Clinical trial NCT02829996
Conditions: Primary Open-Angle Glaucoma (POAG) Ocular Hypertension (OHT)
Keywords: glaucoma primary open-angle glaucoma ocular hypertension adenosine agonist eye drop trabodenoson trabecular meshwork
Sponsor: Inotek Pharmaceuticals Corporation
Start date: 2016-08-19; Completion date: 2017-05-31
Enrollment: 201 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase II, randomized, double-masked study to evaluate the efficacy and tolerability of topical ocular delivery of fixed-dosed combinations of trabodenoson and latanoprost in subjects with Ocular Hypertension or Primary Open-Angle Glaucoma.

All subjects who meet the study's enrollment criteria following Screening will undergo washout of all prohibited medications (if washout is needed), including their routine glaucoma medications. During the Placebo Run-In Period, placebo is applied twice daily to both eyes in all subjects. During the Treatment Period, study drug is applied to both eyes for a total of 8 weeks. Each subject will be assigned 4 weeks of AM and 4 weeks of PM dosing in a masked manner. AM vs PM dosing is masked utilizing Placebo in addition to the active drug product. During the Treatment Period, study drug (Active and Placebo) eye drop applications will occur twice daily, in the morning and in the evening. The Treatment Period will be followed by an Observation Period of approximately 7 days wherein no study eye drops are instilled.

The purpose of the study is to assess the overall benefit/risk profile of binocular topical application of different doses of trabodenoson (3.0% and 6.0%) when combined with latanoprost (0.005% or 0.0025%) one drop daily (QD) for 8 weeks.

Detailed description:
This is a phase II, randomized, double-masked study to evaluate the efficacy and tolerability of topical ocular delivery of fixed-dose combinations of trabodenoson and latanoprost in subjects with OHT or POAG.

The Primary Objective of this Trial is to evaluate the efficacy of different topical ocular doses of trabodenoson (3.0% and 6.0%) when added to latanoprost (0.005% or 0.0025%), one drop daily to both eyes over two consecutive 4 week periods. The Secondary Objective is to evaluate the tolerability and safety of different doses of trabodenoson (3.0% and 6.0%) when added to latanoprost (0.005% or 0.0025%), one drop daily to both eyes over two consecutive 4 week periods. the Hypotheses is that topical ocular co-administration of 3.0% or 6.0% trabodenoson plus latanoprost 0.0025% or 0.005% ophthalmic formulation will reduce IOP and be well-tolerated.

All subjects who meet the study's enrollment criteria following Screening will undergo washout of all prohibited medications, including their routine glaucoma medications. During the Placebo Run-In Period, placebo (vehicle control matched to trabodenoson) is applied twice daily to both eyes in all subjects. During the Treatment Period, study drug is applied to both eyes for a total of 8 weeks. Each subject will be assigned 4 weeks of AM and 4 weeks of PM dosing in a manner that is masked to the patient. The Treatment Period will be followed by an Observation Period of approximately 7 days wherein no study eye drops are instilled.

To mimic what is generally seen in clinical trials, the number of subjects with ocular hypertension as their diagnosis will be limited to approximately 30% of the total subjects enrolled. Additionally, so the trial mirrors the general population demographics (so as to improve generalizability of the results) the proportion of African American subjects will be approximately 25% or less but not less than 12% of the total subjects enrolled.

The purpose of the study is to assess the efficacy, tolerability, and safety of binocular topical application of different doses of trabodenoson (3.0% and 6.0%) when added to latanoprost (0.005% or 0.0025%) one drop daily over two consecutive 4 week periods in subjects with POAG or OHT. Data collection will include efficacy (masked-IOPs), local (ophthalmic) and systemic tolerability and safety assessments

Arms: arm 1: trabodenoson 6.0% / latanoprost 0.005% QD FDC arm 2: trabodenoson 3.0% / latanoprost 0.005% QD FDC arm 3: trabodenoson 6.0% /latanoprost 0.0025% QD FDC arm 4: latanoprost 0.005% ophthalmic solution QD arm 5: latanoprost 0.0025% ophthalmic solution QD
Interventions: intervention 1: trabodenoson 6.0% / latanoprost 0.005% QD intervention 2: trabodenoson 3.0% / latanoprost 0.005% QD intervention 3: trabodenoson 6.0% / latanoprost 0.0025% QD intervention 4: latanoprost 0.005% QD intervention 5: latanoprost 0.0025% QD
Intervention descriptions: intervention 1: Trabodenoson 6.0% / latanoprost 0.005% administered once per day in both eyes and placebo administered once per day in both eyes, for 8 weeks. intervention 2: Trabodenoson 3.0% / latanoprost 0.005% administered once per day in both eyes and placebo administered once per day in both eyes, for 8 weeks. intervention 3: Trabodenoson 6.0% / latanoprost 0.0025% administered once per day in both eyes and placebo administered once per day in both eyes, for 8 weeks. intervention 4: Latanoprost 0.005% administered once per day in both eyes and placebo administered once per day in both eyes, for 8 weeks. intervention 5: Latanoprost 0.0025% administered once per day in both eyes and placebo administered once per day in both eyes, for 8 weeks.

Protocol documents:
Prot_001.pdf: 
Trabodenoson/Latanoprost Fixed-Dose Combination
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1. 
CLINICAL PROTOCOL 
Clinical Protocol Number: 
IPC-02-2015 
Final Clinical Protocol Date: 
1 December 2015 
Clinical Protocol Version: 
3.0 
Clinical Protocol Amendment Date: 26 June 2016 
Clinical Protocol Amendment: 
2.0 
Study Drug Identification: 
Trabodenoson/Latanoprost Fixed-Dose Combination 
Clinical Protocol Title (Long): 
A Phase II, Randomized, Double-masked Study to 
Evaluate the Efficacy, Safety and Tolerability of Topical 
Ocular Administration of Fixed-Dose Combinations of 
Trabodenoson and Latanoprost in Subjects with Ocular 
Hypertension or Primary Open-Angle Glaucoma. 
Clinical Protocol Title (Short): 
A Phase II Investigation of Fixed-Dose Combinations of 
Trabodenoson and Latanoprost in Subjects with Ocular 
Hypertension or Primary Open-Angel Glaucoma. 
Study Phase: 
Phase II 
U.S. IND NO. 
10092 
Sponsor: 
 
Inotek Pharmaceuticals Corporation 
91 Hartwell Avenue, Second Floor 
Lexington, MA  02421, US 
Tel: 781-676-2100  Fax: 781-676-2155 
Sponsor Medical Monitor: 
 
Cadmus C. Rich, M.D., MBA, CPE 
Inotek Pharmaceuticals Corporation  
VP of Medical Affairs and Clinical Development 
Sponsor Signatory: 
Rudolf Baumgartner, M.D. 
Executive Vice President  
and Chief Medical Officer  
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) as set forth 
in the International Conference on Harmonisation (ICH) guidelines on GCP (ICH E6),  
and applicable local regulatory requirements. 
The concepts and information contained herein are confidential and proprietary to Inotek Pharmaceuticals 
Corporation and shall not be distributed or disclosed in whole or in part without the expressed written 
permission of Inotek Pharmaceuticals Corporation. 
 




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1.2. 
Investigator Signature Page 
 
Clinical Protocol Number: 
IPC-02-2015 
Final Clinical Protocol Date: 
1 December 2015 
Clinical Protocol Version: 
3.0 
Clinical Protocol Amendment Date: 
26 June 2016 
Clinical Protocol Amendment 
2.0 
Study Drug Identification: 
Trabodenoson/Latanoprost Fixed-Dose Combination 
Clinical Protocol Title: 
A Phase II, Randomized, Double-masked Study to 
Evaluate the Efficacy, Safety and Tolerability of Topical 
Ocular Administration of Fixed-Dose Combinations of 
Trabodenoson and Latanoprost in Subjects with Ocular 
Hypertension or Primary Open-Angle Glaucoma. 
I have read and understand this protocol and concur with the study design. I agree to participate 
as an Investigator and to conduct the study in accordance with the protocol, the Food and Drug 
Administration (FDA) Code of Federal Regulations (CFR) for Good Clinical Practice (GCP), 
the International Conference on Harmonization (ICH) Guidelines and local regulations. 
 
Site Number: 
 
 
Investigator’s Name: 
 
 
Investigator’s Signature: 
 
 
Date: 
 
____/________/______ 
 
 
dd 
mmm 
yyyy 
 


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2. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Inotek Pharmaceuticals Corporation 
Name of Investigational Product: Trabodenoson (INO-8875) ophthalmic formulation 
Title of Study: A Phase II, Randomized, Double-masked Study to Evaluate the Efficacy, Safety and 
Tolerability of Topical Ocular Administration of Fixed-Dose Combinations of Trabodenoson and 
Latanoprost in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma. 
Study center(s):  Multi-center, approximately 40 sites within the United States (US).  
Study Duration: ~17 Months 
Phase of development: 2 
Objectives:  
Primary objective: 
• 
To evaluate the efficacy of different topical ocular doses of trabodenoson (3.0% and 6.0%) 
when added to latanoprost (0.005% or 0.0025%), one drop daily to both eyes over two 
consecutive 4 week periods. 
Secondary objectives:  
• 
To evaluate the tolerability and safety of different doses of trabodenoson (3.0% and 6.0%) 
when added to latanoprost (0.005% or 0.0025%), one drop daily to both eyes over two 
consecutive 4 week periods. 
Study Design:  
This is a phase II, randomized, double-masked study to evaluate the efficacy and tolerability of topical 
ocular delivery of fixed-dosed combinations of trabodenoson and latanoprost in subjects with OHT or 
POAG. 
All subjects who meet the study’s enrollment criteria following Screening will undergo washout of all 
prohibited medications (if washout is needed), including their routine glaucoma medications.  During 
the Placebo Run-In Period, placebo (vehicle control matched to trabodenoson) is applied twice daily to 
both eyes in all subjects.  During the Treatment Period, study drug is applied to both eyes for a total of 
8 weeks.  Each subject will be assigned 4 weeks of AM and 4 weeks of PM dosing in a masked 
manner.  The Treatment Period will be followed by an Observation Period of approximately 7 days 
wherein no study eye drops are instilled.  
The purpose of the study is to assess the efficacy, tolerability, and safety of binocular topical 
application of different doses of trabodenoson (3.0% and 6.0%) when combined with latanoprost 
(0.005% or 0.0025%) one drop daily over two consecutive 4 week periods in subjects with POAG or 
OHT.  Data collection will include efficacy (masked-IOPs), local (ophthalmic) and systemic 
tolerability and safety assessments. 
Number of subjects (planned): ~165 
Inclusion / Exclusion Criteria 
Inclusion Criteria: 
1. Subject provides written informed consent prior to any study-related procedure not part of 
normal medical care. 


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Name of Sponsor/Company: Inotek Pharmaceuticals Corporation 
Name of Investigational Product: Trabodenoson (INO-8875) ophthalmic formulation 
2. Subject has the diagnosis of OHT or POAG (subjects with secondary, exfoliative, and/or 
pigmentary glaucomas are excluded from the trial). 
3. Subject with at least 1 eye that meets each of the following criteria in the same eye: (1) mean 
8AM IOP ≥25 and ≤34 on Placebo Run-In Visit, Day -1, and Day 1 (AM predose) mmHg; and 
(2) mean IOP ≥21 mmHg on Day -1 at 8 hours post-dose (~4PM). IOP is taken by Goldmann 
Applanation Tonometry and is not corrected for central corneal thickness. (If one eye fails this 
criterion but the second eye meets this criterion and all other enrollment criteria are met, the 
subject can be randomized). 
4. Subject is aged 18 years or older; 
If female, subject must not be pregnant or nursing, and is either: 
a. Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically 
sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or 
b. Of childbearing potential and meets at least 1 of the following: 
i. 
Is practicing an effective method of contraception (e.g., a. double barrier method, 
b. oral/parenteral contraceptives plus barrier, c. intrauterine device plus barrier), or 
ii. 
Has a vasectomized partner (at least 90 days post vasectomy procedure), or 
iii. 
Is practicing abstinence from sexual intercourse. 
Subjects must be willing to practice the chosen contraceptive method or remain abstinent 
during the conduct of the study and for at least 1 month after last dose of study medication. 
Non-vasectomized males (with a partner of childbearing potential) are required to practice 
effective birth control methods (e.g., abstinence, use of condom [or other barrier device] along 
with partners oral/parenteral contraceptives) during the conduct of the study and for at least 1 
month after last dose of study medication; 
Exclusion Criteria: 
1. Subject has clinically significant abnormalities in their medical history or from the results of 
the physical examinations, vital signs, or clinical laboratory tests performed at Screening or 
during the Placebo Run-in period that may put the subject at risk in this trial or cause the 
subject not to complete the trial per protocol by the Investigator’s judgment (Examples of 
clinically significant laboratory results include: both aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) > 2 times upper limit of normal (ULN) or either >3.0 times 
ULN, Total bilirubin > 2.0 times ULN, BMI > 40 kg/M2, Hemoglobin A1C > 8.0%, or 
creatinine clearance <50 ml/min). 
Note: Subject with creatinine clearance <50 ml/min may still be eligible upon review and 
written approval by the Inotek Medical Monitor or his designee (a Board-certified physician) 
following review of the current medications, laboratory values, and medical history.   
2. Subject has any new clinically significant field loss within the past year in either eye, or any 
non-glaucomatous ophthalmologic disease that might exacerbate during the trial. 


