Clinical trial NCT05913232
Conditions: Glaucoma Open-Angle Primary Ocular Hypertension
Sponsor: D. Western Therapeutics Institute, Inc.
Start date: 2023-08-28; Completion date: 2024-08-29
Enrollment: 201 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The trial will evaluate the safety and efficacy of 3 dose regimens of H-1337 \[0.6% twice daily (b.i.d.), 1.0% b.i.d. and 1.0% once in the morning (q.a.m.), and timolol maleate (0.5%, b.i.d.) in both eyes for 28 days.

Detailed description:

Arms: arm 1: One drop H-1337 twice daily in the study eye for 28 days arm 2: One drop H-1337 twice daily in the study eye for 28 days arm 3: One drop H-1337 every morning and matching placebo every evening in the study eye for 28 days arm 4: One drop Timolol twice daily in the study eye for 28 days
Interventions: intervention 1: H-1337 0.6% intervention 2: H-1337 1.0% intervention 3: H-1337 Placebo intervention 4: Timolol 0.5%
Intervention descriptions: intervention 1: ophthalmic solution intervention 2: ophthalmic solution intervention 3: ophthalmic solution intervention 4: ophthalmic solution

Protocol documents:
Prot_000.pdf: 
Protocol No./Title: A Phase 2b Randomized, Double-masked, Active-controlled, Dose-response 
Study of the Safety and Efficacy of H-1337 in Subjects with Primary Open Angle Glaucoma 
(POAG) or Ocular Hypertension 
NCT No.: 05913232 
Document Date: 19 January 2024 


Clinical Study Protocol 
A Phase 2b Randomized, Double-masked, Active-controlled, Dose-response Study of the 
Safety and Efficacy of H-1337 in Subjects with Primary Open Angle Glaucoma (POAG) or 
Ocular Hypertension 
Protocol Number: 
H1337-CS202 
Investigational Drug Product: 
H-1337
IND Number: 
107,895 
Development Phase: 
Phase 2b 
Medical Monitor: 
Robert D Williams, MD 
Telephone: (360) 298-5325 
Sponsor Contact: 
D. Western Therapeutics, Inc.
7th Floor, CK21 Hirokoujifushimi Building
Nagoya shi
Aichi, Japan 460-0003
Attention: Shigenobu NAKAZORA shinakazora@dwti.co.jp
Telephone: 81-52-218-8785
Date of Protocol: 
19 Jan 2024 
Version: 
3.0 
Amendment History: 
Version 1.0 
7 December 2022 
Version 2.0 
7May 2023 
Confidentiality Statement 
The information contained herein is confidential and proprietary.  It is intended for the use of D. Western 
Therapeutics, 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 D. Western Therapeutics, Inc.




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INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
 
Protocol Number: H1337-CS202 
 
Protocol Title: 
A Phase 2b Randomized, Double-masked, Active-controlled, Dose-response 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 D. Western Therapeutics, 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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Protocol Version 3.0 
19JAN2024 
Approximately 110 subjects enrolled.  
 
Version 2.0 dated 7 May 2023 was changed as follows: 
 
• 
Corrections, clarifications and minor changes to inclusion/exclusion criteria to 
reflect investigator input during conduct of study to date 
• 
Changing +12 hours diurnal IOP measurement to optional due to logistical 
challenges in office practice and subject recruitment 
• 
Statistical section to reflect comments received from U.S. FDA on 4 January 2024, 
as well as changes to diurnal IOP measure analyses.  
 
These modifications do not change subject exposure or safety. 
 
 
Protocol Version 2.0 
7MAY2023 
No subjects enrolled.  
 
Version 1.0 dated 7 December 2022 was changed to clarify study procedures and subject 
qualifications.  
 
This does not change subject exposure or safety.  
 
 
 


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Table of Contents 
CLINICAL STUDY PROTOCOL ............................................................................................................................. 1 
PROTOCOL SYNOPSIS ............................................................................................................................................ 7 
LIST OF ABBREVIATIONS ................................................................................................................................... 16 
1. 
BACKGROUND ............................................................................................................................................. 18 
1.1 
Investigational Agent ...................................................................................................................... 18 
1.2 
Preclinical and Human Data............................................................................................................ 19 
1.3 
Risk/Benefits ................................................................................................................................... 19 
1.4 
Dose Rationale ................................................................................................................................ 19 
1.5 
Trial Conduct .................................................................................................................................. 19 
1.6 
Population ....................................................................................................................................... 20 
2. 
STUDY OBJECTIVES ................................................................................................................................... 20 
3. 
STUDY DESIGN ............................................................................................................................................. 20 
3.1 
Study Design ................................................................................................................................... 20 
3.2 
Randomization ................................................................................................................................ 20 
3.3 
Maintenance of Randomization Codes ........................................................................................... 20 
3.4 
Trial Treatment ............................................................................................................................... 21 
3.5 
Duration .......................................................................................................................................... 21 
3.6 
Drug Packaging and Labeling ......................................................................................................... 22 
3.7 
Drug Accountability and Storage .................................................................................................... 23 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................................................ 23 
4.1 
Inclusion Criteria ............................................................................................................................ 23 
4.2 
Exclusion Criteria ........................................................................................................................... 24 
4.3 
Subject Withdrawal and/or Discontinuation ................................................................................... 26 
4.4 
Medication ...................................................................................................................................... 27 
4.5 
Monitoring for Subject Compliance ................................................................................................ 27 
4.6 
Lifestyle Guidance .......................................................................................................................... 27 
5. 
STUDY VISIT PROCEDURES ..................................................................................................................... 28 
5.1 
Study Visits ..................................................................................................................................... 34 
5.1.1 
Screening ............................................................................................................................... 34 
5.1.2 
Day 0 ..................................................................................................................................... 34 
5.1.3 
Day 1 ..................................................................................................................................... 34 
5.1.4 
Days 7 and 14 ........................................................................................................................ 34 
5.1.5 
Day 28 ................................................................................................................................... 35 
6. 
ASSESSMENT OF EFFICACY .................................................................................................................... 35 
6.1 
Efficacy Parameters ........................................................................................................................ 35 
6.2 
Method and Timing ......................................................................................................................... 35 
7. 
ASSESSMENT OF SAFETY ......................................................................................................................... 36 
7.1 
Adverse Event Reporting ................................................................................................................ 36 
7.2 
Definition of Adverse Event ........................................................................................................... 36 
7.3 
Definitions of Non-Serious Adverse Events ................................................................................... 37 
7.4 
Definition of Serious Adverse Event .............................................................................................. 37 
7.5 
Hospitalization ................................................................................................................................ 37 
7.6 
Pregnancy ........................................................................................................................................ 38 
7.7 
Definition of Unexpected Adverse Events ...................................................................................... 38 
7.8 
Definition of Relationship of Adverse Event to IP ......................................................................... 38 


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7.9 
Documentation of Severity of Adverse Events ............................................................................... 39 
7.10 
Reporting Serious Adverse Events .................................................................................................. 39 
7.11 
Serious Adverse Event Follow-Up .................................................................................................. 40 
8. 
STATISTICAL PLAN .................................................................................................................................... 40 
8.1 
Sample Size ..................................................................................................................................... 40 
8.2 
Statistical Methods .......................................................................................................................... 41 
8.3 
Subject Population(s) for Analysis .................................................................................................. 41 
8.4 
Significance and Adjustment for Multiple Comparisons ................................................................ 41 
8.5 
Accountability Procedure ................................................................................................................ 43 
8.6 
Deviation Reporting ........................................................................................................................ 43 
9. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ................................................................ 43 
10. 
DATA REVIEW AND ANALYSIS ............................................................................................................... 43 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................................ 43 
12. 
ETHICAL CONSIDERATIONS ................................................................................................................... 44 
12.1 
Informed Consent ............................................................................................................................ 44 
12.2 
Institutional Review Board/Ethics Committee ................................................................................ 44 
12.3 
Confidentiality ................................................................................................................................ 44 
12.4 
Early Sponsor Discontinuation of the Trial ..................................................................................... 44 
13. 
DATA HANDLING AND RECORD KEEPING ......................................................................................... 45 
14. 
APPENDICES ................................................................................................................................................. 46 
14.1 
References ....................................................................................................................................... 46 
 


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Protocol Synopsis 
Protocol Number: 
H1337-CS202 
Study Title: 
A Phase 2b Randomized, Double-masked, Active-controlled, 
Dose-response 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 ocular hypotensive efficacy of 3 dose regimens of 
H-1337 compared to timolol maleate 0.5% in subjects with 
POAG or OHT treated for up to 28 days. 
 
Secondary Objectives: 
Evaluate the local ocular and systemic safety of 3 dose 
regimens of H-1337. 
 
Exploratory Objectives: 
• Evaluate the efficacy of diurnal IOP measurements of 3 
dose regimens  of H-1337 compared to timolol 0.5% 
Study Population:  
Subjects with bilateral POAG or OHT 
Number of Subjects: 
Approximately 200 
Investigational Products: 
 
H-1337 0.6% Ophthalmic Solution b.i.d. 
H-1337 1.0% Ophthalmic Solution b.i.d. 
H-1337 1.0% Ophthalmic Solution q.a.m. 
H-1337 placebo q.p.m. 
Timolol 0.5% Ophthalmic Solution b.i.d. 
Route and Duration of 
Administration: 
Topical eye drop; 28 days treatment 
Study Design: 
The trial will evaluate the safety and efficacy of 3 dose 
regimens of H-1337 (0.6% b.i.d., 1.0% b.i.d. and 1.0% q.a.m., 
and timolol maleate (0.5%, b.i.d.) OU for 28 days.  
Efficacy assessments will be made based upon the study eye.  
The study eye is the eye that meets all entry criteria including 
the intraocular pressure (IOP) inclusion criteria.  If both eyes 
qualify the study eye is the eye with the higher 8 am IOP on 
Baseline (Day 1).  If both eyes have the same 8 am IOP on 
Baseline (Day 1), the study eye is the right eye. 
Primary Efficacy 
Measure: 
 
Change from baseline in IOP in 3 dose regimens of H-1337 
compared to timolol 0.5%., b.i.d. at 28 days in subjects with 
POAG or ocular hypertension.   


