1: Schedule of Study Assessments and Procedures 
Assessments/Procedures1 
Screening 
(-422 to -1 
days) 
Day 0 
Baseline/ 
Randomization 
Day 1 
Day 4 
(± 1 day) 
Day 14 
(± 1 day) 
Day 28 
Exit/ET 
(± 2 days) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Informed Consent 
X 
 
 
 
 
 
Medical and Ophthalmic History  
X 
X 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
IP Administration in Office  
 
X 
Unilateral post T0 
+ 12 hrs IOP 
X 
Unilateral 
post IOP 
X 
OU post 
IOP 
X 
OU post 
T0 and T0 
+ 12 hrs 
IOP 
X 
OU post T0 
IOP 
(final dose) 
Assess IP Compliance 
 
 
 
X 
X 
X 
Heart Rate/Blood Pressure  
(± 30 min) 
X 
X 
Pre-T0 
T0 + 1 hr 
T0 + 2 hrs 
T0 + 4 hrs 
 
 
 
X 
Pre-T0 
T0 + 1 hr 
T0 + 2 hrs 
T0 + 4 hrs 
ECG 
X 
 
 
 
 
  
Physical Examination  
X 
 
 
 
 
 
Best-corrected Visual Acuity 
(ETDRS)  
X 
X 
Pre-T0 
X 
X 
Pre-T0 
X 
Pre-T0 
X 
Pre-T0 
Biomicroscopy3 
(± 30 min) 
X 
 
X 
T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 
X 
Pre-T0 
X 
Pre-T0 
X 
Pre-T0 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 
Pupillary Diameter 
(± 30 min) 
 
X 
Pre-T0 
 
 
 
 
X 
Pre-T0 
 
                                                 
1 When possible, one examiner should conduct all ocular assessments for a subject during a single visit. If possible, 
the same examiner should conduct all ocular assessments for a subject throughout the duration of the study. 
2 +1 week permitted to accommodate scheduling considerations 
3 If any adverse findings are noted after IP administration, the subject should continue to be monitored per the 
investigator’s judgment. 


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CONFIDENTIAL 
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Assessments/Procedures1 
Screening 
(-422 to -1 
days) 
Day 0 
Baseline/ 
Randomization 
Day 1 
Day 4 
(± 1 day) 
Day 14 
(± 1 day) 
Day 28 
Exit/ET 
(± 2 days) 
Conjunctival Hyperemia Grading  
(± 30 min) 
 
X 
T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 
 
X 
Pre-T0 
 
X 
Pre-T0 
 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 
Intraocular Pressure4 
(Goldmann Tonometry) 
(± 30 min) 
X 
 
X 
T0 
T0 + 1 hrs 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs  
X 
T0 
X 
T0 
 
X 
T0 
T0 + 1 hr 
T0 + 2 
hrs 
T0 + 4 
hrs 
T0 + 8 
hrs 
T0 + 12 
hrs 
X 
T0 
T0 + 1 hr 
T0 + 2 hrs 
T0+ 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 
Pachymetry5  
X 
 
 
 
 
 
Gonioscopy6 
X 
 
 
 
 
 
Visual Fields (automated, threshold) 
X7 
 
 
 
 
 
Dilated ophthalmoscopy 
X 
 
 
 
 
X8 
Blood Collection for PK of H-1337 
(± 10 min at 2 & 8 hrs) 
 
X 
 
 
 
 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 8 hrs 
Clinical Laboratories 
(hematology, clinical chemistry, 
pregnancy (if applicable), and 
urinalysis)  
X9 
X10 
 
 
 
X11 
                                                 
4 Timing of IOP measurements for each subject should be consistent throughout the study. 
5 Pachymetry performed at screening will be used for inclusion/exclusion criteria only. Pachymetry within 6 months 
of Screening acceptable unless suspected change. 
6 Gonioscopy within 6 months of Screening acceptable unless suspected change. 
7 Historical VF may be used if within 6 months of screening visit unless suspected change. 
8 After T0 + 12 hrs IOP; may be deferred to following day for scheduling convenience. 
9 At Screening, if applicable, a serum pregnancy test should be performed. 
10 At Baseline, if applicable, a urine and serum pregnancy test should be conducted. Urine pregnancy test (UPT) 
must be negative to proceed to randomization; serum pregnancy test results should be reviewed as soon as available 
to confirm negative UPT result. 
11 On Day 28, if applicable, a urine pregnancy test should be conducted.  


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CONFIDENTIAL 
6 SEP 2018 
 
Page 27 of 28 
9.2 
Appendix 2. Efficacy Endpoints and Time Points 
IOP 
Category 
Day 0 Visit 
Day 1 Visit* 
Day 4 Visit* 
Days 14 & 28 Visits 
Eye subgroups 
 
Study eye 
Mean of both eyes 
Study eye 
Study eye 
Study eye 
Mean of both eyes 
Analysis variables 
IOP & Diurnal IOP 
• IOP 
• Change in IOP from 
baseline (Day 0 Visit)* 
• % change in IOP from 
baseline (Day 0 Visit)* 
• Proportion of subjects 
achieving IOP ≤ 18 mmHg 
• IOP 
• Change in IOP from 
baseline (Day 0 Visit)  
• % change in IOP from 
baseline (Day 0 Visit)  
• Proportion of subjects 
achieving IOP ≤ 18 
mmHg 
• IOP & Diurnal IOP 
• Change in IOP & Diurnal 
IOP (Day 0 Visit) 
• % change in IOP & Diurnal 
IOP (Day 0 Visit) 
• Proportion of subjects 
achieving IOP/Diurnal IOP 
≤ 18 mmHg 
Analysis Time points 
• T0 
T0 + 1 hrs 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs  
• Diurnal (mean of 5 
measurements & mean 
of 4 measurements 
excluding T0 + 12 hrs) 
T0 
T0 
• T0 
T0 + 1 hrs 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs  
• Diurnal (mean of 5 
measurements & mean of 
4 measurements 
excluding T0 + 12 hrs) 
Treatment Groups/ Comparisons 
H-1337 vs. Vehicle 
H-1337 vs. Vehicle 
H-1337 vs. Vehicle 
H-1337 vs. Vehicle 
*Note: the non-study eye will not be treated until after T0 on the Day 4 visit. Day 0 measures will be used as baseline for all time points for the non-study eye. 
 


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6 SEP 2018 
 
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Conjunctival Hyperemia by Photographic Assessment 
*Note: the non-study eye will not be treated until after T0 on the Day 4 visit. Day 0 measures will be used as baseline for all time points for the non-study eye. 
Category 
Day 0 Visit 
Day 4 Visit* 
Day 14 Visit 
Days 28 Visit 
Eye subgroups 
 
Study eye 
Mean of both eyes 
Study eye 
Study eye 
Study eye 
Mean of both eyes 
Analysis variables 
Conjunctival Hyperemia by 
Photographic Assessment 
• Hyperemia 
• Change in Hyperemia from 
baseline (Day 0 Visit)* 
 
• Hyperemia 
• Change in Hyperemia 
from baseline (Day 0 
Visit) 
• Hyperemia 
• Change in Hyperemia from 
baseline (Day 0 Visit) 
Analysis Time points 
• Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs  
• Pre-T0 
 
Pre-T0 
• Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs  
Treatment Groups/ Comparisons 
H-1337 vs. Vehicle 
H-1337 vs. Vehicle 
H-1337 vs. Vehicle 
H-1337 vs. Vehicle