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Name of Sponsor/Company: Inotek Pharmaceuticals Corporation 
Name of Investigational Product: Trabodenoson (INO-8875) ophthalmic formulation 
3. Subject’s ETDRS BCVA Snellen equivalent is worse than 20/80 in either eye. 
4. Subject has a vertical cup-to-disc ratio >0.8 or an IOP in either eye above 34 mmHg at any 
examinations prior to Day 1 dosing in either eye. 
5. Subject has a central corneal thickness <490 µm or >610 µm at Screening in both eyes. (If 
only one eye is excluded based upon this criterion but the second eye does not meet this 
exclusion or any other exclusion criteria, the subject can be included).   
6. Subject is currently taking any drug that in the opinion of the Investigator might affect IOP 
including oral or ocular glucocorticoids. (Low to moderate stable doses [no change for 30 
days] of nasal or dermatologic steroids are permitted). 
7. Subject received oral/systemic beta-blocker within 28 days of screening.   
8. Subject has history of clinically significant trauma to the globe of both eyes. (If only one eye is 
excluded based upon this criterion but the second eye does not meet this exclusion or any other 
exclusion criteria, the subject can be included).   
9. Subject has had ocular or orbital surgery (conventional or laser, such as SLT or ALT) to both 
eyes (If only one eye is excluded based upon this criterion but the second eye does not meet 
this exclusion or any other exclusion criteria, the subject can be included). 
However, the following procedures are not exclusionary: 
a. At least 1 year prior to Screening: retinal laser, cataract extraction (no surgical 
complications such as capsular rupture or vitreous loss), peripheral iridotomy (with 
otherwise open angle per Exclusion Criteria # 25), and other extraocular (e.g., tear duct, 
pterygial, or palpebral) surgeries. 
b. At least 180 days prior to Screening: uncomplicated YAG laser capsulotomy. 
10. Subject has any ocular abnormality that in the opinion of the Investigator might preclude 
reliable applanation tonometry in either eye. 
11. Subject has a fundus in either eye that in the opinion of the Investigator cannot be well-
visualized with pupillary dilation.  
12. Subject has a history of or current retinal condition that, in opinion of the Investigator, could 
affect BCVA (i.e., diabetic retinopathy, central or branch retinal vein occlusion, cystoid 
macular edema, etc). 
13. Subject cannot, or is unwilling to, function without contact lenses from Placebo Run-In Visit 
through the completion of the End-of-Study Visit. 
14. Subject uses oral sympathomimetics (e.g., pseudoephedrine) within 14 days of start of Placebo 
Run-In Period, or the Investigator feels may be required during the study. 
15. Subject used inhaled bronchodilators and/or inhaled steroids more than once per week on the 
average in the past 90 days, or the Investigator feels may be required during the study. 


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Name of Sponsor/Company: Inotek Pharmaceuticals Corporation 
Name of Investigational Product: Trabodenoson (INO-8875) ophthalmic formulation 
16. Subject uses dipyridamole, theophylline, or other adenosine antagonist medication within 4 
days of the start of the Placebo Run-In Period, or the Investigator feels may be required during 
the study. 
17. Subject used any of the following drugs (alone or in combination) for treatment of 
ophthalmologic illness: 
a. Parasympathomimetics or carbonic anhydrase inhibitors within 4 days of the start of the 
Placebo Run-In Period. 
b. Sympathomimetics or alpha adrenergic agonists within 14 days of the start of the Placebo 
Run-In Period. 
c. Topical ocular beta-blockers with 28 days of the start of the Placebo Run-In Period. 
d. Prostaglandins, prostamides or prostanoids within 35 days of the start of the Placebo Run-
In Period. 
18. Subject has any acute or chronic ophthalmologic illness requiring use of any non-IOP lowering 
ocular medication at screening and throughout study conduct (specific tear supplements are 
allowed as described in Section 9.3.9). 
19. Subject has a history of significant cardiac rhythm disturbance or a complete left bundle 
branch block (LBBB). (Examples of significant rhythm disturbances include PR intervals 
above 220 msecs, history of 2nd or 3rd degree blocks, acquired or congenital long QT 
syndrome, atrial fibrillation or other atrial arrhythmia, ventricular arrhythmia, bradycardia 
(<50 bpm), or ventricular pre-excitation (WPW). Subjects with PR intervals between 221 msec 
and 240 msec (inclusive) may only be enrolled following receipt of the written approval of the 
Inotek Medical Monitor or his designee (a Board-certified physician) so as to ensure an 
opportunity to review, as necessary, the subject’s ECG, medication and medical history with 
the study cardiologist.) 
20. Subject has clinically significant corneal and/or conjunctival findings (including clinically 
significant hyperemia) related to any recurrent or chronic conditions including allergic 
conjunctivitis, blepharitis, pegueculae/pterygium, or keratoconjunctivitis sicca that might recur 
or worsen during the study and confound the ophthalmologic safety data. 
21. Subject has a closed or occludable angle on gonioscopy (chamber angle less than 10 degrees), 
a history of angle-closure, or any non-POAG glaucoma (including neovascular glaucoma) in 
both eyes at Screening (if only one eye is excluded based upon this criterion but the second eye 
does not meet this exclusion or any other exclusion criteria, the subject can be included). 
22. Subject has a history of, or current, uveitis or any other inflammatory intraocular disease of 
either eye, unless the inflammatory process was caused by a topical ophthalmic medication 
that was stopped and has been in full remission for at least 1 year.   
23. Subject received any investigational device or product within 30 days prior to the start of the 
Placebo Run-In Period or has ever been rejected on medical or psycho-social grounds from 
participation in a clinical trial.  


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Name of Sponsor/Company: Inotek Pharmaceuticals Corporation 
Name of Investigational Product: Trabodenoson (INO-8875) ophthalmic formulation 
24. Subject has a history of allergy to more than 3 structurally unrelated medications, unless 
approved in writing by the Sponsor Medical Monitor (or their designees, a Board-certified 
physician). 
25. Subject has a history of significant sensitivity to latanoprost, trabodenoson, benzalkonium 
chloride, EDTA, or any of the other study drug excipients, or to local anesthetics or topical 
ophthalmic anesthetics such as lidocaine or to fluorescein. 
26. Subject is unable to discontinue the use of prohibited medications delineated in Section 9.3.9 
from the start of the Placebo Run-In Period through completion of the End-of-Study Visit. 
27. Subject is unable to limit their daily consumption to ≤ 24 ounces of beer, ≤ 8 ounces of wine, 
or ≤ 4 ounces of liquor from the start of the Placebo Run-In Period through completion of the 
End-of-Study Visit. 
28. Subject has any recent (acute) or chronic medical, psychiatric, drug or alcohol, or social 
problem that might in the opinion of the Investigator: (1) interfere with the subject’s 
performance or completion of the trial; (2) obfuscate the subject’s study data; or (3) render the 
subject unable to understand the nature, scope, and possible consequences of the study.  Or 
subject is likely to be noncompliant with the protocol (e.g., uncooperative attitude; a history of 
significant mental depression, panic attacks, or manic episodes; inability to return for all 
planned visits, and/or unlikelihood of completing the study). 
29. Subject is involved in any aspect of trial conduct including, Investigator, Sub-Investigator, 
other site staff, and/or immediate family members (first degree relative, spouse, adoptees, legal 
dependents) or employee of Inotek. 
Investigational product:  
The latanoprost-only ophthalmic solutions for use in this trial are sterile, isotonic, buffered aqueous 
solutions of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 
mOsmol/kg. Each mL contains either 25 (0.0025%) or 50 (0.005%) micrograms of latanoprost. 
Benzalkonium chloride (BAC), 0.02% is added as a preservative. The inactive ingredients are: sodium 
chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, and 
water for injection.  
Trabodenoson/latanoprost Fixed Dose Combinations (FDCs) are aqueous ophthalmic suspensions 
containing latanoprost and trabodenoson with a pH of approximately 6.5, containing 0.01% BAK and 
0.03% Ethylenediaminetetraacetic acid (EDTA) as preservatives.  The inactive ingredients are: 
carboxymethyl cellulose, polysorbate 80, monobasic sodium phosphate, boric acid, sodium chloride, 
and water for injection.   
The matched vehicle control/placebo (MVC/placebo) product is composed of the same inactive 
ingredients as the trabodenoson/latanoprost FDCs, but without trabodenoson and latanoprost. 


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Name of Sponsor/Company: Inotek Pharmaceuticals Corporation 
Name of Investigational Product: Trabodenoson (INO-8875) ophthalmic formulation 
Study Endpoints: 
Primary Efficacy Endpoint: 
• 
Daily IOP-change from diurnal baseline (average of the 4 diurnal changes from baseline 
calculated during a dosing interval) calculated at the Week 4 visit and the Week 8 visit. 
Secondary Efficacy Endpoints: 
• 
Daily IOP (average of the 4 serial IOPs taken during a dosing interval) calculated at the 
Week 4 visit and the Week 8 visit. 
• 
Daily IOP-change from study baseline (average of the 4 changes from study baseline 
calculated during a dosing interval) calculated at the Week 4 visit and the Week 8 visit. 
• 
Mean IOP at 8AM, 10AM, 12PM, and 4PM for the subject's ‘study' eye calculated at the 
end of each of the 4 weeks of treatment for each of the doses/combinations tested. 
• 
IOP change from diurnal baseline [this is the time-matched subtraction of each of the 4 
IOP timepoints of the circadian curve post randomization from the pre-randomization 
circadian curve] calculated at the end of the 4 weeks of treatment for each of the 
doses/combinations tested. 
• 
IOP change from study baseline [this calculates the change in IOP from the 8AM  
Day 1 baseline IOP] calculated at the end of the 4 weeks of treatment for each of the 
doses/combinations tested. 
Statistical methods:  
To address the primary objective of this trial, based on an assumed SD of 3.3 mmHg, a sample size of 
30 subjects in each group will provide an estimate of the effect on IOP with a 95% Confidence Interval 
with a ½ width (precision) of no greater than 1.2 mmHg. 
In order to compensate for an anticipated drop-out rate of 10%, approximately 33 subjects will be 
enrolled in each of the 5 treatment groups in order to complete the trial with approximately 165 
enrolled subjects and a total of 150 evaluable subjects. 
All analyses will be presented by treatment group.  Continuous variables will be described as the mean, 
median, standard deviation and range of n observations.  Categorical data will be described with 
contingency tables including frequency and percent.  Statistical analysis and data descriptions will be 
carried out using SAS statistical analysis software (SAS Institute, Inc., Cary, NC) version 9.3 or 
higher.  
Of note, the Statistical Analysis Plan (SAP) will supersede the protocol for all statistical purposes 
including endpoints, hierarchy, and comparisons of interest, subgroups and so forth. 
 
 
 


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SCHEDULE OF ASSESSMENTS 
Note: In the tables below, the number preceding a check denotes the number of times that a 
procedure is performed during that visit.  For example, 3√ means that procedure is performed 3 
times during that visit (specific timepoints are described in Section 9.2).  If no number appears, 
then the procedure is performed only once.  
The order of the assessments listed in Table 7, is random.  However, throughout the study, 
activities that could impact the findings on the external eye examination (e.g., topical ophthalmic 
eye drop application) are performed after any of the external eye assessments.  Masked-IOP 
measurements are performed prior to any assessment that might make the subject anxious or 
uncomfortable (e.g., vital signs, ECGs, or blood sampling) so as not to affect the IOP results.  
Investigators and site personnel will perform study procedures in their appropriate order, as 
delineated in the clinical protocol.     


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Table 7: 
Schedule of Assessments 
Study Period: 
Screening 
Period 
Range 
Washout and Placebo Run-in Period:  
Washout Range: 4 to 39 Days f 
Placebo Run-in Range: 5 to 9 Days 
Treatment Period:  
Day 1 to Day 56 (± 2) 
Observation Period:  
7 Days (± 1)  
after EOT 
 
Visit: 
Procedure: 
1 to 14 
Days  
Washout 
Visit e  
Placebo 
Run-In 
Visit a 
Day -1 a 
Day 1 a 
Day 28 a 
(± 2) 
End-of- Treatment 
(EOT) Visit 
Day 56 a (± 2) 
End-of-Study 
(EOS) Visit g 
7 Days (± 1) 
after EOT 
Informed consent procedures 
√ 
 
 
 
 
 
 
 
Demographics and medical history 
√ 
 
 
 
 
 
 
 
Medication History / Concomitant 
medications 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Enrollment criteria and/or safety data 
review 
√ 
√ 
√ 
√ 
√ 
 
 
 
Subject randomization 
 
 
 
 
√ 
 
 
 
Physical examination, complete (C) or 
directed (D) 
√C 
 
 
 
√D 
 
 
√C 
Height / weight 
√ 
 
 
 
 
 
 
 
Clinical laboratory tests (Central Lab) 
√ 
 
√ 
 
 
√ 
 
√ 
Pregnancy test for females, central (C) 
or at the site (S) 
√C 
Serum 
 
 
√S 
Urine 
 
 
√S 
Urine 
 
Adverse events review /reporting 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Modified ETDRS-BCVA 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
External eye examination h 
√ 
 
√ h 
√ h 
√ 
√ h 
√ h 
√ 
Slit Lamp examination 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Masked-IOPs  
√ 
 
√ 
4√ 
√ 
4√ 
4√ 
√ 
Dilated Fundus examination 
√ 
 
 
 
 
 
 
√ 
Vital signs 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
12-Lead ECG 
√ 
 
√ 
 
 
 
 
√ 
Gonioscopy c 
√ 
 
 
 
 
 
 
 


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Study Period: 
Screening 
Period 
Range 
Washout and Placebo Run-in Period:  
Washout Range: 4 to 39 Days f 
Placebo Run-in Range: 5 to 9 Days 
Treatment Period:  
Day 1 to Day 56 (± 2) 
Observation Period:  
7 Days (± 1)  
after EOT 
 
Visit: 
Procedure: 
1 to 14 
Days  
Washout 
Visit e  
Placebo 
Run-In 
Visit a 
Day -1 a 
Day 1 a 
Day 28 a 
(± 2) 
End-of- Treatment 
(EOT) Visit 
Day 56 a (± 2) 
End-of-Study 
(EOS) Visit g 
7 Days (± 1) 
after EOT 
Central corneal thickness d 
√ 
 
 
 
 
 
 
 
Visual field test b 
√ 
 
 
 
 
 
 
√ 
Drug/Dosing accountability 
 
 
 
√ 
√ 
√ 
√ 
 
Washout prohibited medication 
 
√ 
√ 
√ 
 
 
 
 
Study drug dosing 
 
 
 
 
BID 
BID 
QAM 
 
Placebo Run-In dosing 
 
 
BID 
BID 
 
 
 
 
a  On Placebo Run-In Visit and Days -1, 1, 28, and 56 all procedures will take place at the Investigational site.  
b Measurements can be historical values within 90 days. 
c Measurements can be historical values within 180 days.   
d Measurements can be historical values within 1 year. 
e Upon conclusion of all Screening Period activities, subjects who still meet the study enrollment criteria are invited to attend a Washout Period Visit (if washout 
is needed). This visit may be accomplished in person at the investigative site or by phone. 
f Minimum length of washout required is described in Table 5. 
g End-of-Study Visit is calculated as 7 Days (± 1) after the actual occurrence of the EOT Visit. 
h Hyperemia assessments performed on Placebo Run-in Visit, Day -1, Day 28, and Day 56. 