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Secondary Efficacy 
Measure: 
 
• Mean IOP in 3 dose regimens of H-1337 compared to 
timolol 0.5%., b.i.d. at 28 days in subjects with POAG or 
ocular hypertension. 
• Mean diurnal IOP in 3 dose regimens of H-1337 compared 
to timolol 0.5%., b.i.d. at 28 days in subjects with POAG or 
ocular hypertension.  
• Proportion of subjects with IOP < 18 mmHg at each time 
point at each visit, and with the mean diurnal IOP ≤ 18 
mmHg for each visit. 
Safety Endpoints: 
Ocular and systemic Adverse Events (AE) 
Study Assessments: 
The following assessments and procedures will be performed: 
• Medical and ocular history 
• Prior and current concomitant medications and procedures 
• Adverse events 
• Heart rate and blood pressure  
• Best-corrected visual acuity (ETDRS) OU 
• Biomicroscopy OU 
• Conjunctival Hyperemia Grading OU 
• Intraocular pressure (Goldmann tonometry) OU 
• Gonioscopy OU 
• Pachymetry OU 
• Visual field testing (automated, threshold) OU 
• Ophthalmoscopy (dilated) OU 
Statistical 
Considerations: 
This trial has ≥ 90% power to detect a clinically significant 
difference of 2.0 mm Hg, assuming SD of 3.0 mm Hg 
(ALY337-201), and α=0.05 (1-sided).  A hierarchical analysis 
will be performed starting with 1.0% H-1337 b.i.d.  Thus, no 
adjustment for multiplicity will be performed.  
Pharmacokinetic 
Endpoints 
None 


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Inclusion Criteria: 
 
To be eligible for trial participation subjects must meet all the 
following 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 1) at T0 (T0 = 8 am ± 30 min [IOP time]) 
IOP ≥ 23 mmHg in the study eye. 
4. IOP criteria after washout ≤ 32 mmHg OU at all qualifying 
time points/visits. 
5. Best-corrected visual acuity (BCVA) in both eyes of 20/200 
or better on Snellen, equivalent to + 1.0 log Mar at Visit 1 
Screening.  
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 
investigational product eye drops. 
 


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Exclusion criteria 
To be eligible for trial participation subjects must not meet any 
of the following criteria: 
Ocular: 
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 
(including cyclodestructive procedures).  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 corticosteroid-induced, 
inflammation-induced, or exfoliation glaucoma in either 
eye. Pigment dispersion syndrome/glaucoma is permitted in 
either or both eyes. 
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. Prior netarsudil use in either eye which resulted in clinically 
significant adverse events leading to discontinuation of 
treatment including: conjunctival hyperemia, 
subconjunctival hemorrhage, cornea verticillata, or reticular 
bullous epithelial edema. 
10. History of refractive surgery in either eye (i.e., radial 
keratotomy, PRK, LASIK).  
11. History of corneal cross-linking procedure in either eye. 
12. Unwillingness to be contact lens free during study 
participation.  
13. Any history of uveitis, keratitis, or scleritis in either eye. 
Note: SPK associated with ocular surface disease is 


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permitted. 
14. Any history of penetrating ocular trauma in either eye. 
15. 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 or inactive seasonal allergic conjunctivitis and 
non-infectious dermatitis are acceptable. 
16. Corneal thickness < 480 or > 620 µm in the study eye. 
Pachymetry measurement within 6 months prior to 
Screening Visit is acceptable.  
17. Advanced or severe glaucoma with progressive visual field 
loss, NFL thinning documented by OCT, 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. Note: 1) Subjects 
may be switched to different IOP lowering therapy with a 
shorter washout period as long as the appropriate washout is 
met prior to Visit 2. 2) Visual fields must be reliable, 
defined as those with a) fixation losses less than or equal to 
33%, b) false positives less than or equal to 33% and c) 
false negatives less than or equal to 33%. 
18. In the investigator’s best judgment, 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. Mild BDR is permitted. 
19. Any prior intravitreal corticosteroid injection in either eye. 
20. Sub-tenon’s, sub-conjunctival or periocular corticosteroid 
injections within the 6 months prior to Screening Visit in 
either eye. 
21. 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 Day 1 and ensuing trial participation. 
22. Known hypersensitivity to any component of the H-1337 
formulation, including BAK, timolol maleate, or to topical 
anesthetics or diagnostic drops to be used during the study. 
23. Any ocular condition that, in the investigator’s judgment, 
could prevent the subject from safe participation the study. 
24. Planned ocular surgery or intraocular injection procedure in 
either eye during study participation. 
 
General/Systemic: 
Exclude subjects with: 


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25. Participation in a clinical study with use of any 
investigational drug or treatment within 30 days prior to 
Baseline (Day 1). 
26. Prior use of H-1337 
27. 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. 
28. Contraindication to beta-blocker usage including: reactive 
airway disease, uncontrolled heart failure, or second as well 
as third degree cardiac block, myasthenia gravis. 
29. Anticipated changes or initiation of medications which 
might affect IOP and/or systemic blood pressure within 7 
days prior to Baseline/Day 1 (e.g., including, but not 
limited to: 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 1 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. Note: Vaccines are permitted. 
30. 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 urine pregnancy test result at the Screening 
Visit and at Baseline (Day 1) prior to randomization in the 
study and must not intend to become pregnant during the 
study. 
31. History of drug or alcohol abuse within the last 5 years. 
32. Unwillingness to refrain from consumption of alcohol or 
cannabinoids, including tetrahydrocannabinol (THC) and 
cannabidiol (CBD), in any form by any delivery route, on 


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the day prior to each study visit after Visit 1 Screening. 
33. Related to site study staff and/or site employees. 
 


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Table 1. Time and Events Schedule 
Assessments/Procedures1 
Screening  
(-49 to 1 
days) 
Day 0 
(-4 to -1) 
Day 1 
Baseline/Randomization 
Day 7 
(± 1 day) 
Day 14 (± 1 day) 
Day 28  
(± 2 days) 
Last Dosing Day 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Informed Consent 
X 
 
 
 
 
 
Medical and Ocular History  
X 
X 
X 
 
 
 
Concomitant Medications/Procedures 
X 
X 
X 
X 
X 
X 
Adverse Event Assessments 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
IP Administration in Office (AM dose) 2 
 
 
X 
(T0) 
X 
(T0) 
X 
(T0) 
X 
(T0) 
Assess IP Compliance 
 
 
 
X 
X 
X 
Heart Rate/Blood Pressure (± 30 min)  
 
X 
Pre-T0 
T0 + 1 hr 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 3 
X 
Pre-T0 
T0 + 1 hr 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs 3 
 
X 
Pre-T0 
 
X 
Pre-T0 
T0 + 1 hr 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs3 
Urine Pregnancy Test(if applicable) 
X 
X 
 
 
 
X 
Best-corrected Visual Acuity (ETDRS)  
X 
X 
X 
Pre-T0 
X 
Pre-T0 
X 
Pre-T0) 
X 
Pre-T0) 
Biomicroscopy  
X 
 
X 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
X 
Pre-T0 
X 
Pre-T0 
X 
Pre-T0, 
T0 + 2 hrs, 
To + 4 hrs 
Conjunctival Hyperemia Grading 
(direct visual observation using 
photographic reference scale) 
 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs3 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs3 
 
X 
Pre-T0 
 
 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs3 
 
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. Ocular parameters should be assessed OU. 
2 T0 corresponds to actual AM dosing of the investigational product. For Baseline, T0 is immediately after Pre-T0, expected to be 8 am ± 30 mins.    
3 T0 +12 hrs is optional for new subjects participating under Protocol V3.0.    


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Assessments/Procedures1 
Screening  
(-49 to 1 
days) 
Day 0 
(-4 to -1) 
Day 1 
Baseline/Randomization 
Day 7 
(± 1 day) 
Day 14 (± 1 day) 
Day 28  
(± 2 days) 
Last Dosing Day 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Intraocular Pressure4 (Goldmann 
Tonometry) 
X 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs3 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs3 
X 
Pre-T0 
X 
Pre-T0 
X 
Pre-T0 
T0 + 2 hrs 
T0 + 4 hrs 
T0 + 8 hrs 
T0 + 12 hrs3 
Gonioscopy5 
X 
 
 
 
 
 
Pachymetry6 
X 
 
 
 
 
 
Visual Fields (automated, threshold)7 
X 
 
 
 
 
 
Ophthalmoscopy (dilated) 
X 
 
 
 
 
X 
 
4 Timing of IOP measurements for each subject should be consistent throughout the study. Calculate timepoints in relation to T0: timepoints +2 and +4 hrs after T0 must be separated 
from the prior timepoint by at least 1½ hrs and timepoints +8 and +12 hrs must be separated from the prior timepoint by at least 3 ½ hours. Every effort should be made to conduct 
Visit 6 Day 28 Pre-T0 and In-Office IP Administration (AM dose) at the identical time as done on Visit 3 Day 1. 
5 Gonioscopy within 6 months of Screening acceptable.  
6 Pachymetry performed at screening will be used for inclusion/exclusion criteria only. Pachymetry within 6 months of Screening acceptable. 
7 Reliable visual fields within 6 months of Screening acceptable. 


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List of Abbreviations 
AE 
Adverse Event 
ALT 
Argon Laser Trabeculoplasty 
AMD 
Age-related Macular Degeneration 
AUC 
Area Under the Curve 
BAK 
Benzalkonium Chloride 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice Daily 
BP 
Blood Pressure 
CAI 
Carbonic Anhydrase Inhibitor 
°C 
Degrees Celsius 
CFR 
Code of Federal Regulations 
CME 
Cystoid Macular Edema 
CRF 
Case Report Form 
ET 
Early Termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice(s) 
GLP 
Good Laboratory Practice(s) 
Hg 
Mercury 
HR 
Heart Rate 
hr 
Hour 
IB 
Investigator’s Brochure 
IC 
Informed Consent Document 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IWRS 
Interactive Web Response System 
LASIK 
Laser-Assisted In Situ Keratomileusis 
LDPE 
Low Density Polyethylene 
logMAR 
Logarithm of the minimum angle of resolution 
Mins 
Minutes 


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mL 
Milliliter 
Mm 
Millimeter 
mOsm 
Milliosmoles 
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  
QD 
Once-daily 
RGC 
Retinal Ganglion Cells 
ROCKi 
Rho Kinase Inhibitor 
SAE 
Serious Adverse Event  
SLT 
Selective Laser Trabeculoplasty 
SPK 
Superficial Punctate Keratitis 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TM 
Trabecular Meshwork 
US 
United States 
VF 
Visual Fields 
µm 
Micrometer 


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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.  Data from population-based surveys indicate 
that one in 40 adults older than 40 years has glaucoma with loss of visual function, which 
equates to 60 million people worldwide being affected and 8·4 million being bilaterally legally 
blind. Even in developed countries, half of glaucoma cases are undiagnosed (Quigley 2011, 
Glaucoma Research Foundation. https://glaucoma.org/glaucoma-facts-and-stats/).  
 
As elevated intraocular pressure (IOP) is a major risk for loss of visual field and optic nerve, 
reduction of IOP by medical, laser and/or surgical means is the current standard of care for 
patients with glaucoma.   While there are many therapies available, each has its own benefits and 
risks.  Some patients, even with proper diagnosis and treatment, still continue to have 
progressive glaucomatous loss of visual function and/or optic nerve.   
 
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. 
 
In a previous controlled study, H-1337 Ophthalmic Solution showed clinically and statistically 
significant ocular hypotensive activity and was well tolerated, with a relatively low incidence of 
hyperemia.  Further evaluations might explore the dose-response and therapeutic potential 
compared to a positive control, as well as the effect of H-1337 on aqueous humor dynamics 
(Hartman et al, 2022). 
 
The present study aims to extend the previous findings with additional concentrations and doses, 
as well as including a positive control (timolol ophthalmic solution). 
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 enhances 
aqueous outflow by modulating the contractile state of trabecular meshwork ™ cells to decrease 
resistance to fluid transport.  
 
The H-1337 investigational drug product is a preserved, isotonic, sterile ophthalmic solution at 
two concentrations (w/v) (0.6% and 1.0%), buffered at pH 6.5 (range 6.3 – 6.7), as is the 
placebo. 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 with LDPE nozzle/dropper insert and high-density polyethylene (HDPE) ophthalmic cap.  


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The bottle is packaged into an aluminum foil overwrap to protect from water vapor transmission.  
The placebo control (vehicle) will consist of the components of the ophthalmic formulation 
without H-1337.  
 
Timolol ophthalmic solution is supplied as a sterile, isotonic, buffered, aqueous solution of 
timolol maleate.  The pH of the solution is approximately 7.0, and the osmolarity is 274-328 
mOsm/kg.  Each mL of timolol ophthalmic solution 0.5% contains 5 mg of timolol (6.8 mg of 
timolol maleate). Inactive ingredients: monobasic and dibasic sodium phosphate, sodium 
hydroxide to adjust pH, and purified water. Benzalkonium chloride 0.01% is added as 
preservative. 
1.2 
Preclinical and Human Data 
For complete information on the preclinical studies performed, please see the Investigator’s 
Brochure.  
 
H1337, in the first human trial (ALY337-201) was generally well tolerated. Instillation site pain, 
instillation site erythema, and vision blurred were reported, usually mild in severity without an 
apparent dose-response.; instillation site erythema, blurred vision, and muscle strain were 
reported in 3 subjects at moderated intensity. 
 
1.3 
Risk/Benefits 
Based on the results of ALY337-201, the first human trial, the risk/benefit ratio for this trial 
appears acceptable. Refer to the Investigator’s Brochure for complete information on prior 
studies performed with H1337. 
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) are expected to have an acceptable safety profile and have been selected 
based on preclinical toxicology data.  The total daily administered dose of H-1337 in human 
subjects will be approximately 1.72 mg/day (or 0.03 mg/kg/day based on a 60-kg individual) 
when administered twice daily in both eyes at the maximal concentration of 1.0%.  
In a previous clinical study, 3 concentrations of H-1337 Ophthalmic Solution (0.06%, 0.02% and 
0.6%) dosed twice-daily (b.i.d.) provided similar ocular hypotensive outcomes.  In the present 
study, a high concentration of 1.0% is planned to be used both once (q.d.) and twice (b.i.d.)-
daily.  The dose is supported by preclinical safety studies.  The highest dose from the previous 
study (0.6%, b.i.d.), as well as a positive marketed control, timolol ophthalmic solution 0.5%, 
b.i.d., will be included for comparison. 
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. 


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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.  
2. STUDY OBJECTIVES  
Primary Objective:  
• Evaluate the ocular hypotensive efficacy of 3 dose regimens of H-1337 compared to timolol 
maleate 0.5% in subjects with POAG or OHT treated for up to 28 days.   
 
Secondary Objectives: 
• Evaluate the local ocular and systemic safety of 3 dose regimens of H-1337. 
 
Exploratory Objectives: 
• •Evaluate the efficacy of diurnal IOP measurements of 3 dose regimens of H-1337 compared 
to timolol 0.5%. 
3. STUDY DESIGN 
3.1 
Study Design 
The trial will evaluate the safety and efficacy of 3 dose regimens of H-1337 (0.6% b.i.d., 1.0% 
b.i.d. and 1.0% q.a.m., and timolol maleate (0.5%, b.i.d.) OU for 28 days (± 2-day allowable 
window for Day 28). 
 
Approximately 200 subjects will be randomized and dosed for 28 days.  The parallel group, 
double-masked, active-controlled study will include the following dosing cohorts: 
 
• H-1337 0.6% Ophthalmic Solution b.i.d. (n=50) 
• H-1337 1.0% Ophthalmic Solution b.i.d. (n=50) 
• H-1337 1.0% Ophthalmic Solution q.a.m. and H-1337 placebo q.p.m. (n=50) 
• Timolol 0.5% Ophthalmic Solution b.i.d (n=50) 
 
3.2 
Randomization 
H-1337 and its control (timolol) will be packaged in similar bottles which are concealed in 
identical packaging.  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 D. Western Therapeutics, 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.  


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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: 
 
Robert D Williams, MD 
iopdoc1@gmail.com 
 
Telephone: (360) 298-5325 
 
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 (or 
sponsor’s designee) and the IRB.  Every effort should be made to keep the subject in the trial 
after the randomization code is broken until the completion of all visits. 
3.4 
Trial Treatment  
Subjects will receive one of four dosing arms: H-1337 (0.6% b.i.d., 1.0% b.i.d. and 1.0% q.a.m. 
with H-1337 placebo q.p.m.), and timolol maleate (0.5%, b.i.d.) OU for 28 days .  IP will be 
administered bilaterally throughout the trial. 
 
The IWRS will assign a kit number to subjects who qualify for randomization.  Each IP kit will 
contain 3 inner cartons. The first carton containing 2 pouches (each pouch containing 1 a.m. and 
1 p.m. bottle) will be dispensed on Day 1 (Baseline). The second carton will be dispensed to the 
subject on Day 14.  The third carton will serve as a back-up should the subject require a 
replacement carton.   
3.5 
Duration 
Each subject’s participation will consist of two phases: a Screening Phase (Screening and 
Baseline Visit 2 and Visit 3 Pre-T0) where subjects will suspend dosing of any current ocular 
hypotensive therapy, and a Dosing Phase, starting on Day 1 after Pre-T0.  If a subject is not using 
ocular hypotensive therapy at Screening Visit 1, there is no applicable washout period and the 
Baseline Visit should occur within 1 to 42 days after Screening Visit 1.   
 
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.  (Note: At Investigator’s 
discretion for subject’s safety, initiation of a different IOP lowering therapy with a shorter 
washout period is permitted during a long washout period provided all appropriate washout 
periods are met prior to Visit 2.) 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 


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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 
Visit) 
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   
Rho-associated protein kinase (ROCK) inhibitors 
≥ 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 (Stroman et al, 
1997; Johnson and Jampel, 2021). 
 
Following the applicable washout period, the subject will return for applicable 
inclusion/exclusion evaluations on the Baseline Visit (Day 1) and a subject meeting all 
inclusion/exclusion criteria at Pre-T0 will be randomized to IP.  Both eyes will be dosed and 
evaluated for safety throughout the trial.  The study eye is the eye that meets all entry criteria 
including the IOP criteria after washout.  Should both eyes meet the criteria then the study eye 
will be defined as the eye with the higher Pre-T0 8 am IOP on Baseline (Day 1).  If both eyes 
have the same Pre-T0 8 am IOP on Baseline (Day 1), the study eye will be the right eye. 
 
Dosing will be initiated on Day 1 in the office after measurement of the Pre-T0 8 a.m. IOP and 
the completion of all examinations required prior to the Pre-T0 8 a.m. IOP measurement.  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 42 days (+ 7 days) depending on pre-study ocular hypotensive therapy 
Treatment Period: 28 days ± 2 days 
3.6 
Drug Packaging and Labeling 
H-1337 and timolol 5 mL low density polyethylene (LDPE) bottles will be similar but not 
identical. Each bottle will be concealed in an identical foil pouch. Each identical IP kit will 
contain 3 identical inner cartons, each containing 2 identical foil pouches (one a.m. and one p.m. 
pouch). The kits, inner cartons, pouches and bottles will be labeled in a format appropriate for 
the study. 
 
Masking will be maintained by the appointment of an unmasked study coordinator not 


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participating in key endpoint data collection at each clinical site, solely responsible for subject IP 
dispensation and return. 
3.7 
Drug Accountability and Storage 
All IP required for this study will be provided by D. Western Therapeutics, Inc., or its designee.  
The recipient will acknowledge receipt of IP, indicating shipment content and condition.  
Damaged supplies may be replaced upon notification to D. Western Therapeutics, 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 
D. Western Therapeutics, Inc., or its designee.  
 
IP must be stored in a temperature monitored secure and restricted storage area with limited 
access.  Temperature monitoring records must be maintained throughout the trial.  IP should be 
stored at controlled refrigerated temperatures from 2° - 8° C and protected from light.  Once 
dispensed to subjects IP bottles may be stored at room temperature, i.e., 15° - 25° C.  Subjects 
must 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 D. 
Western Therapeutics, Inc.  
4. SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects must fulfill all the inclusion and exclusion criteria and the investigator must obtain 
written approval from the Medical Monitor, 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 1) at T0 (T0 = 8 am ± 30 min [IOP time]) IOP ≥ 23 mmHg in the study eye. 
4. IOP criteria after washout ≤ 32 mmHg OU at all qualifying time points/visits. 
5. Best-corrected visual acuity (BCVA) in both eyes of 20/200 or better on Snellen, equivalent 
to + 1.0 log Mar at Visit 1 Screening.  
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 investigational product eye drops. 
 
 


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4.2 
Exclusion Criteria 
Exclusion criteria: 
Investigators will exclude any subject who they consider unsafe for participation in this study or 
unlikely to complete the requirement of the protocol for any reason. 
 