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3. 
TABLE OF CONTENTS 
1. 
CLINICAL PROTOCOL..............................................................................................1 
1.1. 
Clinical Signature Page .................................................................................................2 
1.2. 
Investigator Signature Page ..........................................................................................3 
2. 
PROTOCOL SYNOPSIS .............................................................................................4 
3. 
TABLE OF CONTENTS ...........................................................................................13 
4. 
LIST OF ABBREVIATIONS.....................................................................................19 
5. 
BACKGROUND AND RATIONALE .......................................................................22 
5.1. 
Indication ....................................................................................................................22 
5.2. 
Ocular Hypertension, Glaucoma, and Medical Need .................................................22 
5.2.1. 
Ocular Hypertension ...................................................................................................22 
5.2.2. 
Primary Open-Angle Glaucoma .................................................................................22 
5.2.3. 
Unmet Medical Need ..................................................................................................22 
5.2.4. 
Pharmacology .............................................................................................................22 
5.3. 
Chemistry and Formulated Drug Products (Latanoprost Ophthalmic 
Solutions, Trabodenoson-Latanoprost Fixed Dose Combinations[FDCs], and 
Trabodenoson-Matched Vehicle Control/Placebo) ....................................................23 
5.4. 
Overview of Clinical Investigations Involving Trabodenoson Ophthalmic 
Formulations ...............................................................................................................24 
5.5. 
Study Rationale ...........................................................................................................25 
5.5.1. 
Role of Study in Development and Registration of Trabodenoson ............................25 
5.5.2. 
Dose and Posology Justification .................................................................................26 
5.5.2.1. 
Justification for Dose Selection ..................................................................................26 
5.5.2.2. 
Justification for Posology Selection ...........................................................................29 
5.6. 
General and Specific Risks .........................................................................................29 
5.6.1. 
General Risks ..............................................................................................................29 
5.6.2. 
Trabodenoson Risks ....................................................................................................29 
5.6.3. 
Latanoprost Risks .......................................................................................................31 
6. 
STUDY DESIGN .......................................................................................................32 
6.1. 
Study Plan, Purpose and Duration ..............................................................................32 
6.2. 
Objectives ...................................................................................................................32 
6.2.1. 
Primary Objective .......................................................................................................32 


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6.2.2. 
Secondary Objective ...................................................................................................32 
6.3. 
Hypotheses ..................................................................................................................32 
6.4. 
Study Period and Visit Schematics .............................................................................33 
6.4.1. 
Period Schematic and Goals .......................................................................................33 
6.5. 
Dosage, Dosage Form, Route, and Dose Regimen .....................................................33 
6.5.1. 
Dosing Regimen for Each Period ...............................................................................33 
6.5.2. 
Study Drug Administration and Drug Accountability ................................................35 
6.5.3. 
Self-Dosing .................................................................................................................36 
6.5.4. 
Definition of the Study Eye ........................................................................................36 
6.6. 
Study Population .........................................................................................................36 
6.7. 
Sample Size Justification ............................................................................................37 
6.8. 
Safety Monitoring and Reporting ...............................................................................37 
7. 
STUDY ASSESMENTS ............................................................................................38 
7.1. 
Study Assessments......................................................................................................38 
7.1.1. 
Primary Endpoint, Efficacy ........................................................................................38 
7.1.2. 
Secondary Endpoints, Efficacy ...................................................................................38 
7.1.3. 
Secondary Parameters, including Safety ....................................................................38 
8. 
STUDY POPULATION .............................................................................................39 
8.1. 
Number of Subjects ....................................................................................................39 
8.2. 
Study Enrollment Criteria ...........................................................................................39 
8.2.1. 
Inclusion Criteria ........................................................................................................39 
8.2.2. 
Exclusion Criteria .......................................................................................................40 
9. 
SCHEDULE OF ASSESSMENTS.............................................................................43 
9.1. 
Study Duration per Subject .........................................................................................46 
9.2. 
Study Periods, Visits, and Procedures ........................................................................46 
9.2.1. 
Pre-Screening ..............................................................................................................46 
9.2.2. 
Screening Period (1 to 14 Days) .................................................................................46 
9.2.3. 
Washout Period (4 to 39 Days) ...................................................................................48 
9.2.3.1. 
Washout Period Visit (if washout is needed) .............................................................48 
9.2.3.2. 
Washout Period (if washout is needed) ......................................................................49 
9.2.4. 
Placebo Run-In Period (5 to 9 Days) ..........................................................................49 
9.2.4.1. 
Placebo Run-In Visit ...................................................................................................49 


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9.2.4.2. 
Placebo Run-In Period ................................................................................................50 
9.2.4.3. 
Day -1 Visit .................................................................................................................51 
9.2.5. 
Treatment Period ........................................................................................................53 
9.2.5.1. 
Day 1 Visit ..................................................................................................................53 
9.2.5.2. 
Day 1 PM to Day 28 ...................................................................................................54 
9.2.5.3. 
Day 28 Visit ................................................................................................................54 
9.2.5.4. 
Day 28 PM to Day 56 .................................................................................................56 
9.2.5.5. 
End-of-Treatment (Day 56) Visit ...............................................................................56 
9.2.6. 
Observation Period (7 ±1 days) ..................................................................................57 
9.2.6.1. 
Observation Period .....................................................................................................57 
9.2.6.2. 
End-of-Study Visit (7 ±1 days) after EOT .................................................................58 
9.3. 
Study Procedure Details .............................................................................................59 
9.3.1. 
Subject Information and Consent Form ......................................................................59 
9.3.2. 
Enrollment and Randomization ..................................................................................59 
9.3.3. 
Masking Procedures ....................................................................................................59 
9.3.4. 
Study Drug Administration.........................................................................................60 
9.3.5. 
Demographics .............................................................................................................60 
9.3.6. 
Medical and Ophthalmologic History ........................................................................60 
9.3.7. 
Medication History .....................................................................................................61 
9.3.8. 
Concomitant Medications and Treatments .................................................................61 
9.3.9. 
Prohibited Medications ...............................................................................................61 
9.3.10. 
Prohibited Activities ...................................................................................................62 
9.3.11. 
Prohibited Foods .........................................................................................................62 
9.3.12. 
Vital Signs, Height, and Weight .................................................................................62 
9.3.13. 
Physical Examination .................................................................................................62 
9.3.14. 
Laboratory Tests .........................................................................................................63 
9.3.14.1. 
Hematology, Coagulation Parameters, and Clinical Chemistry Profile .....................63 
9.3.14.2. 
Urinalysis ....................................................................................................................63 
9.3.14.3. 
Pregnancy Testing ......................................................................................................64 
9.3.14.4. 
Determination of Clinical Significance ......................................................................64 
9.3.15. 
Electrocardiogram (12-Lead ECG) .............................................................................64 
9.3.16. 
Ophthalmologic Examinations and Measurements ....................................................64 


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9.3.16.1. 
Ophthalmologic Procedures........................................................................................64 
9.3.16.2. 
Instructions for Masked-IOP Readings via Goldmann Applanation 
Tonometry ...................................................................................................................66 
9.4. 
Withdrawal of Subjects ...............................................................................................66 
9.5. 
Rescue Plan .................................................................................................................67 
10. 
TOLERABILITY AND SAFETY ..............................................................................68 
10.1. 
Adverse Events ...........................................................................................................68 
10.2. 
Clarification of the Difference between “Severe” and “Serious” ...............................68 
10.2.1. 
Laboratory Test and Diagnostic Procedure Abnormalities ........................................68 
10.2.2. 
Follow-up of Adverse Events .....................................................................................68 
10.2.3. 
Documentation and Reporting of Adverse Events by Investigator ............................69 
10.3. 
Serious Adverse Events ..............................................................................................69 
10.4. 
Special Interest Adverse Events and Overdoses .........................................................70 
10.5. 
Reporting of Adverse Events ......................................................................................70 
10.5.1. 
Reporting of Serious Adverse Events by Investigators ..............................................70 
10.5.2. 
Reporting of Serious Adverse Events by Sponsor ......................................................71 
10.5.3. 
Periodic Reporting of Adverse Events by Sponsor ....................................................71 
11. 
EMERGENCY PROCEDURES ................................................................................72 
11.1. 
Emergency Sponsor Contacts .....................................................................................72 
11.2. 
Emergency Unmasking ...............................................................................................72 
11.3. 
Emergency Treatment .................................................................................................72 
12. 
STATISTICAL PLAN................................................................................................73 
12.1. 
Sample Size Determination ........................................................................................73 
12.2. 
Analysis Populations ..................................................................................................73 
12.2.1. 
Intent-to-Treat Population ..........................................................................................73 
12.2.2. 
Per-Protocol Population ..............................................................................................73 
12.2.3. 
Treated Population ......................................................................................................73 
12.2.4. 
Washout Failure Population .......................................................................................73 
12.3. 
Handling of Dropouts or Missing Data ......................................................................74 
12.4. 
Statistical Analyses .....................................................................................................74 
12.5. 
Demographic and Baseline Characteristics ................................................................74 
12.6. 
Efficacy .......................................................................................................................74 


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12.6.1. 
Efficacy Endpoints ......................................................................................................74 
12.6.2. 
Efficacy Analyses .......................................................................................................75 
12.7. 
Safety ..........................................................................................................................75 
12.7.1. 
Safety Analyses ..........................................................................................................75 
12.7.2. 
Pharmacodynamic Assessments .................................................................................75 
13. 
CLINICAL SUPPLIES ...............................................................................................76 
13.1. 
Storage and Handling of Ophthalmic Study Drug and Matched Placebo 
Product ........................................................................................................................76 
13.2. 
Dose Verification and Drug Accountability ...............................................................76 
14. 
STUDY DOCUMENTATION AND RECORDS RETENTION ..............................77 
14.1. 
Data Collection Methods ............................................................................................77 
14.2. 
Monitoring ..................................................................................................................77 
14.3. 
Data Retention ............................................................................................................78 
15. 
CLINICAL STUDY ADMINISTRATION, ETHICS, AND CONDUCT .................79 
15.1. 
Good Clinical Practice ................................................................................................79 
15.2. 
Confidentiality ............................................................................................................79 
15.2.1. 
Study Confidentiality ..................................................................................................79 
15.2.2. 
Subject Anonymity .....................................................................................................79 
15.2.3. 
Financial Disclosure ...................................................................................................79 
15.3. 
Subject Information and Informed Consent ...............................................................79 
15.4. 
Study Closure..............................................................................................................80 
15.5. 
Early Termination of the Clinical Trial ......................................................................80 
15.6. 
Termination of an Investigative Site ...........................................................................80 
16. 
INVESTIGATOR'S OBLIGATIONS ........................................................................81 
16.1. 
General ........................................................................................................................81 
16.2. 
Institutional Review Board .........................................................................................81 
16.3. 
Protocol Adherence ....................................................................................................82 
16.4. 
Protocol Amendments ................................................................................................82 
16.5. 
Audits and Inspections ................................................................................................82 
17. 
USE OF DATA AND PUBLICATIONS ...................................................................83 
18. 
REFERENCES ...........................................................................................................84 
19. 
APPENDICES ............................................................................................................85 


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19.1. 
Declaration of Helsinki ...............................................................................................85 
 
LIST OF TABLES 
Table 1: 
Drug Products for Trial ...............................................................................................24 
Table 2: 
Mean Percent Change in Exposure from Monocular to Binocular 
Application of Trabodenoson (Study IPC-09-2009) ..................................................26 
Table 3: 
Safety Factors Between Exposure (Steady State Plasma Cmax) at the NOAEL 
in the Monkey and Dog 13-Week Ocular Toxicity Studies and the Projected 
Exposure for the Proposed Phase 3 Doses ..................................................................28 
Table 4: 
Safety Factors Between Exposure (Steady State Plasma AUC0-t) at the 
NOAEL in the Monkey and Dog 13-Week Ocular Toxicity Studies and the 
Projected Exposure for the Proposed Phase 3 Doses ..................................................28 
Table 5: 
Minimum Washout Requirements Prior to Placebo Run-In Visit as a 
Function of Screening Medication History.................................................................34 
Table 6: 
Binocular Dosing Regimen of Each Treatment Group ...............................................35 
Table 7: 
Schedule of Assessments ............................................................................................44 
 
LIST OF FIGURES 
Figure 1: 
Chemical Structure of Trabodenoson (INO-8875) .....................................................23 
Figure 2: 
Chemical Structure of Latanoprost .............................................................................23 
Figure 3: 
Relationship Between AUC and Dose in Study IPC-09-2009 (Cohorts 1 
through 6) ....................................................................................................................27 
Figure 4: 
Trial Schematic ...........................................................................................................33 
 


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4. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ß 
Beta 
°C 
Degrees Celsius 
µg 
Microgram 
µm 
Micron 
A1 
Adenosine receptor sub-type 1 
A2A 
Adenosine receptor sub-type 2a 
A2B 
Adenosine receptor sub-type 2b 
A3 
Adenosine receptor sub-type 3 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AM 
Morning 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve from time zero (t0) to the time of the 
last measured sample (tlast) 
AUC0-τ 
Area under the plasma concentration-time curve from time zero to the last measurable 
concentration 
BCVA 
Best-Corrected Visual Acuity 
BID 
Twice daily 
BL 
Baseline 
CFR 
Code of Federal Regulations 
Cmax 
Peak plasma concentration 
COA 
Certified Ophthalmic Assistant 
COT 
Certified Ophthalmic Technician 
CPK 
Creatinine phosphokinase 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CV 
Curricula Vitae 
D5W 
5% Dextrose 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic acid  
e.g. 
Exempli gratia, for example 
EP 
Electrophysiology 


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Abbreviation 
Definition 
ERK  
Extracellular Signal-Regulated kinase 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
FDC 
Fixed-Dose Combination 
GCP 
Good Clinical Practice 
GFR 
estimated glomerular filtration rate 
HED 
Human Equivalent Doses 
hr 
Hour 
IB 
Investigators Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
 i.e. 
Id est, in other words 
IND 
Investigational New Drug 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
kg 
Kilogram 
LOCF 
Last observation carried forward 
μg 
Microgram(s) 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram 
min 
Minutes 
mL 
Milliliter 
mmHg 
Millimeters of mercury 
MMRM 
Mixed Model Repeated Measures 
N/A 
Not applicable 
nM 
Nanomoles 
NOAEL 
No observed adverse effect limit 
OD 
Right eye 
OHT 
Ocular hypertension 
OS 
Left eye 
OU 
Each eye 
PBS 
Phosphate buffered saline 
pg 
Picogram 