Ocular: 
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(including cyclodestructive procedures).  
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 corticosteroid-induced, inflammation-
induced, or exfoliation glaucoma in either eye. Pigment dispersion syndrome/glaucoma is 
permitted in either or both eyes. 
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. Prior netarsudil use in either eye which resulted in clinically significant adverse events 
leading to discontinuation of treatment including: conjunctival hyperemia, subconjunctival 
hemorrhage, cornea verticillata, or reticular bullous epithelial edema.  
10. History of refractive surgery in either eye (i.e., radial keratotomy, PRK, LASIK).  
11. History of corneal cross-linking procedure in either eye. 
12. Unwillingness to be contact lens free during study participation.  
13. Any history of uveitis, keratitis, or scleritis in either eye. Note: SPK associated with ocular 
surface disease is permitted. 
14. Any history of penetrating ocular trauma in either eye. 
15. 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 or inactive seasonal allergic conjunctivitis and non-infectious 
dermatitis are acceptable. 
16. Corneal thickness < 480 or > 620 µm in the study eye. Pachymetry measurement within 6 
months prior to Screening Visit is acceptable.  
17. Advanced or severe glaucoma with progressive visual field loss, NFL thinning documented 
by OCT, and/or optic nerve changes in either eye that, in the investigator’s best judgment, 


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prevent safe withdrawal from treatment for the time periods required in this protocol. Notes: 
1) Subjects may be switched to a different IOP lowering therapy with a shorter washout 
period as long as the appropriate washout is met prior to Visit 2. 2) Visual fields must be 
reliable, defined as those with a) fixation losses less than or equal to 33%, b) false positives 
less than or equal to 33% and c) false negatives less than or equal to 33%. 
18. In the investigator’s best judgment, 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. Mild BDR is permitted. 
19. Any prior intravitreal corticosteroid injection in either eye. 
20. Sub-tenon’s, sub-conjunctival or periocular corticosteroid injections within the 6 months 
prior to Screening Visit in either eye. 
21. 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 Day 1 and 
ensuing trial participation. 
22. Known hypersensitivity to any component of the H-1337 formulation, including BAK, 
timolol maleate, or to topical anesthetics or diagnostic drops to be used during the study. 
23. Any ocular condition that, in the investigator’s judgment, could prevent the subject from safe 
participation the study. 
24. Planned ocular surgery or intraocular injection procedure in either eye during study 
participation. 
 
General/Systemic: 
Exclude subjects with: 
25. Participation in a clinical study with use of any investigational drug or treatment within 30 
days prior to Baseline (Day 1). 
26. Prior use of H-1337. 
27. 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. 
28. Contraindication to beta-blocker usage including: reactive airway disease, uncontrolled heart 
failure, or second as well as third degree cardiac block, myasthenia gravis. 
29. Anticipated changes or initiation of medications which might affect IOP and/or systemic 
blood pressure within 7 days prior to Baseline/Day 1 (e.g., including, but not limited to: 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 1 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. Note: Vaccines are permitted. 
30. 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 


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childbearing potential unless she is one year post-menopausal or three months post-surgical 
sterilization. All females of childbearing potential must have a negative urine pregnancy test 
result at the Screening Visit and at Baseline (Day 1) prior to randomization in the study and 
must not intend to become pregnant during the study. 
31. History of drug or alcohol abuse within the last 5 years. 
32. Unwillingness to refrain from consumption of alcohol or cannabinoids, including 
tetrahydrocannabinol (THC) and cannabidiol (CBD), in any form by any delivery route, on 
the day prior to each study visit after Visit 1 Screening. 
33. 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. The investigator or D. Western Therapeutics, Inc. 
designee, 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. 
• 
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. 
 
If a subject withdraws or is withdrawn from IP treatment, every effort should be made to ensure 
the subject continues to participate in the remaining trial visits. 
 
If a subject withdraws or is withdrawn from IP treatment, either at her/his request or at the 
discretion of the investigator or D. Western Therapeutics, Inc. the reason for withdrawal should 
be recorded.  All subjects withdrawing or withdrawn from IP 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.  
 


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It is vital to obtain follow-up data for any subject withdrawn due to an AE.  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 between Visits 1 and 2 from prior IOP-lowering therapy, 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 1). 
 
Current systemic mediations which may influence intraocular pressure should be stable without 
anticipated changes 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 study Medical Monitor.  If the subject is withdrawn from 
IP treatment, the subject will continue to be followed during routine trial visits or 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 IP treatment and 
institute IOP treatment. 
4.5 
Monitoring for Subject Compliance 
Subjects or their caretakers will administer study medications according to the IP dosing 
instructions and training provided, ie; as close as possible to 8 a.m. and 8 p.m. Compliance will 
be assessed at each visit by asking the subject for their recollection about any missed doses. 
Confirmation of compliant IP dosing the evening prior to a study visit must be confirmed or the 
visit should be rescheduled. If the subject reports missing more than 4 doses since the prior visit, 
a Protocol Deviation will be documented and the subject will be counseled on IP compliance.  
4.6 
Lifestyle Guidance 
During the study, subjects of childbearing potential (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 subjects of child-bearing potential: 
• Abstinence 


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• 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 
5. STUDY VISIT PROCEDURES 
All study visit procedures should be conducted in the order listed in 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. The original document should be retained in the 
Investigator’s Site File (ISF) or with the Subject’s source documents. 
 
Medical and Ocular History:  Relevant and clinically significant medical and ocular history must 
be recorded. This includes reported changes between Screening Visit 1 and first IP 
administration. 
 
Concomitant Medications/Procedures:  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.  Additionally, all ocular hypotensive medications taken within 45 days prior to the 
Screening Visit will be recorded. Diagnostic and anesthetic eye drops do not need to be recorded. 
All procedures occurring during the study and 30 days prior to the Screening Visit will 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 by study staff 
after the IOP measurement at T0 on Day 1. Subjects will self-dose for the remainder of the trial 
except on study visit days when subjects will be instructed to refrain from self-dosing prior to the 
visit and the study morning IP will be administered by the unmasked dosing coordinator after the 
related IOP measurements; evening IP will be self-dosed (out of view of study staff) after the 
related IOP measurements. Compliance will be assessed at applicable visits by asking the subject 
their recollection of any missed doses. Confirmation of compliant IP dosing the evening prior to 
a study visit must be confirmed or the visit should be rescheduled. If the subject reports missing 
more than 4 doses since the prior visit, a Protocol Deviation will be documented and the subject 
will be counseled on IP compliance. 


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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 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. 
Heart rate measurements will be measured by radial pulse for at least 30 seconds. The subject 
should be in a seated and relaxed state.  An automated blood pressure unit may be used to 
measure the heart rate.   
 
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 logarithm of the 
minimum angle of resolution (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 and lighting 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 specified 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 


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mistakes.  When a subject reaches a level where he/she cannot guess, the examiner may stop the 
test. 
 
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 
and must 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 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 
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) 
 
 
 


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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 
Aphakic 
Yes/No 
Pseudophakic 
Yes/No 
 
For phakic only 
 
Crystalline Lens 
 
Normal (0) 
No opacity in the lens 
Abnormal 
 
Nuclear Cataract 
 
None (0)  
 
Minimal (1+) 
Minimal changes in nuclear zone 
Mild (2+) 
Mild opacity with central zone still distinguishable 
Moderate (3+) 
Moderate opacity 
Severe (4+) 
Dense opacity 
Cortical Cataract 
 
None (0)  
 
Minimal (1+) 
<1/8 of the circumference 
Mild (2+) 
<1/8, but less than 1/4 of the circumference 
Moderate (3+) 
<1/4, but less than 1/2 of the circumference 
Severe (4+) 
≥1/2 of the circumference 
Posterior Subcapsular Cataract 
None (0)  
 
Minimal (1+) 
 
Mild (2+) 
 
Moderate (3+) 
 
Severe (4+) 
 
For pseudophakic only 
 
Posterior capsular opacification (PCO) 
None (0)  
 
Trace/Mild (1+) 
<2 mm 
Moderate (2+) 
≥2 mm, but <3 mm 
Severe (3+) 
≥3 mm 
Clear central axis (s/p YAG Capsulotomy) 
 
Conjunctival Hyperemia:  Hyperemia will be assessed and recorded separately from 
biomicroscopy through direct visual observation using photographic reference scale 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 
3 
Deep, severe, bright and diffuse reddening of the bulbar conjunctiva 
 


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Tonometry (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 and always prior to dilation. 
 
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 2 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 acquire all IOP 
measurements for each subject using the same tonometer and approximately at the same time at 
all visits. Every effort should be made to use the same examiner for each unique timepoint. 
 
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.  The subject will be in a seated position and fixating on a target 
straight ahead.  Three measurements will be taken in the right eye first, and the average will be 
recorded in micrometers (μm).  The same procedure is then performed on the left 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).  


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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 33%, 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 (i.e., < 3 mm) that dilation is 
required.  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 
(e.g., 1% tropicamide or cyclopentolate and/or 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 occurring after 
the first IP dose 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. Changes 
observed between Screening Visit 1 and prior to the first IOP dose will be reported as ocular 
history. 
 