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Abbreviation 
Definition 
PG 
prostaglandin 
PI 
Principal Investigator 
pH 
hydrogen ion concentration 
PK 
Pharmacokinetic 
PM 
Evening 
POAG 
Primary open-angle glaucoma 
QAM 
Each morning 
QD 
Once daily 
QPM 
Each evening 
QS 
Quantum statis, the amount which is needed. 
QTcB 
QTc interval corrected using Bazett’s formula 
QTcF 
QTc interval corrected using Fridericia’s formula 
SAE 
Serious adverse event 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
t½ 
Terminal plasma half-life 
Tmax 
Time of the peak plasma concentration 
TVC 
Trabodenoson vehicle-matched placebo control 
US 
United States 
 


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5. 
BACKGROUND AND RATIONALE  
5.1. 
Indication 
Trabodenoson, a highly selective adenosine mimetic that targets the A1 receptor, is under 
development for the reduction of elevated intraocular pressure (IOP) in subjects with Ocular 
hypertension (OHT) or Primary Open-Angle Glaucoma (POAG). Latanoprost, a prostaglandin F-
2α analogue, is currently approved for the reduction of elevated intraocular pressure (IOP) in 
subjects with Ocular hypertension (OHT) or Primary Open-Angle Glaucoma (POAG). 
5.2. 
Ocular Hypertension, Glaucoma, and Medical Need 
5.2.1. 
Ocular Hypertension 
Ocular hypertension is a condition in which IOP is elevated but no glaucomatous findings (e.g., 
structural changes in cup-to disc-ratio or visual field loss) have been observed.  The National Eye 
Institute estimates that 3 to 6 million Americans have elevated IOP (1, 2) The Ocular Hypertension 
Study demonstrated that subjects with OHT have an overall risk of developing glaucoma of 10% 
over 5 years and that this risk can be cut in half by medical treatment (3). 
5.2.2. 
Primary Open-Angle Glaucoma 
Glaucoma refers to a group of optic neuropathies that are characterized by loss of retinal 
ganglion cells and atrophy of the optic nerve with resultant visual field loss (4). The disease is the 
leading cause of irreversible blindness worldwide and the second leading cause of blindness, 
behind cataracts (5).  Clinical trials have demonstrated that elevated IOP is a major risk factor for 
glaucoma and have validated the role of IOP lowering in the management of this disease.  
However, despite the use of current medical and surgical therapies that reduce IOP, progressive 
vision loss is common among glaucoma subjects.  The most common form of glaucoma is 
POAG.  In 2004 the World Health Organization estimated that 7 million people in the world 
were blind due to POAG and this disease accounts for >90% of the more than 3 million cases of 
glaucoma in the United States (6-8). 
5.2.3. 
Unmet Medical Need 
The ideal glaucoma medication would be one that has once daily dosing, reduced IOP in all 
subjects, has negligible ocular and no systemic side effects or contraindications, is neuro-
protective, and increases blood flow to the optic nerve.  No current glaucoma drug or drug 
combination fulfills all these criteria; few meet most of these criteria.  Considering the enormity 
of the number of subjects with increased IOP, the impact visual loss has on the quality of life, 
and the absence of even a nearly-ideal drug, an unmet medical need clearly exists in the 
treatment of OHT and POAG.  
5.2.4. 
Pharmacology 
Adenosine is an endogenous purine nucleoside that modulates many physiologic processes.  
Cellular signaling by adenosine occurs through the adenosine receptor subtypes (A1, A2A, A2B, 
and A3).  Trabodenoson has a high binding affinity to the adenosine A1 receptor subtype 
(Ki=0.97 nM) and a high selectivity for A1 receptors over the other adenosine subtypes, the 


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stimulation of which has been shown to increase IOP in animal models (11).  Trabodenoson 
reduces IOP following topical instillation in the eye in rabbits and monkeys.  Studies in human 
primary trabecular meshwork cells, the proposed site of action of adenosine A1 receptor agonists 
in the eye, demonstrated that trabodenoson (0.1 µm) activated extracellular signal-regulated 
kinase (ERK) 1/2 phosphorylation and increased MMP-2 release, and effect inhibited by 
cyclopentyltheophylline, a selective adenosine A1 receptor antagonist (12). 
5.3. 
Chemistry and Formulated Drug Products (Latanoprost Ophthalmic 
Solutions, Trabodenoson-Latanoprost Fixed Dose 
Combinations[FDCs], and Trabodenoson-Matched Vehicle 
Control/Placebo) 
Trabodenoson, an adenosine mimetic selectively targeting the A1 receptor, is 5’-O-nitro-N6-
cyclopentyladenosine. Synonyms include INO-8875, PJ-875, N6-cyclopentyl-5’-O-nitro-
adenosine; 5’-Nitrate-N6-cyclopentyl adenosine; N6-Cyclopentyladenosine-5’-nitrate; N6-
Cyclopentyl-5’-nitrateadenosine; N6-Cyclopentyl-9-(5-nitrate-ß-D-ribofuranosyl)-purine; N6-
Cyclopentyl-9-(5-nitrate-ß-D-ribofuranosyl)-purine.  Its molecular weight is 380.4 grams.   
The chemical structure of trabodenoson is shown in Figure 1.  
Figure 1: 
Chemical Structure of Trabodenoson (INO-8875) 
Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl-(Z)- 
7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5- heptenoate. 
Its molecular formula is C26H40O5 and its molecular weight is 432.58 grams. 
The chemical structure of latanoprost is shown in Figure 2.
Figure 2: 
Chemical Structure of Latanoprost 
The latanoprost-only ophthalmic solutions for use in this trial are sterile, isotonic, buffered 
aqueous solutions of latanoprost with a pH of approximately 6.7 and an osmolality of 
approximately 267 mOsmol/kg. Each mL contains either 25 (0.0025%) or 50 (0.005%) 
micrograms of latanoprost. Benzalkonium chloride (BAC), 0.02% is added as a preservative. The 
N
N
N
N
HN
O
HO
OH
O
N+
O
-O


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inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium 
hydrogen phosphate anhydrous, and water for injection.  
Trabodenoson/latanoprost Fixed Dose Combinations (FDCs) are aqueous a trabodenoson 
ophthalmic suspensions in a buffered, isotonic aqueous solution of containing latanoprost and 
trabodenoson with a pH of approximately 6.5, and containing 0.01% BAK and 0.03% 
Ethylenediamine tetraacetic acid (EDTA) as preservatives.  The inactive ingredients are: 
carboxymethyl cellulose, polysorbate 80, monobasic sodium phosphate, boric acid, sodium 
chloride, and water for injection.   
The trabodenoson-matched vehicle control/placebo (MVC/placebo) product is composed of the 
same inactive ingredients as the active trabodenoson/latanoprost drug product FDCs, but without 
trabodenoson and latanoprost. 
The drug products prepared for use in the trial are shown in Table 1 below. 
 
Table 1: 
Drug Products for Trial 
 
% Active w/w 
Dosage Form 
Trabodenoson Latanoprost 
Latanoprost Low 
- 
0.0025% 
Latanoprost High 
- 
0.005% 
Trabodenoson Low/ Latanoprost High 
3% 
0.005% 
Trabodenoson High/ Latanoprost Low 
6% 
0.0025% 
Trabodenoson High/ Latanoprost High 
6% 
0.005% 
 
All drug products, are packaged in identical sterile low density polyethylene eye dropper bottles 
that contain approximately 3.5 mL.  The dosing volume is one drop. 
 
5.4. 
Overview of Clinical Investigations Involving Trabodenoson 
Ophthalmic Formulations 
Trabodenoson has been investigated in 2 completed Phase 1 trials and 2 completed Phase 2 trials.  
Approximately 230 subjects have received trabodenoson in these trials.  The findings from these 
trials demonstrate that trabodenoson is well-tolerated at all doses tested.  In addition, treatment 
with trabodenoson lowered IOP in a dose-dependent fashion.   
After 28 days of dosing in the Phase 2 Monotherapy trial (IPC-10-2009), the trabodenoson 500 
μg twice daily (BID) dose demonstrated the most consistent response over the dosing interval, 


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with statistically significant reductions in IOP from the placebo group at all timepoints.  In a 
Prostaglandin (PG)-Additivity trial (IPC-01-2013), trabodenoson 500 μg BID co-administered 
with latanoprost in prostaglandin poor-responders (defined as an IOP>24 mmHg on latanoprost), 
demonstrated a statistically significant reduction in IOP compared with latanoprost alone.  
Further, trabodenoson once daily (QD) dosing with 1000 μg for 4 weeks resulted in similar, if 
not greater, reduction in IOP compared with 500 μg BID dosing, indicating that once daily 
dosing with trabodenoson is achievable. 
The first confirmatory (Phase 3) trial of trabodenoson monotherapy is ongoing. This is a 
randomized, double masked, active and placebo-controlled trial involving the binocular topical 
application of trabodenoson ophthalmic formulation 3.0% (1000 mcg) or 6.0% (2,000 mcg) QD 
or 4.5% (1500 mcg) BID, placebo BID or timolol 0.5% BID for 12 weeks in adult subjects with 
OHT and POAG. Results for this trial are anticipated in the fourth quarter of 2016. 
Refer to the Investigator’s Brochure (IB) for additional information on the clinical experience 
with trabodenoson. 
5.5. 
Study Rationale 
The current trial is designed to inform internal decision making regarding various 
trabodenoson/latanoprost fixed-dose combination products comprised of differing amounts of 
trabodenoson and latanoprost, with the objective of identifying an Fixed Dose Combination 
(FDC) with an appropriate benefit/risk profile for further clinical study.  The trial will examine 
both high and low doses of trabodenoson with high and low doses of latanoprost. The efficacy as 
well as the safety profile of the different FDC products will be assessed.  The trial is designed 
and powered to produce a precision-estimate of IOP-lowering efficacy of the various treatments, 
but not a defined detectable difference between treatment arms. 
5.5.1. 
Role of Study in Development and Registration of Trabodenoson 
The completed clinical ophthalmic trials described in the IB demonstrated that trabodenoson: (1) 
was well-tolerated both locally in the eye as well as systemically in subjects with increased IOPs 
at doses as high as 500 μg BID when applied to 1 eye for 4 weeks; (2) after 14 and 28 days of 
BID treatment, significantly reduced the mean IOP of subjects enrolled in the 200 and 500 μg 
cohorts, respectively; and (3) the IOP reduction lasted 24 hours after the final dose of the study.  
In addition, trabodenoson was well-tolerated in healthy adult volunteers at doses as high as 3200 
μg BID when applied for 14 days to the 1 study eye and up to at least a single dose of 3200 μg in 
each eye (6400 μg total dose).  Furthermore, in a trial conducted in patients who were 
prostaglandin-poor responders maintained on prostaglandin therapy, addition of concomitant 
trabodenoson (500 mcg BID or 1000 mcg QD), while being well-tolerated, further reduced their 
IOP indicating that the mechanism of IOP lowering of trabodenoson is complimentary to that of 
prostaglandin analogues. 
Pharmacokinetic data from these trials demonstrated that trabodenoson and its major metabolite: 
(1) had short plasma half-lives; (2) did not accumulate in plasma; and (3) developed plasma 
concentrations that were dose-proportional at low doses, dose-dependent at moderate doses, but 
plateaued at doses at or above 2400 μg. 


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Therefore, based upon these safety and efficacy data, we propose herein to administer 
trabodenoson ophthalmic formulation to subjects with OHT or POAG who, off all glaucoma 
medications, have IOPs between 25 and 34 mmHg.  The goals of this proposed clinical trial are 
to understand in subjects with OHT or POAG the effectiveness, safety, and tolerability of several 
fixed-dose combinations of trabodenoson/latanoprost when applied to both eyes for 8 weeks. 
5.5.2. 
Dose and Posology Justification 
This trial will investigate five different treatments dosed once daily, QAM for 4 weeks of the 
treatment period and QPM for 4 weeks of the treatment period.  Therefore the total double-
masked treatment period in this study will be 8 weeks.  AM vs PM Dosing is masked utilizing 
placebo in addition to the active drug product.  The five different treatments to be investigated 
are as follows: 
1. Trabodenoson 6%/Latanoprost 0.005% 
2. Trabodenoson 3%/Latanoprost 0.005% 
3. Trabodenoson 6%/Latanoprost 0.0025% 
4. Latanoprost 0.005% 
5. Latanoprost 0.0025% 
5.5.2.1. 
Justification for Dose Selection 
The trabodenoson doses for this Phase 2 trial were chosen based on the data obtained from the 
completed clinical trials, specifically the Phase 2 Monotherapy (IPC-10-2009) and PG-Additivity 
(IPC-01-2013) trials.  All trabodenoson doses administered to date have been well-tolerated.  
Because dose increases continue to result in additional efficacy and dose-limiting tolerability 
(ocular or systemic) has not been observed, it is proposed to study 3% / 1000 μg (which was 
observed to have a tolerability profile similar to placebo in the PG-Additivity trial [IPC-01-2013 
see IB]) and additional doses up to 6% / 2000 μg. 
The results of Study IPC-09-2009 have shown that the percent increase in plasma AUC0-last and 
Cmax ranged from 14% to 44% when doubling the whole body dose by dosing both eyes 
(Table 2). 
Table 2: 
Mean Percent Change in Exposure from Monocular to Binocular 
Application of Trabodenoson (Study IPC-09-2009) 
Dose 
Change in AUC0-last 
(%) 
Change in Cmax 
(%) 
1600 μg 
44 
44 
2400 μg 
26 
28 
3200 μg 
14 
15 
AUC0-last=area under the plasma concentration-time curve from time zero to the last timepoint; Cmax=peak plasma 
concentration 
The impact on exposure of increasing the dose was also evaluated in order to project the 
exposure when the 3% / 1000 μg dose is increased to 4.5% / 1500 μg or doubled to 6% / 2000 


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μg.  In all clinical trials to date, it has been observed that exposure, measured by AUC or Cmax of 
the drug in plasma, increases with increasing dose.  However, as the dose increases, it has been 
found that the exposure increases are dose-dependent, but smaller than dose-proportional.  This 
is shown in Figure 3 which presents the relationship between increasing doses and AUC in Study 
IPC-09-2009.  Note that doses of 2400 μg and above have similar AUCs. 
A similar plateau effect was also observed in the single dose portion of Study IPC-09-2009 when 
the single-eye doses rose above 6% / 2000 μg (total doses greater than 4000 μg) as shown by 
AUC0-last and Cmax (see Trabodenoson IB). 
Figure 3: 
Relationship Between AUC and Dose in Study IPC-09-2009 (Cohorts 1 
through 6) 
 
Based on the observed increases in exposure when doses are increased in the range of the 
proposed Phase 3 doses, a 6% / 2000 μg dose is projected (estimated) to result in an exposure of 
1200 pg•hr/mL for AUC0-t and a Cmax of 800 pg/mL. 
Safety factors were calculated by assessing the plasma exposures in the 13-week monkey and 
dog studies at the respective no observed adverse effect levels (NOAELs), measured as Cmax of 
AUC0-t, and comparing them to the projected exposures for the planned Phase 3 doses. Please see 
Table 3 and Table 4 below.  The dose exposures for a 1000 μg/3% single-eye dose from study 
IPC-01-2013 are included for comparison. 