Pregnancy Test: 
Urine pregnancy testing will be required at the Screening Visit for subjects of child-bearing 
potential and at 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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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/ocular and concomitant medication history, with review of inclusion/exclusion 
criteria 
• 
Any unfavorable medical occurrence should be reported as medical or ocular history 
• 
BCVA 
• 
Biomicroscopy 
• 
Goldmann tonometry 
• 
Gonioscopy 
• 
Pachymetry 
• 
Dilated ophthalmoscopy  
• 
At any time during the visit after informed consent: 
• 
Urine pregnancy test (if applicable); result must be negative 
• 
Visual field testing 
5.1.2 Day 0 
• 
Medical/ocular and concomitant medication history, with review of inclusion/exclusion 
criteria 
• 
Urine pregnancy test (if applicable, at any time during the visit); result must be negative 
• 
Any unfavorable medical occurrence should be reported as medical or ocular history 
• 
Heart rate/blood pressure at all required timepoints 
• 
BCVA (may be performed prior to heart rate/blood pressure) 
• 
Biomicroscopy 
• 
Conjunctival hyperemia grading at all required timepoints 
• 
Goldmann tonometry at all required timepoints 
5.1.3 Day 1 
• 
Medical/ocular and concomitant medication history, with review of inclusion/exclusion 
criteria (and again after Pre-T0 Goldmann tonometry) 
• 
Any pre-dose unfavorable medical occurrence should be reported as medical or ocular 
history 
• 
Heart rate/blood pressure at all required timepoints 
• 
BCVA(may be performed prior to heart rate/blood pressure) 
• 
Biomicroscopy at all required timepoints 
• 
Conjunctival hyperemia grading at all required timepoints 
• 
Goldmann tonometry at all required timepoints 
• 
Randomization and IP administration immediately after 8 AM T0 IOP timepoint 
• 
Any post-dose unfavorable medical occurrence should be reported as an Adverse Event 
5.1.4 Days 7 and 14 
• 
Concomitant medications 


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• 
Adverse events 
• 
IP compliance 
• 
BCVA(may be performed prior to heart rate/blood pressure) 
• 
Biomicroscopy at all required timepoints  (i.e., Pre-T0) 
• 
Conjunctival hyperemia grading at all required timepoints  (i.e., Pre-T0) 
• 
Goldmann tonometry (Pre-T0) 
• 
IP administration (8 AM only) 
5.1.5 Day 28 
• 
Concomitant medications 
• 
Adverse events 
• 
IP compliance 
• 
Heart rate/blood pressure at all required timepoints 
• 
BCVA(may be performed prior to heart rate/blood pressure) 
• 
Biomicroscopy at all required timepoints  
• 
Conjunctival hyperemia grading at all required timepoints 
• 
Goldmann tonometry at all required timepoints 
• 
IP administration (8 AM only) 
• 
Urine pregnancy test (if applicable) at any time during the visit 
• 
Dilated ophthalmoscopy after final Goldmann tonometry – may be performed on following 
day for scheduling convenience. 
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 1) IOP 
(mmHg) for each group on Day 28 at each matched time point as compared to timolol. 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 with IOP < 18 mmHg at each time point at each visit, and with the 
mean diurnal IOP ≤ 18 mmHg for each visit.  
6.2 
Method and Timing 
The efficacy parameter for this study is IOP as measured by Goldman applanation tonometry.  
The timing of the IOP measurements is based on standard diurnal measurements, and data from 
the previous clinical study of H1337.  


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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.  Changes will be reported as AEs after the subject receives the first 
dose of IP (Day 1).  Ongoing AEs at study completion (Day 28) or the final study visit 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. 
 
Non-clinically significant incremental < 2 unit grade changes in conjunctival hyperemia 
(according to the photographic reference scale provided for the trial) are not required to be 
reported as adverse events; changes ≥2 unit grade changes must be reported as an Adverse Event 
and tracked until returning to baseline. 
 
To capture the most potentially relevant safety information during a clinical study, it is important 
that investigators record accurate AE terms.  Wherever possible, a specific disease or syndrome 
rather than individual associated signs and symptoms should be identified by the investigator and 
recorded.  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. 
 
Investigators are required to report to D. Western Therapeutics, 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 a causal relationship 
with the treatment.  An AE can, therefore, be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of an investigational product, whether or not 
considered related to the 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 judged clinically significant by PI, and/or induces clinical signs or 
symptoms and/or requires active intervention and/or requires interruption or 
discontinuation of IP  


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• Clinically significant symptoms and signs 
• Hypersensitivity 
• Progression/worsening of underlying disease (not therapeutic failure of IP) 
• Loss of > 3 lines BCVA  
• 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 
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.   
7.4 
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-patient 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 after the first dose of IP (Day 1) have been administered, 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. 
7.5 
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 


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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 
• 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 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.  
7.6 
Pregnancy 
If a subject becomes pregnant during the study or up until 30 days after the last dose of IP (i.e., 
the final clinical visit), the Investigator must notify D. Western Therapeutics, Inc. or its 
representative immediately and within 24 hours of learning of its occurrence by completing a 
Pregnancy Report Form and forwarding to D. Western Therapeutics, Inc. or its representative.  
The pregnancy should be followed to determine the 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.   
7.7 
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. 
7.8 
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 and report such an assessment in 


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accordance with the serious AE reporting requirements, if 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 D. Western 
Therapeutics, 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 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. 
 
7.9 
Documentation of Severity of Adverse Events 
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. 
 
7.10 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 1) will be reported to D. Western 


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Therapeutics, Inc. or its representative, followed until the event resolves or stabilizes, the 
subject’s final visit 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 using the SAE Report Form within 24 hours of knowledge of the 
occurrence to D. Western Therapeutics, 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:  
H1337-202sae@safety-sphere.com 
Office Phone: 844-965-1070 
Office Fax: 
855-805-2406 
 
When the initial report is made verbally or by telephone to D. Western Therapeutics, Inc. or 
designee, 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 D. Western Therapeutics, Inc. or its 
representative. D. Western Therapeutics, Inc. (or designee) will report all Suspected Unexpected 
Serious Adverse Reactions (SUSARs) to Regulatory Authorities within 7/15 days of receipt 
depending on reporting requirements. 
 
SAEs that come to the attention of the investigator within 30 days following the final study visit 
or Day 28 will be reported to D. Western Therapeutics, Inc. or its representative within 24 hours 
of knowledge of the occurrence. 
7.11 Serious Adverse Event Follow-Up  
For all SAEs, the investigator must submit follow-up reports to D. Western Therapeutics, Inc. or 
designee, 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.  
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 non-inferior to the timolol 
control in the reduction of IOP.  As benefit is represented by a negative number, non-inferiority 


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is achieved when the upper limit of the confidence interval of the difference in treatment (H-
1337 minus Timolol) is strictly lower than the non-inferiority margin. 
 
A sample size of 45 subjects per group will allow for at least 90% power to establish non-
inferiority of H-1337 over Timolol based on a non-inferiority limit of -2 mmHg, a standard 
deviation of 3.0 mmHg and a 1-sided t-test (alpha=0.05). 
 
Assuming that 10% of the subjects will not be eligible in the ITT population, a total of 50 
subjects per group is required. 
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 from baseline value.  In addition, percentage change 
from baseline will be summarized for IOP measurements. 
 
Baseline is defined as the last non-missing measurement prior to first IP administration. 
 
A statistical analysis plan will be finalized prior to unmasking the treatment assignments. 
 
An analysis of results will be conducted when the database has been locked and the treatment 
assignments have been revealed.  No interim analyses are planned. 
8.3 
Subject Population(s) for Analysis 
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 randomized subjects will be evaluable for the ITT analyses.  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 (PP) population 
analysis.  Individual subject visits and data points that do not satisfy protocol criteria may be 
excluded from PP analyses.  Evaluability will be determined prior to unmasking of treatment 
assignments. 
8.4 
Significance and Adjustment for Multiple Comparisons 
Change from Baseline in IOP (mmHg) at Day 28 and Day 1 (on-treatment time points) in the 
study eye is the primary efficacy endpoint. It will be summarized by timepoint and treatment 
group in the ITT population primarily and in the PP population secondarily. The differences 
between treatments (H-1337 vs Timolol) will be calculated for each H-1337 treatment group. A time-
matched longitudinal model adjusting for baseline and including a random effect for subject will be 
used to calculate the LSmean, SE, and 2-sided 95% CI for the between treatments differences. 
To account for the multiple comparisons of the primary endpoints, adjustment for multiplicity 
will be fulfilled by using a hierarchical testing, based on a fixed-sequence procedure defined in 


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Table 3. First, the primary endpoint is tested for non-inferiority at all 4 time points at Day 28 
(excluding +12 hours) and all 3 on-treatment time points at Day 1 (excluding +12 hours) for the 
first pre-defined Group comparison listed in Table 3. If the upper limit of the 2-sided 95% CI of 
the difference between H-1337 and Timolol is strictly lower than the value 1.5, then non-
inferiority is concluded. If non-inferiority is concluded at the 7 timepoints, then testing of the 
second listed Group Comparison in Table 3 can take place at the 2-sided alpha level of 0.05. 
Otherwise, non-inferiority cannot be concluded and no further formal testing takes place. The 
same sequential approach is then applied to the remaining endpoints listed in Table 3.  
 
Table 3  Pre-defined Sequence for Hierarchical Testing  
 
Order Group Comparison 
Non-Inferiority Criteria 
1 
H-1337 1.0% Ophthalmic Solution b.i.d. vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.5 threshold at all 7 time points 
2 
H-1337 0.6% Ophthalmic Solution b.i.d vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.5 threshold at all 7 time points 
3 
H-1337 1.0% Ophthalmic Solution q.a.m. vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.5 threshold at all 7 time points 
4 
H-1337 1.0% Ophthalmic Solution b.i.d. vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.0 threshold at 5 or more time points 
5 
H-1337 0.6% Ophthalmic Solution b.i.d vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.0 threshold at 5 or more time points 
6 
H-1337 1.0% Ophthalmic Solution q.a.m. vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.0 threshold at 5 or more time points 
 
 


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8.5 
Accountability Procedure 
To reduce the incidence of missing data, sites and subjects will be trained in methods to 
encourage continued participation to maximize the completion rate and overall quality of the 
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 final statistical plan will be described 
and justified in the clinical study report. 
9. DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Study visits will be conducted by an authorized D. Western Therapeutics, 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 D. Western Therapeutics, Inc., or its 
representative, the Food and Drug Administration (FDA), and any appropriate health authorities 
to inspect facilities and records relevant to this study. 
10. DATA REVIEW AND ANALYSIS 
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 
except the unmasked dosing coordinator, and D. Western Therapeutics, Inc. personnel 
responsible for the daily conduct of the study will remain masked to the results to maintain the 
scientific rigor and credibility of the trial.  D. Western Therapeutics, Inc. personnel and selected 
external consultants will be unmasked once the data is locked.  Data will then be reviewed, the 
safety and efficacy for each dose determined. 
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 D. Western Therapeutics, 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, D. Western 
Therapeutics, Inc. and/or its representative will conduct periodic monitoring visits to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  These representatives may 
review source documents to confirm that the data recorded in CRFs is accurate.  The investigator 
and institution will allow D. Western Therapeutics, Inc., representatives, or agents and 
appropriate regulatory authorities direct access to source documents and CRFs to perform this 
verification. 
 