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Table 3: 
Safety Factors Between Exposure (Steady State Plasma Cmax) at the NOAEL 
in the Monkey and Dog 13-Week Ocular Toxicity Studies and the Projected 
Exposure for the Proposed Phase 3 Doses 
NOAELs 
Exposure (Cmax) 
Human Dose 
(Study IPC-01-2013) 
Projected Human Exposure at 
Highest Proposed Phase 3 Dose 
From 13-week  
Ocular Toxicity Studies1 
1000 μg/3% QD 
2000 μg/6% QD 
351 pg/mL 
(Cmax at Day 84) 
800 pg/mL2 
(Cmax) 
Safety Factors 
Monkey 
(500 μg BID/  
1000 μg/day) 
4,857 pg/mL  
(Day 91) 
14 
6.1 
Dog 
(3000 μg BID/  
6000 μg/day) 
36,200 pg/mL  
(Day 93) 
103 
45 
Abbreviations:  Cmax = maximum plasma concentration; BID = twice daily; NOAEL = no observed adverse effect 
level; QD = once daily 
1 Males 
2 Projected 
 
Table 4: 
Safety Factors Between Exposure (Steady State Plasma AUC0-t) at the 
NOAEL in the Monkey and Dog 13-Week Ocular Toxicity Studies and the 
Projected Exposure for the Proposed Phase 3 Doses 
NOAELs 
Exposure (AUC0-last) 
Human Dose 
(Study IPC-01-2013) 
Projected Human Exposure at 
Highest Proposed Phase 3 Dose 
From 13-week  
Ocular Toxicity Studies1 
1000 μg/3% QD 
2000 μg/6% QD 
527 pg•hr/mL 
(AUC0-last at Day 84) 
1200 pg•hr/mL2 
(AUC0-last) 
Safety Factors 
Monkey 
(500 μg BID/  
1000 μg/day) 
5,611 pg•hr/mL 
(Day 91) 
11 
4.7 
Dog 
(3000 μg BID/  
6000 μg/day) 
16,300 pg•hr/mL 
(Day 93) 
31 
14 
Abbreviations:  AUC0-last = area under the concentration x time curve through last timepoint; BID = twice daily; 
NOAEL = no observed adverse effect level; QD = once daily 
1 Males 
2 Projected 
The comparison of the animal exposure data and the projected human exposures indicate robust 
safety factors between no-effect doses in both safety species, and the projected levels of drug in 
plasma at the planned Phase 3 doses. 


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The latanoprost doses selected in this trial include the approved commercial dose (0.005%) and, 
for purposes of dose-ranging, half the approved latanoprost dose of 0.0025%.  The safety of the 
‘half-dose’ of latanoprost is assumed to be better than or equal to the safety profile of the higher 
approved dose. 
5.5.2.2. 
Justification for Posology Selection 
The IOP lowering from Study IPC-01-2013 showed an increase in efficacy when the same 
subjects were switched from a 1.5% / 500 μg BID dose to a 3% / 1000 μg QD dose.  These data 
indicate that trabodenoson given once-daily (QD) was effective.  Latanoprost has also been 
shown to be effective when given once–daily (QD), supporting the once-daily posology of the 
fixed-dose combinations to be investigated in this trial.  Additionally, because latanoprost is 
typically administered at night and trabodenoson once-daily has only been administered in the 
morning, the difference in night time versus morning dosing is also being investigated in this 
trial. 
5.6. 
General and Specific Risks 
5.6.1. 
General Risks 
Trabodenoson is a new drug and its effects on the unborn child, the reproductive system, and the 
fetus are unknown.  The effects of latanoprost on the unborn child, the reproductive system and 
the fetus are also unknown.  In the proposed study, women who are pregnant or are nursing are 
to be excluded.  Female subjects who enroll in the study and male subjects and their female 
partners must use a medically-accepted contraceptive regimen from the time of enrollment to 1 
month following study drug application, as described in the inclusion criteria.  
Blood collection can cause local pain, swelling, and/or discoloration of the skin, mild 
lightheadedness, a feeling of weakness, sweating, slowing of the heartbeat, a decrease in blood 
pressure, or, sometimes, fainting.  Approximately 40 mL of blood for central laboratory testing 
(~3 tablespoons or ~10% of a routine Red Cross blood donation) will be collected.  No samples 
for genetic testing will be collected. 
5.6.2. 
Trabodenoson Risks 
With treatment of OHT or POAG there is a risk that subjects may not achieve adequate control 
of their IOP.  Subject withdrawal procedures and a rescue plan have been incorporated in the 
protocol to ensure safe treatment of subjects (see Sections 9.4 and 9.5).  Hyperemia of the 
conjunctiva, reported to date following administration of the drug, was short-lived and self-
limited. No underlying inflammation or tissue damage was seen in any eye treated.   
When trabodenoson was administered to older-adult healthy volunteers at daily and single-eye 
doses higher than those proposed in this protocol (3200 μg BID for 14 days to one eye in Study 
IPC-09-2009) and to subjects with POAG or OHT at single-eye doses of 500 μg/1.5% BID for 8 
weeks and 1000 μg/3% QD for 4 weeks, systemic AEs were generally mild, short-lived, self-
limited, and appeared to be un-related to adenosine-associated effects in the body.  Please refer 
to the IB for further details.   


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Safety findings from Inotek’s pre-clinical toxicology studies (performed in animals administered 
trabodenoson) and from clinical trials reported by other pharmaceutical companies (in human 
subjects exposed to adenosine agonists less selective than trabodenoson) are discussed below.  
The specific systemic risks, and in particular those thought to be associated with adenosine-
related systemic effects, observed in these studies were not observed in the completed Phase 1 or 
Phase 2 clinical trials described above, but will be monitored for in the proposed clinical trial. 
Humans enrolled in the Phase 1 clinical study (IPC-09-2009) and administered total daily doses 
as high as 6400 μg of trabodenoson 3200 ug OU) for 14 days experienced no significant AEs.  
Nonetheless, as with all new drugs and formulations being developed, these or other previously 
unknown side-effects could occur, including life-threatening problems.  
In a previous Phase Ia study (IPC-11-2006) conducted at the Royal Adelaide Hospital in 
Australia (not under a US IND), 5 adults received 1 μg/kg of trabodenoson as a 5-minute IV 
bolus in an electrophysiology (EP) laboratory following an elective EP study and/or procedure.  
The extensive cardiac electrophysiologic data collected showed no consistent drug effects.  
However, 1 subject might have had detectable effects consistent with adenosine receptor 
agonism (i.e., slowing of the conduction of the sinus node and the atrioventricular node).  While 
similar observations were not observed in the other 4 subjects, a drug effect in this 1 subject 
could not be ruled out.  There were no serious adverse events (SAEs) or dose-limiting toxicities 
observed.  Despite extensive cardiac, renal, pulmonary and central nervous system monitoring, 
and assessments in Studies IPC-09-2009 and IPC-10-2009, no effects on these or any other organ 
system were detected.   
As plasma exposure following topical ophthalmic application plateaus at doses above 2400 μg, 
high systemic exposures are unlikely even in the case of accidental overdose.  However, in a rare 
event of a high systemic exposure that resembles the exposure observed following a rapid bolus 
IV administration, cardiovascular symptoms similar to other adenosine agonists may be 
expected.  These include non-selective adenosine agonists to humans (marketed as Adenocard IV 
and Adenoscan by Fujisawa Healthcare, Inc.) that may cause systemic findings, most notably 
slowed atrioventricular node conduction or atrioventricular block, chest pain, 
bronchoconstriction, nausea, hypotension, flushing, and headache. 
In the Phase 2 and 3 trials conducted with tecadenoson administered as an IV bolus, the 
adenosine agonist with a chemical structure most closely resembling that of trabodenoson, 
recurrent tachycardia, paresthesias (e.g., heaviness or burning sensation of the extremities), and 
dyspnea were events considered possibly or probably attributable to the drug.  Subjects with a 
history of asthma or chronic obstructive lung disease tolerated the drug without developing 
bronchospasm. 
Based upon the clinical safety finding with topical ocular trabodenoson administered as a single 
total dose of 6400 μg, or doses of 3200 μg BID for 14 days, it is unlikely to expect cardiac 
effects similar to those described with other adenosine-like agents.  Subjects in the clinical trial 
under discussion in this protocol (IPC-01-2015) will receive doses of 1500 μg/4.5% BID, 1000 
μg/3.0% and 2000 μg/6.0% QD.  Other safety precautions include careful ophthalmic and 
systemic monitoring (including particular attention to cardiac assessments) at the time of the 
anticipated trabodenoson Tmax and selection of experienced investigative sites. 


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5.6.3. 
Latanoprost Risks 
Latanoprost 0.005% ophthalmic solution is a commercially available product currently marketed 
in the United States, Canada and European Union as branded latanoprost and as generic 
latanoprost.  Latanoprost is available as a 0.005% ophthalmic solution that has a well-defined 
risk profile based on multiple clinical trials and post-marketing/clinical experience.  Adverse 
events in the latanoprost product insert (PI) that occurred at a rate of 5-15%that includes: blurred 
vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased 
pigmentation of the iris and punctate epithelial keratopathy.  Adverse events that were reported 
in 1 to 4% of subjects were dry eye, excessive tearing, eye pain, lid crusting, lid discomfort/pain, 
lid edema, lid erythema and photophobia. In addition, conjunctivitis, diplopia and discharge from 
the eye were reported in less than 1% of subjects.   
Hyperemia with latanoprost was recently evaluated in a meta-analysis and the percent of subjects 
reported with hyperemia was 19.7% (271 subjects with hyperemia out of 1379 subjects) and, 
when available, the percent of subjects reported with hyperemia greater than mild was 13.1% 
(160 subjects out of 1219 total subjects)(9). Hyperemia is reversible and does resolve after 
discontinuation of latanoprost and a discontinuation rate due to hyperemia in the latanoprost PI is 
less than 1%. 
Iris pigmentation with latanoprost was also recently evaluated in a second meta-analysis and the 
percent of subjects reported to have an increase in pigmentation by 12 months was 4.3% (21 
subjects out of a total of 478 subjects) and the range in the individual trials was 4.8% to 18.4%. 
This is a particularly important adverse event because iris pigmentary changes may persist after 
discontinuation of latanoprost. (10) 
Post-marketing surveillance/clinical use reporting included in the latanoprost PI due to 
seriousness, frequency of reporting, possible causal connection to latanoprost or a combination 
of these factors include: asthma and exacerbation of asthma,; corneal edema and erosions; 
dyspnea,; eyelash and vellus hair changes(increased length, thickness, pigmentation, and 
number); eyelid skin darkening; herpes keratitis; intraocular inflammation (iritis/uveitis); 
keratitis; macular edema, including cystoid macular edema; misdirected eyelashes sometimes 
resulting in eye irritation; dizziness, headache and toxic epidermal necrolysis; periorbital and lid 
changes resulting in deepening of the eyelid sulcus. 
Latanoprost has not been associated with systemic adverse effects and has not been reported to 
alter routine blood analyses.  
In the IPC-01-2013 trial trabodenoson and latanoprost were studied as an unfixed combination 
with latanoprost 0.005% co-administered (concomitant administration) with either trabodenoson 
1.5% or trabodenoson 3%. No unexpected adverse events were noted with co-administration and 
the incidence of adverse events was in the range that would be expected based on current data 
with both drugs. 
In this trial latanoprost will be investigated at both 0.005% and 0.0025% and the risks of both 
doses should be contained in the risk information above related to the higher commercially 
available 0.005% dose. 


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6. 
STUDY DESIGN 
6.1. 
Study Plan, Purpose and Duration 
This is a phase II, randomized, double-masked study to evaluate the efficacy and tolerability of 
topical ocular delivery of fixed-dose combinations of trabodenoson and latanoprost in subjects 
with OHT or POAG. 
All subjects who meet the study’s enrollment criteria following Screening will undergo washout 
of all prohibited medications (if washout is needed), including their routine glaucoma 
medications.  During the Placebo Run-In Period, placebo (vehicle control matched to 
trabodenoson) is applied twice daily to both eyes in all subjects.  During the Treatment Period, 
study drug is applied to both eyes for a total of 8 weeks.  Each subject will be assigned 4 weeks 
of AM and 4 weeks of PM dosing in a masked manner.  The Treatment Period will be followed 
by an Observation Period of approximately 7 days wherein no study eye drops are instilled.  
To mimic what is generally seen in clinical trials, the number of subjects with ocular 
hypertension as their diagnosis will be limited to approximately 30% of the total subjects 
enrolled.  Additionally, so the trial mirrors the general population demographics (so as to 
improve generalizability of the results) the proportion of African American subjects will be 
approximately 25% or less but not less than 12% of the total subjects enrolled. 
The purpose of the study is to assess the efficacy, tolerability, and safety of binocular topical 
application of different doses of trabodenoson (3.0% and 6.0%) when combined with latanoprost 
(0.005% or 0.0025%) one drop daily over two consecutive 4 week periods in subjects with 
POAG or OHT.  Data collection will include efficacy (masked-IOPs), local (ophthalmic) and 
systemic tolerability and safety assessments 
Approximately 40 sites in the United States (US) will participate in this trial.  
6.2. 
Objectives 
6.2.1. 
Primary Objective  
• To evaluate the efficacy of different topical ocular doses of trabodenoson (3.0% and 
6.0%) when added to latanoprost (0.005% or 0.0025%), one drop daily to both eyes 
over two consecutive 4 week periods.  
6.2.2. 
Secondary Objective  
• To evaluate the tolerability and safety of different doses of trabodenoson (3.0% and 
6.0%) when added to latanoprost (0.005% or 0.0025%), one drop daily to both eyes 
over two consecutive 4 week periods. 
6.3. 
Hypotheses 
• Topical ocular co-administration of 3.0% or 6.0% trabodenoson plus latanoprost 
0.0025% or 0.005% ophthalmic formulation will reduce IOP and be well-tolerated. 