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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. 
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 (ISF) and must be 
available for verification by study monitors at any time; 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 D. Western Therapeutics, Inc., in connection with the 
development of the IP.  The study investigator is obliged to provide D. Western Therapeutics, 
Inc., or designee with complete test results and all data developed in this study.  This information 
may be disclosed to other physicians who are participating in this trial, and to the FDA as 
deemed necessary by D. Western Therapeutics, 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 may 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 
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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 be 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. APPENDICES 
14.1 References 
Glaucoma Research Foundation. https://glaucoma.org/glaucoma-facts-and-stats/. (Accessed 28 
February 2022). 
 
Hartman PJ, Cooke DL, Hsu HH, Stewart J, Sumi K, Yoshida Y, et al. Phase Ⅰ/Ⅱ, Double-
Masked, Randomized, Vehicle-Controlled Study of H-1337 Ophthalmic Solution for Glaucoma 
and Ocular Hypertension. Ophthalmol Glaucoma. 2022;1-8. 
 
Johnson TV, Jampel HD. Systemic beta-Blockers Do Not Affect Glaucoma Eye Drop 
Effectiveness. Ophthalmology. 2021;128(2):326-8. 
 
Quigley HA. Glaucoma. Lancet. 2011;377(9774):1367-77. 
 
Stroman GA, Stewart WC, Stewart JA, Deitz TM. Safety of beta-adrenergic blocker washout 
period in clinical trials. Acta Ophthalmol Scand. 1997;75(1):94-5. 
 
 

SAP_001.pdf: 
Protocol No./Title: A Phase 2b Randomized, Double-masked, Active-controlled, Dose-response 
Study of the Safety and Efficacy of H-1337 in Subjects with Primary Open Angle Glaucoma 
(POAG) or Ocular Hypertension 
NCT No.: 05913232 
Document Date: 30 January 2024 


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D. Western Therapeutics Institute, Inc.
Statistical Analysis Plan
Protocol Number: H1337-C202 
Investigational Drug Product: H-1337 
IND Number: 131440 
A Phase 2b Randomized, Double-masked, Active-controlled, 
Dose-response Study of the Safety and Efficacy of H-1337 in 
Subjects with Primary Open Angle Glaucoma (POAG) or 
Ocular Hypertension 
Author(s): 
Esmeralda Meunier, M.Sc. 
Document Status: 
Final 
Version Dates: 
Version 1.0: 19SEP23 
Version 2.0: 30JAN24 
STATEMENT OF CONFIDENTIALITY 
This Statistical Analysis Plan is the property of D. Western Therapeutics Institute, Inc. It is not to be transmitted, copied 
or published without written permission from D. Western Therapeutics Institute, Inc. and must be kept in a confidential 
manner. Persons to whom the information is disclosed must be informed that the information is CONFIDENTIAL and 
may not be further disclosed by them. 




 
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Contents 
SUMMARY OF CHANGES ................................................................................................... 4 
ABBREVIATIONS .................................................................................................................. 5 
1 INTRODUCTION................................................................................................................. 6 
1.1 
STUDY BACKGROUND ................................................................................................. 6 
2 STUDY OBJECTIVES ......................................................................................................... 7 
2.1 
PRIMARY OBJECTIVE .................................................................................................. 7 
2.2 
SECONDARY OBJECTIVE ............................................................................................. 7 
2.3 
EXPLORATORY OBJECTIVE.......................................................................................... 7 
2.4 
PRIMARY EFFICACY ENDPOINT ................................................................................... 7 
2.5 
SECONDARY EFFICACY ENDPOINTS ............................................................................ 7 
2.6 
SAFETY ENDPOINTS .................................................................................................... 7 
3 STUDY DESIGN AND PROCEDURES ............................................................................ 8 
3.1 
OVERALL STUDY DESIGN ........................................................................................... 8 
3.2 
SCHEDULE OF VISITS AND ASSESSMENTS ................................................................... 8 
3.3 
SAMPLE SIZE JUSTIFICATION ...................................................................................... 8 
3.4 
ANALYSIS POPULATIONS ............................................................................................ 8 
3.4.1 Safety Analysis Population ......................................................................................... 8 
3.4.2 Intent-to-Treat Population .......................................................................................... 9 
3.4.3 Per-Protocol Population ............................................................................................. 9 
4 STATISTICAL METHODOLOGY.................................................................................. 10 
4.1 
DEFINITIONS AND CONVENTIONS .............................................................................. 10 
4.2 
HANDING OF MISSING DATA..................................................................................... 10 
4.3 
ADJUSTMENT FOR MULTIPLICITY.............................................................................. 10 
4.4 
DISPOSITION ............................................................................................................. 11 
4.5 
WASHOUT PERIOD .................................................................................................... 11 
4.6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................................. 11 
4.7 
MEDICAL AND OCULAR HISTORY ............................................................................. 12 
4.8 
PRIOR AND CONCOMITANT MEDICATIONS ................................................................ 12 
4.9 
CONCOMITANT PROCEDURES .................................................................................... 12 
4.10 
TREATMENT EXPOSURE ............................................................................................ 12 
4.11 
EFFICACY ANALYSES ................................................................................................ 12 
4.11.1 
Primary Efficacy Analyses .................................................................................... 12 
4.11.2 
Secondary Efficacy Analyses ................................................................................ 13 
4.11.3 
Additional Efficacy Analyses ................................................................................ 13 
4.12 
SAFETY ANALYSES ................................................................................................... 13 
4.12.1 
Adverse Events ...................................................................................................... 13 
4.12.2 
Vital Signs ............................................................................................................. 14 
4.12.3 
Best-corrected Visual Acuity................................................................................. 14 
4.12.4 
Slit Lamp Biomicroscopy ...................................................................................... 14 
4.12.5 
Conjunctival Hyperemia Grading......................................................................... 14 
4.12.6 
Dilated Ophthalmoscopy ...................................................................................... 14 
4.13 
SUBGROUP ANALYSIS ............................................................................................... 14 
4.14 
INTERIM ANALYSIS ................................................................................................... 15 
5 SUMMARY OF CHANGES FROM THE PROTOCOL ............................................... 16 
6 LIST OF PROGRAMMING SUMMARY & ANALYSIS TABLES ............................. 17 
7 APPENDICES ..................................................................................................................... 18 
7.1 
APPENDIX 1 – TIME AND EVENT SCHEDULE.............................................................. 18 
 


 
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Summary of Changes 
 
Version 1.0 
Initial Version 
Version 2.0 
Updates to reflect Protocol Version 3.0 and comments received from U.S. 
FDA on 4 January 2024. 
The Intent-to-Treat population is redefined as per FDA’s comments. 
The main analyses are conducted on the Intent-to-Treat population instead of 
the Per-Protocol population. 
The repeated measures model of the main analysis contains additional 
information as per FDA’s feedback. The random effect is updated to subject 
instead of center. 
Details on diurnal intraocular pressure calculations are added.   
 
 
 


 
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Abbreviations 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Distance Visual Acuity 
b.i.d. 
twice a day 
CI 
Confidence Interval 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
LS 
Least Square 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimetre of mercury 
OD 
right eye 
OHT 
Ocular Hypertension 
OS 
left eye 
OU 
both eyes 
POAG 
Primary Open Angle Glaucoma  
PP 
Per-Protocol 
PT 
Preferred Term 
q.a.m. 
every morning 
q.p.m. 
every afternoon/evening 
RGC 
retinal ganglion cells 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
WHODRUG 
World Health Organization Drug Dictionary 


 
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1 Introduction 
This document presents the statistical analysis plan (SAP) for D. Western Therapeutics Institute, Inc. 
Protocol H1337-CS202: A Phase 2b Randomized, Double-masked, Active-controlled, Dose-response 
Study of the Safety and Efficacy of H-1337 in Subjects with Primary Open Angle Glaucoma (POAG) 
or Ocular Hypertension (OHT). This SAP describes the endpoints, datasets and analyses planned for 
the efficacy and safety of this study. The variables and methods described in this plan supersede those 
described in the protocol. If revisions are needed after finalizing, then this document will be amended. 
All SAP amendments will be finalized prior to locking the database. All deviations from the analyses 
described in the final SAP will be noted in the clinical study report. 
This analysis plan is based on protocol version 3.0, dated 19JAN2024. 
1.1 Study 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. As elevated intraocular pressure (IOP) is a major 
risk for loss of visual field and optic nerve, reduction of IOP by medical, laser and/or surgical means 
is the current standard of care for patients with glaucoma. While there are many therapies available, 
each has its own benefits and risks. Some patients, even with proper diagnosis and treatment, still 
continue to have progressive glaucomatous loss of visual function and/or optic nerve. 
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 IOP 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. 
In a previous controlled study, H-1337 Ophthalmic Solution showed clinically and statistically 
significant ocular hypotensive activity and was well tolerated, with a relatively low incidence of 
hyperemia. The present study aims to extend the previous findings with additional concentrations and 
doses, as well as including an active control (timolol ophthalmic solution). 
 
 
 
 
 


 
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2 Study Objectives 
2.1 Primary Objective 
The primary objective of this study is to evaluate the ocular hypotensive efficacy of 3 dose regimens 
of H-1337 compared to timolol maleate 0.5% in subjects with POAG or OHT treated for up to 28 days.   
2.2 Secondary Objective 
The secondary objective of this study is to evaluate the local ocular and systemic safety of 3 dose 
regimens of H-1337. 
2.3 Exploratory Objective 
The exploratory objective of this study is to evaluate the efficacy of diurnal IOP measurements of 3 
dose regimens of H-1337 compared to timolol 0.5%. 
2.4 Primary Efficacy Endpoint 
The primary efficacy measure is the mean change in IOP from Baseline IOP (mmHg) in the study eye 
for each group on Day 28 at each matched time point as compared to Timolol. 
2.5 Secondary Efficacy Endpoints 
The secondary efficacy endpoints of the study are as follows: 
• 
The observed IOP, change from Baseline, and % change from Baseline in IOP in the study eye 
at each matched time point at each visit. 
• 
The observed mean diurnal IOP, change from Baseline and % change from Baseline in the 
study eye in mean diurnal IOP at each visit, 
• 
The proportion of subjects with IOP ≤ 18 mmHg in their study eye at each time point at each 
visit, and with the mean diurnal IOP ≤ 18 mmHg in the study eye for each visit. 
2.6 Safety Endpoints 
The safety endpoints of the study are as follows: 
• 
Incidence of Ocular and systemic Adverse Events (AE), 
• 
The observed blood pressure and pulse, and change from Baseline at each visit, 
• 
The observed best-corrected visual acuity (BCVA) and change from Baseline at each visit. 
 