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6.4. 
Study Period and Visit Schematics 
6.4.1.
Period Schematic and Goals 
The following is a high-level schematic of the trial treatment plan. Please note that Screening, 
Washout, and Placebo Run-In Periods can vary in length and therefore are presented as ranges 
throughout the protocol instead of specific days. 
Figure 4: 
Trial Schematic 
 
6.5. 
Dosage, Dosage Form, Route, and Dose Regimen 
6.5.1.
Dosing Regimen for Each Period 
• Screening Period: Subject eligibility is assessed and if found appropriate, baseline 
safety assessment is performed. Subjects remain on their routine medications during 
this period.  
• Washout Period: This period begins with the conclusion of the Screening Period. 
The need for and duration of the Washout Period will vary from subject to subject 
based upon their ophthalmologic medication history at Screening, as depicted in 
Table 5.    Once Screening results have been received and approved by the 
Investigator, subjects are notified that they have passed Screening and may proceed 
into the Washout Period.  Washout Period procedures may be performed during a 
phone conversation.  Maximum duration of washout is 39 days.  Subjects requiring 
no washout must remain in Screening until all the Screening safety results have been 


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reviewed by the Investigator and will then proceed directly to the Placebo-Run-In 
Period. 
Table 5: 
Minimum Washout Requirements Prior to Placebo Run-In Visit as a 
Function of Screening Medication History  
Drug Class 
Minimum Length of Washout Required 
Prior to Placebo Run-In Period 
Topical ophthalmic prostaglandins, prostamides, or combination 
drugs containing any of these medications 
35 days 
Topical or oral β-blockers or combination drugs containing these 
medications 
28 days 
Sympathomimetics, topical α-agonists, or combination drugs 
containing any of these medications 
14 days 
Parasympathomimetics, (topical or oral) carbonic anhydrase 
inhibitors, dipyridamole, theophylline, or combination drugs 
containing any of these medications 
4 days 
None of the above drugs 
No washout needed. 
 
Note: Subjects receiving glaucoma medications requiring a long washout period may be placed 
on glaucoma medications with short washouts so long as adequate time is given for the washout 
of the second medication based upon the washout period required in Table 5.  
 
• Placebo Run-in Period: For 5 to 9 days, subjects will receive 1 drop of placebo in 
the morning and in the evening to both eyes.  In general, during this period, morning 
eye drop applications will occur between 7:00 AM and 9:00 AM while evening doses 
will be instilled between 7:00 PM and 9:00 PM. Washout of all prohibited medications 
(if needed) will continue during this period.  
Treatment Period: Subjects who continue to meet the study enrollment criteria on 
Day 1 AM will be randomized to 1 of 5 treatment arms. AM vs PM Dosing is masked 
utilizing Placebo in addition to the active drug product.  During the Treatment Period, 
study drug (Active and Placebo) eye drop applications will occur twice daily, in the 
morning (between 7:00 AM – 9:00 AM) and in the evening (between 7:00 PM – 9:00 
PM). 
− (1) trabodenoson 6.0% / latanoprost 0.005% QD and Placebo QD, instilled OU 
for a total of 8 weeks; 
− (2) trabodenoson 3.0% / latanoprost 0.005% QD and Placebo QD, instilled OU 
for a total of 8 weeks;  
− (3) trabodenoson 6.0% / latanoprost .0025% QD and Placebo QD, instilled OU 
for a total of 8 weeks;  
− (4) latanoprost 0.005% QD and Placebo QD, instilled OU for a total of 8 weeks; 
− (5) latanoprost 0.0025% QD and Placebo QD, instilled OU for a total of 8 weeks;   


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From Day 1 through Day 56, subjects will receive 1 drop of study drug, twice daily, 
in each eye (OU).  No prohibited medications are permitted during this period.  Of 
note, the one study eye will be determined on Day 1 (6.5.4 Definition of Study Eye). 
 
• Observation Period: During this 7-day period no study medications are administered 
and all prohibited medications remain restricted. 
The dosing regimen for each treatment group is depicted in Table 6. 
 
Table 6: 
Binocular Dosing Regimen of Each Treatment Group 
 
Study Period 
 
Screening 
Washout 
Period 
Placebo 
Run-In 
Treatment 
Period 
Observation 
Period 
Randomized 
Group: 
BID Dosing 
Range: 
1 to 14 days  
Range: 
4 to 39 days  
Range: 
5 to 9 days  
28 Days 
±2 days 
(Day 1 to 
 Day 28) 
28 Days 
 ± 2 days 
(Day 29 to 
Day 56) 
7 ±1 days 
 
Trabo 6.0% / 
LP 0.005% QD 
& 
Placebo QD 
Continue 
routine 
medications 
& ensure 
subject 
meets 
general 
study entry 
criteria. 
No 
prohibited 
medications 
are 
allowed. 
Placebo 
BID 
 
No 
prohibited 
medications 
are 
allowed. 
Study Drug 
Dosing BID 
(Active or 
Placebo) 
Study Drug 
Dosing BID 
(Active or 
Placebo) 
No 
prohibited 
medications 
are allowed. 
Trabo 3.0% / 
LP 0.005% QD 
& 
Placebo QD  
Trabo 6.0% / 
LP .0025% QD 
& 
Placebo QD 
LP 0.005% QD 
& 
Placebo QD 
LP 0.0025% QD 
& 
Placebo QD 
 
6.5.2. 
Study Drug Administration and Drug Accountability 
During scheduled visit days, study drug will be administered at the investigative site.  On all 
other days, upon approval of the Investigator, qualified subjects may be dosed at home by 
themselves or by their caregiver. 


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Drug/Dosing accountability will be performed at all visits beginning with the Placebo Run-In 
Visit. 
Study drug eye drop will be applied to the inferior conjunctival sac (fornix) of the study eye.  
Following administration of the drop, subjects will be instructed to gently close their eye for at 
least 1 minute.  No punctal occlusion pressure will be applied. 
6.5.3. 
Self-Dosing 
Subjects (or caregiver) who demonstrate proper self-dosing technique may self-dose at home for 
a majority of study days.  In order to demonstrate appropriate self-dosing technique, the Placebo 
Run-In Visit AM applications of the eye drops by the subject (or caregiver) must be observed by 
site personnel trained and experienced in ophthalmic drop administration and instruction.  
Subjects approved for self-dosing at Placebo Run-In Visit are permitted to administer the study 
drug at home on all the remaining days of the trial except for the dosing at the investigative sites 
by site personnel on Day -1, Day 1, Day 28 and Day 56.  Subjects (or caregiver) incapable of 
proper self-dosing must either be dosed daily by site personnel or withdrawn from the study.  
6.5.4. 
Definition of the Study Eye 
The study eye will be an eye that meets all the following criteria: (1) mean 8AM IOP on Placebo 
Run-In Visit, Day -1, and Day 1 (AM predose) of ≥25 and ≤34 mmHg; and (2) mean IOP ≥21 
mmHg on Day -1 at 8 hours post-dose (~4PM).  If both eyes meet the above IOP criteria, then the 
eye with the highest mean 8AM IOP on Day 1 will be designated as the ‘study’ eye. In the event 
that the mean IOPs in both eyes are equivalent, the right eye will arbitrarily be designated as the 
‘study’ eye.  If only 1 eye meets all the Study Enrollment Criteria, that eye will automatically be 
designated as the ‘study’ eye. 
6.6. 
Study Population 
Application of the Inclusion and Exclusion (Enrollment) Criteria and definitions will give rise to 
a study population on Day 1 characterized by subjects who: 
• Have OHT or POAG, are aged 18 years or older, and have signed the approved 
written informed consent form. 
• Have appropriately washed out all prohibited medications. 
• Have at least 1 eye that meets the following criteria: (1) mean 8AM IOP on Placebo 
Run-In Visit, Day -1, and Day 1 (AM predose) of ≥25 and ≤34 mmHg; and (2) mean 
IOP ≥21 mmHg on Day -1 at 8 hours post-dose (~4PM). (If one eye fails this criterion 
but the second eye meets this criterion and all other enrollment criteria are met, the 
subject can be randomized). 
• Do not have ongoing medical, psychiatric, or social problems that might interfere 
with the performance, completion, and/or interpretation of the trial assessments or 
threaten subject safety. 
• By Day 1 have received 1 drop of placebo to each eye BID for a minimum of 5 days. 


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6.7. 
Sample Size Justification 
The sample size was chosen to provide a desired level of precision.  Specifically, it was selected 
so the ½ width of the 95% CI for the primary endpoint of IOP would be no greater than 1.2 
mmHg. 
6.8. 
Safety Monitoring and Reporting 
All randomized subjects will undergo adverse event (AE) and concomitant medication reviews, 
vital signs, Best-Corrected Visual Acuity (BCVA) testing, complete eye examinations and IOP 
measurements on Days 28 and 56. 
As part of the rescue plan in Section 9.5, any subject whose mean IOP in either eye exceeds 34 
mmHg, at any timepoint or who an investigator judges there being significant clinical risk will be 
withdrawn from the study.  Please refer to Section 9.4 for complete instructions on withdrawal of 
subjects from the trial. 
Board-certified consulting cardiologists will over-read the masked ECG data and, when 
necessary, inform the sites of any alerts.  
Inotek will ensure that all federal (Code of Federal Regulations and International Conference on 
Harmonization-Good Clinical Practice and local (Institutional Review Board [IRB]) reporting 
requirements are met within applicable timelines. 
Any SAEs, including death due to any cause, which occurs in any subject entered into treatment 
in this study or within 30 days following cessation of treatment, whether or not related to the 
investigational product, must be reported to the Sponsor within 24 hours.  All subjects with 
SAEs must be followed-up for outcome. 


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7. 
STUDY ASSESMENTS 
7.1. 
Study Assessments 
7.1.1. 
Primary Endpoint, Efficacy 
• Daily IOP-change from diurnal baseline (average of the 4 diurnal changes from 
baseline calculated during a dosing interval) calculated at the Week 4 visit and the 
Week 8 visit. 
7.1.2. 
Secondary Endpoints, Efficacy 
• Daily IOP (average of the 4 serial IOPs taken during a dosing interval) calculated at 
the Week 4 visit and the Week 8 visit. 
• Daily IOP-change from study baseline (average of the 4 changes from study baseline 
calculated during a dosing interval) calculated at the Week 4 visit and the Week 8 
visit. 
• Mean IOP at 8AM, 10AM, 12PM, and 4PM for the subject's ‘study' eye calculated at 
the end of each of the 4 weeks of treatment for each of the doses/combinations tested. 
• IOP change from diurnal baseline [this is the time-matched subtraction of each of the 
4 IOP timepoints of the circadian curve post randomization from the pre-
randomization circadian curve] calculated at the end of the 4 weeks of treatment for 
each of the doses/combinations tested. 
• IOP change from study baseline [this calculates the change in IOP from the 8AM  
Day 1 baseline IOP] calculated at the end of the 4 weeks of treatment for each of the 
doses/combinations tested. 
7.1.3. 
Secondary Parameters, including Safety 
• Clinical and laboratory evaluations including results of the bilateral eye examinations 
tests (e.g., IOPs, BCVA, visual fields, central corneal thickness, and conjunctival 
hyperemia grading), vital signs, physical examinations, clinical laboratory tests, 12-
lead ECGs, AEs, concomitant medications, withdrawals/ terminations, and drug 
exposure will be used to assess tolerability and safety. 


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8. 
STUDY POPULATION 
8.1. 
Number of Subjects 
In order to assess 150 evaluable subjects, approximately 33 adults who meet the study 
enrollment criteria will be enrolled in each of the 5 treatment groups in order to complete the 
trial with approximately 165 enrolled and a total of 150 evaluable subjects.  
8.2. 
Study Enrollment Criteria 
8.2.1. 
Inclusion Criteria 
1. Subject provides written informed consent prior to any study-related procedure not part 
of normal medical care. 
2. Subject has the diagnosis of OHT or POAG (subjects with secondary, exfoliative, and/or 
pigmentary glaucomas are excluded from the trial). 
3. Subject with at least 1 eye that meets each of the following criteria in the same eye: (1) 
mean 8AM IOP ≥25 and ≤34 on Placebo Run-In Visit, Day -1, and Day 1 (AM predose) 
mmHg; and (2) mean IOP ≥21 mmHg on Day -1 at 8 hours post-dose (~4PM). IOP is 
taken by Goldmann Applanation Tonometry and is not corrected for central corneal 
thickness. (If one eye fails this criterion but the second eye meets this criterion and all 
other enrollment criteria are met, the subject can be randomized). 
4. Subject is aged 18 years or older; 
If female, subject must not be pregnant or nursing, and is either: 
a. Not of childbearing potential, defined as postmenopausal for at least 1 year or 
surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy; or 
b. Of childbearing potential and meets at least 1 of the following: 
iv. 
Is practicing an effective method of contraception (e.g., a. double barrier 
method, b. oral/parenteral contraceptives plus barrier, c. intrauterine device 
plus barrier), or 
v. 
Has a vasectomized partner (at least 90 days post vasectomy procedure), or 
vi. 
Is practicing abstinence from sexual intercourse. 
Subjects must be willing to practice the chosen contraceptive method or remain abstinent 
during the conduct of the study and for at least 1 month after last dose of study 
medication. 
Non-vasectomized males (with a partner of childbearing potential) are required to 
practice effective birth control methods (e.g., abstinence, use of condom [or other barrier 
device] along with partners oral/parenteral contraceptives) during the conduct of the 
study and for at least 1 month after last dose of study medication; 