 
 


 
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3 Study Design and Procedures 
3.1 Overall Study Design 
This is a parallel group, double-masked, active-controlled study to evaluate the ocular hypotensive 
efficacy of 3 dose regimens of H-1337 compared to timolol maleate 0.5% in subjects with POAG or 
OHT treated for up to 28 days. 
Each subject’s participation will consist of two phases: a Screening Phase (Screening and Baseline 
Visits) where subjects will suspend dosing of any current ocular hypotensive therapy, and a Dosing 
Phase, starting on Day 1. 
Following the washout period (if required), the subject will return for applicable inclusion/exclusion 
evaluations at the Baseline Visit (Day 1). A subject meeting all inclusion/exclusion criteria at Pre-T0   
will be randomized to the Investigational Product (IP). Both eyes will be dosed and evaluated for safety 
throughout the trial.  
Dosing will be initiated at Day 1. Subjects will be dosed for up to 28 days during which time they will 
be monitored for safety, tolerability, and efficacy. 
Subjects will be randomized to 4 arms: 
• 
Group 1: H-1337 0.6% Ophthalmic Solution b.i.d. 
• 
Group 2: H-1337 1.0% Ophthalmic Solution b.i.d. 
• 
Group 3: H-1337 1.0% Ophthalmic Solution q.a.m. and H-1337 placebo q.p.m. 
• 
Group 4: Timolol 0.5% Ophthalmic Solution b.i.d 
The trial will evaluate the safety and efficacy of 3 dose regimens of H-1337 and timolol maleate (0.5%, 
b.i.d.) OU for 28 days. 
Efficacy evaluation will be made based upon the study eye.  
3.2 Schedule of Visits and Assessments 
The schedule of visits is defined as follow: 
• 
Screening Visit 
• 
Day 0 
• 
Day 1 
• 
Day 7 
• 
Day 14 
• 
Day 28 
A schedule of study assessments and procedures is available in Appendix 1. 
3.3 Sample Size Justification 
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 non-inferior to the timolol control in the 
reduction of IOP. As benefit is represented by a negative number, non-inferiority is achieved when the 
upper limit of the confidence interval of the difference in treatment (H-1337 minus Timolol) is strictly 
lower than the non-inferiority margin. 
A sample size of 45 subjects per group will allow for at least 90% power to establish non-inferiority 
of H-1337 over Timolol based on a non-inferiority limit of 2 mmHg, a standard deviation of 3.0 mmHg 
and a 1-sided t-test (alpha=0.05). 
Assuming that 10% of the subjects will not be eligible in the Intent-to-Treat (ITT) population, a total 
of 50 subjects per group is required. 
3.4 Analysis Populations 
3.4.1 Safety Analysis Population 
The Safety population is comprised of all randomized subjects who receive at least one dose of IP. If 
subjects received the wrong IP at any time during the study, the IP actually received for the 
majority of the study will be used as the treatment group for that subject. 


 
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3.4.2 Intent-to-Treat Population 
The ITT population is defined as all randomized. Subjects will be analyzed according to the treatment 
assigned at randomization, irrespective of dosing adherence or any deviations in the IP received. 
3.4.3 Per-Protocol Population 
The Per-Protocol (PP) population is defined as subjects from the ITT population who satisfy pre-
randomization inclusion/exclusion criteria, receive at least dose of IP and complete at least one on-
therapy study visit. Individual subject visits and data points that do not satisfy protocol criteria may be 
excluded from PP analyses. Evaluability will be determined prior to unmasking of treatment 
assignments.  
 
 
 
 
 


 
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4 Statistical Methodology 
4.1 Definitions and Conventions 
Listings present the subjects individual data, while summary tables present the summary statistics of 
subjects data. 
Summary statistics will be presented for continuous variables, by way of n, mean, standard deviation 
(SD), median, minimum and maximum. For categorical variables including binary variables, frequency 
counts and percentages will be presented. Percentages will be calculated using the total number of 
subjects per treatment groups or the total number of subjects with an assessment per treatment groups, 
depending on the nature of the analysis.  
In addition, 95% 2-sided confidence intervals (CIs) will be presented, where relevant. In case of 
percentages, the CI will be computed using the Clopper-Pearson method. The CI will be computed for 
continuous variables using a t-test analysis. 
Summary statistics will be displayed by treatment groups, which will be labelled as follow: 
• 
Group 1: H-1337 0.6% 
• 
Group 2: H-1337 1.0% b.i.d 
• 
Group 3: H-1337 1.0% q.a.m 
• 
Group 4: Timolol 0.5% 
Baseline Value is defined as the last non-missing value prior to the first IP administration for vital 
signs, BCVA, biomicroscopy and dilated ophthalmoscopy (Day 1 Pre-T0 for vital signs, BCVA and 
biomicroscopy; Screening for dilated ophthalmoscopy). For IOP and conjunctival hyperemia grading, 
time-matched baseline values are defined at Pre-T0 on Day 1 (Visit 3), T0+2 hours, T0+4 hours, T0+8 
hours and T0+12 hours on Day 0 (Visit 2). For mean diurnal IOP, baseline is defined at Day 0. 
Change from Baseline is defined as the difference in value of the assessment between the considered 
visit and the baseline value. In the case of IOP and conjunctival hyperemia grading, change from 
Baseline is the difference in value of the assessment between the considered visit at a particular 
timepoint and the corresponding baseline value. 
Study eye is defined as the eye that meets all entry criteria including the IOP criteria after washout. 
Should both eyes meet the criteria then the study eye will be the eye with the higher 8 am IOP at 
Baseline (Day 1). If both eyes have the same 8 am IOP at Baseline (Day 1), the study eye will be the 
right eye. 
SAS® version 9.4 or above will be used to perform the analyses.  
4.2 Handing of Missing Data 
To reduce the incidence of missing data, sites and subjects will be trained in methods to encourage 
continued participation to maximize the completion rate and overall quality of the trial. With regard to 
the primary efficacy variable, IOP, there are steps taken in the procedure for collecting these data to 
minimize the likelihood of spurious data. 
Missing data will not be imputed. 
4.3 Adjustment for Multiplicity 
To account for the multiple comparisons of the primary endpoints, adjustment for multiplicity will be 
fulfilled by using a hierarchical testing, based on a fixed-sequence procedure defined in Table 1.  
First, the primary endpoint is tested for non-inferiority at all 5 time points at Day 28 and all 4 on-
treatment time points at Day 1 for the first pre-defined Group comparison listed in Table 1. If the upper 
limit of the 2-sided 95% CI of the difference between H-1337 and Timolol is strictly lower than the 
value 1.5, then non-inferiority is concluded. If non-inferiority is concluded at the 9 timepoints, then 
testing of the second listed Group Comparison in Table 1 can take place at the 2-sided alpha level of 
0.05. Otherwise, non-inferiority cannot be concluded and no further formal testing takes place. 
The same sequential approach is then applied to the remaining endpoints listed in Table 1. Endpoints 
are tested in the order defined in Table 1.  
For the first 3 rows in Table 1, non-inferiority at the 1.5 threshold at all 9 timepoints must be shown to 
allow to proceed to the next row. For the last 3 rows in Table 1, non-inferiority at the 1.0 threshold at 
5 or more timepoints must be shown to allow to proceed to the next row. 
 


 
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Table 1  Pre-defined Sequence for Hierarchical Testing  
Order Group Comparison 
Non-Inferiority Criteria 
1 
H-1337 1.0% Ophthalmic Solution b.i.d. vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.5 threshold at all 9 time points 
2 
H-1337 0.6% Ophthalmic Solution b.i.d vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.5 threshold at all 9 time points 
3 
H-1337 1.0% Ophthalmic Solution q.a.m. vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.5 threshold at all 9 time points 
4 
H-1337 1.0% Ophthalmic Solution b.i.d. vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.0 threshold at 5 or more time points 
5 
H-1337 0.6% Ophthalmic Solution b.i.d vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.0 threshold at 5 or more time points 
6 
H-1337 1.0% Ophthalmic Solution q.a.m. vs 
Timolol 0.5% Ophthalmic Solution b.i.d 
1.0 threshold at 5 or more time points 
4.4 Disposition 
The number and percentage of subjects enrolled (signed informed consent), randomized, and the 
number of subjects who receive at least one dose of IP will be summarized by treatment groups and 
overall. The following additional summaries will be presented: 
• 
The number and percentage of subjects included in the Safety Analysis population, the ITT 
population and the PP population; 
• 
The number and percentage of subjects who complete the study; 
• 
The number and percentage of subjects who withdraw from the study and the reason for 
withdrawal; 
• 
The number and percentage of subjects with a protocol violation and with a major protocol 
violation; 
• 
The number and percentage of subjects who attend a study visit, for each study visit. 
Percentages will be calculated on the number of subjects who are randomized. 
4.5 Washout Period 
A listing including information on whether a subject enters the washout period or not, the type of used 
ocular hypotensive therapy and the length of the washout period will be created for each subject in the 
Safety Analysis Population.  
4.6 Demographics and Baseline Characteristics 
Gender, age, ethnicity, race and iris colour will be summarized by treatment groups and overall. 
Age will be calculated as the number of years, as an integer value, from date of birth to the date of the 
informed consent signature. In other words, age is the truncated integer of the difference between date 
of birth and the date of the informed consent signature. 
Baseline IOP, BCVA and central corneal thickness (measured by pachymetry) will be summarised by 
treatment group (and overall) and eye (study eye and fellow eye). Central corneal thickness will be 
calculated as the mean of the 3 collected measurements. 
Gonioscopy 
The number and percentage of subjects with a confirmed normal anatomy will be summarized by 
treatment group (and overall) and eye. In addition, the number and percentage of subjects within each 
category of the Shaffer grade will be summarized by treatment group (and overall) and eye (study eye 
and fellow eye). 
Visual Fields 
The number and percentage of subjects with a normal, abnormal not clinically significant and abnormal 
clinically significant visual fields assessment will be summarized by treatment group (and overall) and 
eye (study eye and fellow eye). This will be calculated on the subgroup of eyes with a visual fields 
assessment meeting the protocol definition of reliability. 
Summaries will be presented for the Safety, ITT and PP populations.  