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8.2.2. 
Exclusion Criteria 
1. Subject has clinically significant abnormalities in their medical history or from the results 
of the physical examinations, vital signs, or clinical laboratory tests performed at 
Screening or during the Placebo Run-in period that may put the subject at risk in this trial 
or cause the subject not to complete the trial per protocol by the Investigator’s judgment 
(Examples of clinically significant laboratory results include: both aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) > 2 times upper limit of 
normal (ULN) or either >3.0 times ULN, Total bilirubin > 2.0 times ULN, BMI > 40 
kg/M2, Hemoglobin A1C > 8.0%, or creatinine clearance <50 ml/min).  
Note: Subject with creatinine clearance <50 ml/min may still be eligible upon review and 
written approval by the Inotek Medical Monitor or his designee (a Board-certified 
physician) following review of the current medications, laboratory values, and medical 
history.   
2. Subject has any new clinically significant field loss within the past year in either eye, or 
any non-glaucomatous ophthalmologic disease that might exacerbate during the trial. 
3. Subject’s ETDRS BCVA Snellen equivalent is worse than 20/80 in either eye. 
4. Subject has a vertical cup-to-disc ratio >0.8 or an IOP in either eye above 34 mmHg at 
any examinations prior to Day 1 dosing in either eye. 
5. Subject has a central corneal thickness <490 µm or >610 µm at Screening in both eyes. 
(If only one eye is excluded based upon this criterion but the second eye does not meet 
this exclusion or any other exclusion criteria, the subject can be included).   
6. Subject is currently taking any drug that in the opinion of the Investigator might affect 
IOP including oral or ocular glucocorticoids. (Low to moderate stable doses [no change 
for 30 days] of nasal or dermatologic steroids are permitted). 
7. Subject received oral/systemic beta-blocker within 28 days of screening.   
8. Subject has history of clinically significant trauma to the globe of both eyes. (If only one 
eye is excluded based upon this criterion but the second eye does not meet this exclusion 
or any other exclusion criteria, the subject can be included).   
9. Subject has had ocular or orbital surgery (conventional or laser, such as SLT or ALT) to 
both eyes (If only one eye is excluded based upon this criterion but the second eye does 
not meet this exclusion or any other exclusion criteria, the subject can be included). 
However, the following procedures are not exclusionary: 
a. At least 1 year prior to Screening: retinal laser, cataract extraction (no surgical 
complications such as capsular rupture or vitreous loss), peripheral iridotomy (with 
otherwise open angle per Exclusion Criteria # 25), and other extraocular (e.g., tear 
duct, pterygial, or palpebral) surgeries. 
b. At least 180 days prior to Screening: uncomplicated YAG laser capsulotomy. 
10. Subject has any ocular abnormality that in the opinion of the Investigator might preclude 
reliable applanation tonometry in either eye. 


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11. Subject has a fundus in either eye that in the opinion of the Investigator cannot be well-
visualized with pupillary dilation.  
12. Subject has a history of or current retinal condition that, in opinion of the Investigator, 
could affect BCVA (i.e., diabetic retinopathy, central or branch retinal vein occlusion, 
cystoid macular edema, etc). 
13. Subject cannot, or is unwilling to, function without contact lenses from Placebo Run-In 
Visit through the completion of the End-of-Study Visit. 
14. Subject uses oral sympathomimetics (e.g., pseudoephedrine) within 14 days of start of 
Placebo Run-In Period, or the Investigator feels may be required during the study. 
15. Subject used inhaled bronchodilators and/or inhaled steroids more than once per week on 
the average in the past 90 days, or the Investigator feels may be required during the study. 
16. Subject uses dipyridamole, theophylline, or other adenosine antagonist medication within 
4 days of the start of the Placebo Run-In Period, or the Investigator feels may be required 
during the study. 
17. Subject used any of the following drugs (alone or in combination) for treatment of 
ophthalmologic illness: 
a. Parasympathomimetics or carbonic anhydrase inhibitors within 4 days of the start of 
the Placebo Run-In Period. 
b. Sympathomimetics or alpha adrenergic agonists within 14 days of the start of the 
Placebo Run-In Period. 
c. Topical ocular beta-blockers with 28 days of the start of the Placebo Run-In Period. 
d. Prostaglandins, prostamides or prostanoids within 35 days of the start of the Placebo 
Run-In Period. 
18. Subject has any acute or chronic ophthalmologic illness requiring use of any non-IOP 
lowering ocular medication at screening and throughout study conduct (specific tear 
supplements are allowed as described in Section 9.3.9). 
19. Subject has a history of significant cardiac rhythm disturbance or a complete left bundle 
branch block (LBBB). (Examples of significant rhythm disturbances include PR intervals 
above 220 msecs, history of 2nd or 3rd degree blocks, acquired or congenital long QT 
syndrome, atrial fibrillation or other atrial arrhythmia, ventricular arrhythmia, 
bradycardia (<50 bpm), or ventricular pre-excitation (WPW). Subjects with PR intervals 
between 221 msec and 240 msec (inclusive) may only be enrolled following receipt of 
the written approval of the Inotek Medical Monitor or his designee (a Board-certified 
physician) so as to ensure an opportunity to review, as necessary, the subject’s ECG, 
medication and medical history with the study cardiologist.) 
20. Subject has clinically significant corneal and/or conjunctival findings (including 
clinically significant hyperemia) related to any recurrent or chronic conditions including 
allergic conjunctivitis, blepharitis, pegueculae/pterygium, or keratoconjunctivitis sicca 
that might recur or worsen during the study and confound the ophthalmologic safety data. 
21. Subject has a closed or occludable angle on gonioscopy (chamber angle less than 10 
degrees), a history of angle-closure, or any non-POAG glaucoma (including neovascular 


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glaucoma) in both eyes at Screening (if only one eye is excluded based upon this criterion 
but the second eye does not meet this exclusion or any other exclusion criteria, the 
subject can be included). 
22. Subject has a history of, or current, uveitis or any other inflammatory intraocular disease 
of either eye, unless the inflammatory process was caused by a topical ophthalmic 
medication that was stopped and has been in full remission for at least 1 year.   
23. Subject received any investigational device or product within 30 days prior to the start of 
the Placebo Run-In Period or has ever been rejected on medical or psycho-social grounds 
from participation in a clinical trial.  
24. Subject has a history of allergy to more than 3 structurally unrelated medications, unless 
approved in writing by the Sponsor Medical Monitor (or their designees, a Board-
certified physician). 
25. Subject has a history of significant sensitivity to latanoprost, trabodenoson, benzalkonium 
chloride, EDTA, or any of the other study drug excipients, or to local anesthetics or 
topical ophthalmic anesthetics such as lidocaine or to fluorescein. 
26. Subject is unable to discontinue the use of prohibited medications delineated in 
Section 9.3.9 from the start of the Placebo Run-In Period through completion of the End-
of-Study Visit. 
27. Subject is unable to limit their daily consumption to ≤ 24 ounces of beer, ≤ 8 ounces of 
wine, or ≤ 4 ounces of liquor from the start of the Placebo Run-In Period through 
completion of the End-of-Study Visit. 
28. Subject has any recent (acute) or chronic medical, psychiatric, drug or alcohol, or social 
problem that might in the opinion of the Investigator: (1) interfere with the subject’s 
performance or completion of the trial; (2) obfuscate the subject’s study data; or (3) 
render the subject unable to understand the nature, scope, and possible consequences of 
the study.  Or subject is likely to be noncompliant with the protocol (e.g., uncooperative 
attitude; a history of significant mental depression, panic attacks, or manic episodes; 
inability to return for all planned visits, and/or unlikelihood of completing the study). 
29. Subject is involved in any aspect of trial conduct including, Investigator, Sub-
Investigator, other site staff, and/or immediate family members (first degree relative, 
spouse, adoptees, legal dependents) or employee of Inotek. 


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9. 
SCHEDULE OF ASSESSMENTS 
Note: In the tables below, the number preceding a check denotes the number of times that a 
procedure is performed during that visit.  For example, 3√ means that procedure is performed 3 
times during that visit (specific timepoints are described in Section 9.2).  If no number appears, 
then the procedure is performed only once.  
The order of the assessments listed in Table 7, is random.  However, throughout the study, 
activities that could impact the findings on the external eye examination (e.g., topical ophthalmic 
eye drop application) are performed after any of the external eye assessments.  Masked-IOP 
measurements are performed prior to any assessment that might make the subject anxious or 
uncomfortable (e.g., vital signs, ECGs, or blood sampling) so as not to affect the IOP results.  
Investigators and site personnel will perform study procedures in their appropriate order, as 
delineated in the clinical protocol.     


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Table 7: 
Schedule of Assessments 
Study Period: 
Screening 
Period 
Range 
Washout and Placebo Run-in Period:  
Washout Range: 4 to 39 Days f 
Placebo Run-in Range: 5 to 9 Days 
Treatment Period:  
Day 1 to Day 56 (± 2) 
Observation Period:  
7 Days (± 1)  
after EOT 
 
Visit: 
Procedure: 
1 to 14 
Days  
Washout 
Visit e  
Placebo 
Run-In 
Visit a 
Day -1 a 
Day 1 a 
Day 28 a 
(± 2) 
End-of- Treatment 
(EOT) Visit 
Day 56 a (± 2) 
End-of-Study 
(EOS) Visit g 
7 Days (± 1) 
after EOT 
Informed consent procedures 
√ 
 
 
 
 
 
 
 
Demographics and medical history 
√ 
 
 
 
 
 
 
 
Medication History / Concomitant 
medications 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Enrollment criteria and/or safety data 
review 
√ 
√ 
√ 
√ 
√ 
 
 
 
Subject randomization 
 
 
 
 
√ 
 
 
 
Physical examination, complete (C) or 
directed (D) 
√C 
 
 
 
√D 
 
 
√C 
Height / weight 
√ 
 
 
 
 
 
 
 
Clinical laboratory tests (Central Lab) 
√ 
 
√ 
 
 
√ 
 
√ 
Pregnancy test for females, central (C) 
or at the site (S) 
√C 
Serum 
 
 
√S 
Urine 
 
 
√S 
Urine 
 
Adverse events review /reporting 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Modified ETDRS-BCVA 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
External eye examination h 
√ 
 
√ h 
√ h 
√ 
√ h 
√ h 
√ 
Slit Lamp examination 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Masked-IOPs  
√ 
 
√ 
4√ 
√ 
4√ 
4√ 
√ 
Dilated Fundus examination 
√ 
 
 
 
 
 
 
√ 
Vital signs 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
12-Lead ECG 
√ 
 
√ 
 
 
 
 
√ 
Gonioscopy c 
√ 
 
 
 
 
 
 
 


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Study Period: 
Screening 
Period 
Range 
Washout and Placebo Run-in Period:  
Washout Range: 4 to 39 Days f 
Placebo Run-in Range: 5 to 9 Days 
Treatment Period:  
Day 1 to Day 56 (± 2) 
Observation Period:  
7 Days (± 1)  
after EOT 
 
Visit: 
Procedure: 
1 to 14 
Days  
Washout 
Visit e  
Placebo 
Run-In 
Visit a 
Day -1 a 
Day 1 a 
Day 28 a 
(± 2) 
End-of- Treatment 
(EOT) Visit 
Day 56 a (± 2) 
End-of-Study 
(EOS) Visit g 
7 Days (± 1) 
after EOT 
Central corneal thickness d 
√ 
 
 
 
 
 
 
 
Visual field test b 
√ 
 
 
 
 
 
 
√ 
Drug/Dosing accountability 
 
 
 
√ 
√ 
√ 
√ 
 
Washout prohibited medication 
 
√ 
√ 
√ 
 
 
 
 
Study drug dosing 
 
 
 
 
BID 
BID 
QAM 
 
Placebo Run-In dosing 
 
 
BID 
BID 
 
 
 
 
a  On Placebo Run-In Visit and Days -1, 1, 28, and 56 all procedures will take place at the Investigational site.  
b Measurements can be historical values within 90 days. 
c Measurements can be historical values within 180 days.   
d Measurements can be historical values within 1 year. 
e Upon conclusion of all Screening Period activities, subjects who still meet the study enrollment criteria are invited to attend a Washout Period Visit (if washout 
is needed). This visit may be accomplished in person at the investigative site or by phone. 
f Minimum length of washout required is described in Table 5. 
g End-of-Study Visit is calculated as 7 Days (± 1) after the actual occurrence of the EOT Visit. 
h Hyperemia assessments performed on Placebo Run-in Visit, Day -1, Day 28, and Day 56. 


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9.1. 
Study Duration per Subject 
The maximum time that subjects may participate in this study following performance of the first 
Screening Period procedure is 128 days. 
9.2. 
Study Periods, Visits, and Procedures 
The procedures to be performed during the trial are discussed below and are listed in the 
Schedule of Assessments. 
The clinical trial will include 5 study periods: Screening Period, Washout Period (if washout is 
needed), Placebo-Run-In Period, Treatment Period, and Observation Period.  However, sites may 
pre-screen subjects before inviting them to review the Informed Consent Form (ICF) in order to 
increase the chances of a successful screening.  
9.2.1. 
Pre-Screening 
Sites will review medical records (utilizing inclusion/exclusion criteria) in order to identify 
potential subjects to be screened.  Sites and subjects may also begin the informed consent 
procedures before the Screening Period begins.  Doing so will provide adequate time for the site 
personnel, subjects, and the subjects’ friends, families, and/or physicians to discuss the details of 
the study before subjects sign the ICF. 
No study procedures (including Screening activities) may be performed before the ICF has been 
signed and dated, with a copy given to the subject and another copy placed in the subject’s 
medical records. Only after the ICF has been signed may Screening activities be initiated. 
9.2.2. 
Screening Period (1 to 14 Days) 
Following completion of all the required informed consent procedures, subjects will enter the 
Screening Period and be assigned consecutive screening numbers.  Screening may continue for a 
maximum of 14 days and may require more than 1 site visit.  Subjects will remain in the 
Screening Period until the results (including central lab and ECG) obtained during Screening are 
reviewed and approved by an Investigator.  Only subjects who continue to meet the study 
enrollment criteria at the conclusion of Screening may proceed into the Washout Period (if 
washout is needed) or Placebo Run-In Period.  
Throughout the study, activities that could impact the findings on the external eye examination 
(e.g., topical ophthalmic eye drop application) are performed after any external eye assessment.  
In addition, masked-IOP measurements are performed prior to any assessment that might make 
the subject anxious or uncomfortable (e.g., vital signs, electrocardiograms [ECGs], or blood 
sampling) so as not to affect the IOP results.  Investigators and site personnel will perform study 
procedures in their appropriate order, as delineated in the clinical protocol. 
The following procedures are performed during the Screening Period: 
Prior to Masked-IOPs: 
• Demographics. 
• Medical history. 