 
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4.7 Medical and Ocular History 
Medical and ocular history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 26 or higher. 
The number and percentage of subjects under each medical history term, coded by system organ class 
(SOC) and preferred term (PT), will be summarized by treatment for the safety population. Ocular 
history will also be presented on both the study eye and the fellow eye. All percentages will be based 
on the number of subjects or eyes in the safety population within each treatment group. If a subject has 
a medical/ocular history term more than once, the subject will be counted only once under any given 
SOC or PT. 
4.8 Prior and Concomitant Medications 
All medications will be coded using the World Health Organization drug dictionary (WHODRUG) 
version January, 2023 or higher. 
Incidence of prior and concomitant medication will be presented by treatment, Anatomical Therapeutic 
Chemical (ATC) Level 4 and PT for the safety population. Ocular medication will be presented on 
both the study eye and the fellow eye combined. 
Prior medications are those that start and stop before exposure to treatment. Concomitant medications 
are all medications taken during the study period, including those started before but ongoing at the 
time of the first IP dose. 
A subject with more than one occurrence of the same medication in a particular ATC class will be 
counted only once in the total of those reporting medications in that particular ATC class.  
4.9 Concomitant Procedures 
Procedures will be coded using the MedDRA Version 26 or higher. 
The number and percentage of subjects under each procedure term, coded by SOC and PT, will be 
summarized by treatment for the safety population. Percentages will be based on the number of subjects 
in the safety population within each treatment group. If a subject has a procedure term more than once, 
the subject will be counted only once under any given SOC or PT. 
4.10 Treatment Exposure 
The number and percentage of subjects by number of missed doses will be summarized by eye and 
treatment. In addition, the number of missed doses will be summarized by eye and treatment using 
summary statistics for continuous variables. 
Duration of drug exposure is defined as the number of days a subject receives an IP dose. The number 
and percentage of subjects in each category will be summarized by eye and treatment. The categories 
are: <7 days, 7 to <14 days, 14 to <21 days, 21 to <28 days, ≥28 days. 
4.11 Efficacy Analyses 
All efficacy analyses will be performed using both the ITT and PP populations. Missing values will 
not be imputed. 
4.11.1 Primary Efficacy Analyses 
Change from Baseline in IOP (mmHg) at Day 28 and Day 1 (on-treatment time points) in the study 
eye is the primary efficacy endpoint. It will be summarized by timepoint and treatment group in the 
ITT population primarily and in the PP population secondarily. The endpoints will be analysed using 
an analysis of covariance (ANCOVA) model including baseline value and treatment groups as 
independent variables. The least square (LS) means, standard error (SE) and 2-sided 95% CI will be 
reported for each treatment group at each post-randomization visit. 
In addition, the differences between treatments (H-1337 vs Timolol) will be calculated for each H-
1337 treatment group. A time-matched longitudinal model adjusting for baseline and including a 
random effect for subject will be used to calculate the LS mean, SE, and 2-sided 95% CI for the 
between-treatments differences. The model will also be tested for treatment by visit and treatment by 
time points interactions. If no interactions are detected, the main effect model will be used. The 
variance-covariance matrix-structure used in the model will be the unstructured (TYPE=UN). If 
convergence is not achieved, a compound-symmetry structure will be used (TYPE=CS). 
The testing procedure for non-inferiority will be performed as described in Section 4.3.  
Missing values will not be imputed. 


 
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All summaries generated for IOP will be using the mean/median value recorded in the case report form. 
4.11.2 Secondary Efficacy Analyses 
The secondary efficacy endpoints are all related to IOP in the study eye. 
Change from Baseline in IOP at Day 7 and Day 14 in the study eye will be summarised by visit, 
timepoint and treatment group. The endpoints will be analyzed using an ANCOVA model including 
baseline value and treatment groups as independent variables. The LS means, SE and 2-sided 95% CI 
will be reported for each treatment group at each post-randomization visit. 
In addition, the differences between treatments (H-1337 vs Timolol) will be calculated and summarised 
by visit, timepoint and treatment group (for each of the H-1337 groups). The ANCOVA model will be 
used to calculate the LS mean, SE, and, 2-sided 95% CI for the between-treatments differences. 
Similar analyses will be performed for the following endpoints: 
• 
IOP, 
• 
percentage change from Baseline in IOP, 
• 
mean diurnal IOP (12-hour diurnal), 
• 
change from Baseline in mean diurnal IOP (12-hour diurnal), 
• 
percentage change from Baseline in mean diurnal IOP (12-hour diurnal), 
• 
mean diurnal IOP (8-hour diurnal), 
• 
change from Baseline in mean diurnal IOP (8-hour diurnal), 
• 
percentage change from Baseline in mean diurnal IOP (8-hour diurnal). 
Where multiple IOP assessments are made on the same day, mean diurnal IOP (12-hour diurnal) is 
defined as the average of all multiple assessments (Pre T0 is excluded from the calculation). Mean 
diurnal IOP (8-hour diurnal) is defined as the average of all assessments up to 04:00pm (Pre T0 is 
excluded from the calculation). The visit at which a subject is missing more than (>) 2 assessments 
for the calculation of mean diurnal IOP will be excluded from the analysis in the PP population. 
The number and percentage of subjects with IOP ≤18 mmHg will be summarized by visit, timepoint 
and treatment group. The 2-sided 95% CI will be calculated using the Clopper-Pearson method. In 
addition, the difference in proportions between treatments (H-1337 vs Timolol) will be calculated and 
summarised by visit, timepoint and treatment group (for each of the H-1337 groups). The 2-sided 95% 
CI for the difference in proportions will be computed using the Wald method. 
A similar analysis will be performed for the following 2 endpoints: 
• 
number and percentage of subjects with mean diurnal IOP (12-hour diurnal) ≤18 mmHg, and 
• 
number and percentage of subjects with mean diurnal IOP (8-hour diurnal) ≤18 mmHg. 
4.11.3 Additional Efficacy Analyses 
Intraocular Pressure 
All analyses performed for IOP in the study eye will be repeated for the fellow eye. 
4.12 Safety Analyses 
All safety analyses will be performed in the Safety population. Missing data will not be imputed. 
4.12.1 Adverse Events 
Treatment-emergent adverse events (TEAE) are defined as AEs starting on or after the first dose of IP. 
A pre-existing event that worsens in severity after receiving the first dose of IP is treated as a new 
TEAE with date of onset set to the date of the increased severity. Summary tables will include TEAEs 
only. TEAEs will be summarized by treatment and overall. Non-treatment emergent AEs will be listed 
only. 
An ocular event is an event where the site of the event is reported as both eyes (OU), right eye (OD) 
or left eye (OS). 
Proportion of subjects reporting an event will be calculated based on the number of subjects in the 
corresponding treatment group. The 95% CI will be calculated using the Clopper-Pearson method. 
The number and percentage of subjects reporting any event, any non-ocular event, and any ocular event 
will be summarized. 


 
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An overall summary table of TEAE will be provided by treatment group and location (non-ocular and 
ocular) for the following categories: 
• 
Number and percentage of subjects with a TEAE 
• 
Number and percentage of subjects with a treatment-related TEAE 
• 
Number and percentage of subjects with a TEAE leading to IP discontinuation 
• 
Number and percentage of subjects with a TEAE leading to study discontinuation 
• 
Number and percentage of subjects with a serious TEAE 
• 
Number and percentage of subjects with a treatment-related serious TEAE 
• 
Number and percentage of subjects with a TEAE leading to death 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 26 or higher. 
The following summaries will be provided: 
• 
TEAEs by System Organ Class (SOC) and Preferred Term (PT) 
• 
Serious TEAEs by SOC and PT 
• 
TEAEs leading to IP discontinuation by SOC and PT 
• 
TEAEs leading to study discontinuation by SOC and PT 
• 
TEAE leading to death by SOC and PT 
• 
TEAEs by SOC, PT, and maximum severity 
• 
Treatment-related TEAEs by SOC and PT 
In the above summaries, when multiple events of the same SOC or PT are reported, subjects are 
counted only once under each SOC and PT. If a subject has the same AE on multiple occasions, the 
highest severity (severe, moderate, mild) recorded for the event will be presented. Missing severity 
will be considered as severe. Events reported as definitely, probably or possible related to IP and events 
with a missing relationship will be considered as related to IP. The above summaries will be ordered 
by overall descending frequency of SOC and then, within a SOC, by overall descending frequency of 
PT. 
In addition, listings for SAEs, deaths, and AEs leading to IP discontinuation will be provided. 
4.12.2 Vital Signs 
Heart rate and blood pressure (systolic and diastolic), and change from baseline, will be summarized 
by treatment group, visit and timepoint. 
4.12.3 Best-corrected Visual Acuity 
Best-corrected visual acuity (BCVA) and change from Baseline in BCVA will be summarized in the 
logMAR scale by eye (study eye and fellow eye), visit and treatment group.  
In addition, categorical summaries of change from Baseline in BCVA will be generated. The number 
and percentage of subjects with >2 lines loss, >1-2 lines loss, 0-1 line loss, >0 to 1 line gain, >1 to 2 
lines gain and >2 lines gain will be summarized by eye (study eye and fellow eye), visit and treatment 
group. 
4.12.4 Slit Lamp Biomicroscopy 
The number and percentage of subjects within each category of slit lamp examinations will be 
summarized by treatment group, visit, timepoint and eye (study eye and fellow eye). 
4.12.5 Conjunctival Hyperemia Grading 
The number and percentage of subjects within each grading category will be summarized by treatment 
group, visit, timepoint and eye. In addition, shift from baseline will be summarized by treatment group, 
visit, timepoint and eye (study eye and fellow eye). 
4.12.6 Dilated Ophthalmoscopy 
The number and percentage of subjects within each assessment category will be summarized by 
treatment group, visit and eye (study eye and fellow eye). 
4.13 Subgroup Analysis 
No subgroup analyses will be performed. 


 
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4.14 Interim Analysis 
No interim analysis is planned. 
 


 
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5 Summary of Changes from the Protocol 
The sample size section of the protocol refers to a non-inferiority limit of 2, while the thresholds of 1.5 
and 1 will be used in the analysis of the primary endpoint. 
In the protocol, the primary endpoint refers to Day 28 only. In the SAP, the primary endpoint is 
concluded as non-inferior based on the 5 time points at Day 28 and the 4 on-treatment time points at 
Day 1. 
 
 
 


 
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6 List of Programming Summary & Analysis Tables 
The list and layout of the summary tables and listings will be described in a separate document. 
 
 
 
 


 
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7 Appendices 
7.1 Appendix 1 – Time and Event Schedule 
 
 
 
 
 
 
 


 
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