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• Medications used in the past 45 days.  These will herein be called Medication 
History.  
• BCVA assessed. 
• External eye and slit lamp examinations. 
Masked-IOPs: 
• Masked-IOPs performed (Following application of topical anesthetic and fluorescein 
or combined product [e.g. Fluress®]). 
After Masked-IOPs: 
• Gonioscopy performed (this is the only time this procedure is performed in this trial 
in order to confirm that the angle is not occludable).  If this procedure was performed 
and documented in the subject’s medical record within the past 180 days, this 
procedure need not be repeated (unless the Investigator suspects a change).  The 
results are recorded.  Note, must be performed prior to pupillary dilation. 
• Fundus examination with pupillary dilation. 
• Vital signs (supine position). 
• 12-lead ECG performed. 
• Complete physical examination (excluding eye, breast, rectal, or pelvic 
examinations). 
• Height and weight determined. 
• Collection of blood and urine samples for central clinical laboratory safety 
assessments. 
• Pregnancy testing (serum), for females only. 
The following procedures may be performed at any time during the Screening Period:   
• Central corneal thickness measurements.  If this procedure was performed and 
documented in the subject’s medical record within the past year, this procedure need 
not be repeated and the data may be recorded.  
• Visual field test.  If this procedure was performed and documented in the subject’s 
medical record within the past 90 days, this procedure need not be repeated and those 
data may be recorded. 
• AEs occurring during the screening period will be documented.  
At the conclusion of the final Screening visit, the following will be performed: 
• Exclusion and inclusion (enrollment) criteria reviewed. 
• Visit Closure Procedures for subjects who meet the enrollment criteria.  These 
procedures include:  
− Providing subjects with relevant study instructions. 


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− Obtaining emergency contact information. 
− Scheduling clinic appointments for the next scheduled site visit. 
Only subjects who continue to meet the study enrollment criteria at the conclusion of the 
Screening Period may proceed to the following period.  Note that subjects with equivocal or 
questionable findings obtained during the Screening Period may proceed into the next Period, but 
clarification of those findings is required.  Subjects with clinically significant abnormal findings 
may not proceed into the next Period. 
Subjects who fail screening may be re-screened at any time, without a 30-day waiting period, 
since the subjects never stopped their routine medications.  
As soon as Screening has been satisfactorily completed, Washout Period activities (if washout is 
needed or Placebo Run-in Period activities may be initiated.   
9.2.3. 
Washout Period (4 to 39 Days) 
Upon conclusion of all Screening activities, subjects who still meet the study enrollment criteria 
are invited to attend a Washout Period Visit If washout is needed).  This visit (if washout is 
needed) may be accomplished in person at the investigative site or by phone.  The Washout 
Period begins with the initiation of the Washout Period Visit activities.  The maximum time 
subjects may remain in this period is 39 days; the minimum is 4 days.  
Subjects requiring no washout cannot continue to Placebo Run-In Period until all the Screening 
safety results have been reviewed by the Investigator.  Once Screening results have been 
received and approved by the Investigator, subjects are notified that they have passed Screening 
and may proceed directly into the Placebo Run-In Period.   
9.2.3.1. 
Washout Period Visit (if washout is needed) 
The main goal of this visit is to begin washout of all IOP-lowering medications and other 
prohibited medications.  At the discretion of the Investigator, this visit may be accomplished in 
person at the site or via a carefully documented telephone conversation.  
The following activities are performed: 
• Medication History (and prohibited medications identified). 
• Washout of prohibited medication begins. 
• AEs documented. 
• Exclusion and inclusion (enrollment) criteria reviewed. 
• Visit Closure Procedures will commence after the above activities have been 
completed:  
− Provide emergency telephone numbers. 
− Schedule the Placebo Run-In Visit. 
− Instruct subjects to begin washing out prohibited medications, including any 
prohibited anti-glaucoma medications. 


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9.2.3.2. 
Washout Period (if washout is needed) 
During this interval, the following procedures are followed: 
• Subjects will wash out prohibited medications for the period of time listed in the 
enrollment criteria and/or listed in Table 5. 
• On the last day of the Washout Period, the site personnel will contact each subject 
and remind them to:  
− Arrive at the investigative site the next morning for their Placebo Run-In Visit. 
− Refrain from ingesting any caffeinated products on the Placebo Run-In Visit, and 
on all other site visit days, between 5 AM and 10:15 AM. 
9.2.4. 
Placebo Run-In Period (5 to 9 Days) 
Following completion of the Washout Period or screening period (if no washout is needed), 
subjects will enter the Placebo Run-In Period.  During this period subjects will instill one drop of 
placebo into both eyes each morning and each evening.  
This period includes 2 required visits to the investigative site, on the first day of Placebo Run-In 
(Placebo Run-In Visit) and the last day of Placebo Run-In (Day -1 Visit).  The maximum time a 
subject will remain in the Placebo Run-In Period is 9 days; the minimum is 5 days.  
9.2.4.1. 
Placebo Run-In Visit 
Subjects will return to the site on the morning of the Placebo Run-In Visit, having refrained from 
ingesting any caffeine-containing foods or drinks between 5 AM and 10:15 AM.  
Throughout the study, activities that could impact the findings on the biomicroscopy 
examination (e.g., topical ophthalmic eye drop application) are performed after all the anterior 
segment ophthalmic assessments.  In addition, masked-IOP measurements are performed prior to 
any assessment that might make the subject anxious or uncomfortable (e.g., vital signs, ECGs, or 
blood sampling) so as not to affect the IOP results. 
The following procedures are performed during the Placebo Run-In Visit:  
Prior to Masked-IOPs: 
• BCVA assessed. 
• External eye* and slit lamp examinations. 
*Including baseline hyperemia assessment (utilizing grading scale). 
Masked-IOPs: 
• Masked-IOPs performed between 7:00 AM and 8:40 AM (Following application of 
topical anesthetic and fluorescein or combined product [e.g. Fluress®]). 
After Masked-IOPs: 
• Vital signs (supine position). 
• 12-lead ECG performed. 


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• Collection of blood and urine samples for central clinical laboratory safety 
assessments. 
The following procedures may be performed at any time during this visit: 
• Medication history/Concomitant medications recorded. 
• AEs documented. 
At this visit, a subject with mean morning (7:00 AM through 8:40 AM) IOP values <25 mmHg in 
both eyes are ineligible to continue in the trial.  However, if only 1 eye fails to meet the 
enrollment criteria and the contralateral eye qualifies, the subject can continue to participate.  
After the initial activities are completed, the following procedures are performed at the site on 
subjects who continue to meet the enrollment criteria: 
• Instillation of the first dose of matched placebo eye drops OU, between 7:40 AM and 
9:00 AM.   
Site Investigators must approve subjects for self-dosing.  Subjects (or their caregivers) must 
demonstrate their eye drop dosing technique on Placebo Run-In Visit AM. 
• Following completion of the above activities visit closure procedures are performed 
including:  
− Enrollment criteria reviewed. 
− Provide emergency telephone numbers and trial instructions. 
− Schedule the Day -1 site visit. 
− Distribute study drug (placebo) and dosing instructions.  
− Subjects are discharged from the site (subjects with continuing AEs are to remain 
under close observation until the Investigator determines that it is safe to 
discharge the subject from the site). 
Subjects in the Placebo Run-In Period will continue to apply placebo to both eyes each morning 
between 7:00 AM and 9:00 AM and each evening between 7:00 PM and 9:00 PM.   
NOTE: Whether 1 eye or both eyes qualify for the study, both eyes will receive matched 
placebo BID during the Placebo Run-In Period.  
9.2.4.2. 
Placebo Run-In Period 
During this interval, the following procedures are performed: 
• Washout of prohibited medications continues (if washout was required). 
• Apply matched placebo to both eyes each morning; apply matched placebo to both 
eyes each evening. 
• On Day -2, site personnel will contact each subject and remind them to:  
− Not apply the Day -1 eye drops as dosing on that day must occur at the 
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− Refrain from ingesting any caffeinated products in the morning of Day -1 from 5 
AM to 10:15 AM;  
− Bring the study medications to the site on Day -1 (the next day); and 
− Apply matched placebo between 7:00 PM and 9:00 PM. 
Subjects who fail to meet enrollment criteria (i.e. central lab or ECG) during this period may be 
re-screened 30 days later.  However, subjects who failed the IOP criteria in both eyes may 
never be re-screened for this trial. 
9.2.4.3. 
Day -1 Visit 
Day -1 is defined as the day before Day 1 randomization.  On Day -1, all subjects are required to 
visit the investigative site.  Subjects will have refrained from applying any eye drops that 
morning and from ingesting caffeinated products between 5 AM and 10:15 AM.   
Throughout the study, activities that could impact the findings on the external eye examination 
(e.g., topical ophthalmic eye drop application) are performed after any of the external eye 
assessments.  In addition, masked-IOP measurements are performed prior to any assessment that 
might make the subject anxious or uncomfortable (e.g., vital signs, ECGs, or blood sampling) so 
as not to affect the IOP results.     
The following procedures are performed during the Day -1 Visit: 
Prior to Masked-IOPs: 
• Drug/Dosing (i.e., placebo) accountability reviewed (including time of last dose). 
• BCVA assessed. 
• External eye* and slit lamp examinations. 
*Including hyperemia assessment (utilizing grading scale). 
Masked-IOPs: 
• Masked-IOPs performed between 7:00 AM and 8:40 AM (Following application of 
topical anesthetic and fluorescein or combined product [e.g. Fluress®]). 
After Masked-IOPs: 
• Vital signs (supine position). 
• Urine pregnancy test. 
The following procedures may be performed at any time during this visit: 
• AEs documented. 
• Concomitant medications recorded. 
At this visit, a subject with mean IOP values <25 mmHg in both eyes are ineligible to continue in 
the trial.  However, if only 1 eye fails to meet the enrollment criteria and the contralateral eye 
qualifies, then the subject can continue to participate.  


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• The Investigator will review the enrollment criteria.  Only eligible subjects may 
proceed to the morning dosing. 
After the initial activities are completed, the following dosing procedures are performed at the 
site by qualified and experienced personnel: 
• Apply Placebo eye drops to both eyes between 7:40 AM and 9:00 AM. 
Following application of the Day -1 AM eye drops to both eyes, the following procedures are 
performed over the ensuing 8 hours post-dose:  
• Masked-IOPs are performed at 2, 4, and 8 hours (each ±30 minutes) after the morning 
dose. (Reminder: the 8 hour IOP qualification is >21 mmHg for the study eye). 
• Hyperemia assessment (utilizing grading scale) within 30 minutes prior to 4 hour IOP 
Measurement. 
Note:  Subjects may leave the site between the 4 hour and 8 hour post-dose IOP measurements. 
However, care should be taken to restrict subjects’ sodium and liquid intake so as not to impact 
their IOPs.  In addition, subjects should return at least 15 minutes prior to the 8 hour IOP reading 
so as to allow the subjects to rest and re-acclimate to the office conditions. 
• Enrollment criteria are reviewed following completion of the above activities. Only 
subjects who complete the Placebo Run-In Period and meet the study enrollment 
criteria at the conclusion of Day -1 (including the minimum IOP measurement of at 
least 21 mm Hg at the 8 hour post dose time point) may proceed to Day 1 activities. 
• Following completion of all the Day -1 activities, the following Visit Closure 
Procedures are performed: 
− Emergency telephone numbers and trial instructions reviewed. 
− Schedule the Day 1 Visit. 
− Site personnel will make arrangements for telephone contact between 7-9 PM with 
self-dosing subjects to assure proper dosing; and remind subjects to refrain from 
ingesting any caffeinated products in the morning of Day 1 between 5:00 AM and 
10:15 AM. 
− Placebo is redistributed to subjects for self-dosing the Day -1 pm dose between 
7:00-9:00 PM. 
− Subjects are discharged from the site. 
Note:  Subjects who withdraw from the trial prior to randomization or who fail to meet the 
Enrollment Criteria (for reasons other than failing the IOP criteria) after successfully screening 
but prior to randomization, may be re-screened 30 days after their exit.  However, subjects who 
were excluded because they failed to meet the IOP Enrollment Criterion may never be re-
screened for this trial.  


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9.2.5. 
Treatment Period 
9.2.5.1. 
Day 1 Visit 
All subjects are required to visit the investigative site on Day 1.  Subjects will have refrained 
from applying any eye drops that morning or from ingesting caffeinated products from 5 AM to 
10:15 AM.    
Throughout the study, activities that could impact the findings on the external eye examination 
(e.g., topical ophthalmic eye drop application) are performed after any of the external eye 
assessments.  Masked-IOP measurements are performed prior to any assessment that might make 
the subject anxious or uncomfortable (e.g., vital signs, ECGs, or blood sampling) so as not to 
affect the IOP results.     
The following procedures are performed during the Day 1 Visit: 
Prior to Masked-IOPs: 
• Drug/Dosing (i.e. Placebo Run-In) accountability reviewed (including time of last 
dose). 
• BCVA assessed. 
• External eye and slit lamp examinations.   
Masked-IOPs: 
• Masked-IOPs between 7:00 AM and 08:40 AM (Following application of topical 
anesthetic and fluorescein or combined product [e.g. Fluress®]).  Note: This IOP 
measurement will be performed the same time (±30 minutes) as the IOP was 
measured on Day -1 AM. 
After Masked-IOPs: 
• Vital signs (supine position). 
• Directed physical examination performed. 
The following procedures may be performed at any time during this visit: 
• AEs documented. 
• Concomitant medications recorded. 
At this visit, the Placebo Run-In Visit, or the Day -1 Visit, a subject with mean IOP values <25 
mmHg in both eyes is ineligible to continue in the trial.  However, if only 1 eye fails to meet the 
enrollment criteria and the contralateral eye qualifies, then the subject can continue to 
participate. 
• The Investigator will review the enrollment criteria.  Results of all data from 
beginning of Placebo Run-In Period through Day 1 AM, including pregnancy tests 
(females of childbearing potential), must be reviewed by the Investigator prior to 
randomization. 


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• Subjects who continue to meet the study enrollment criteria are randomized for 
masked assignment to 1 of 5 treatment cohorts. 
• The study eye (see Section 6.5.4) is determined for randomized subjects and 
documented in source documentation for each subject. 
After the safety assessments have been completed and results approved by the site Investigator, 
the following Day 1 AM dosing procedures may proceed. 
• Site personnel to apply 1 drop of study drug between 7:40 AM and 9:00 AM to each 
eye.  Note: Study drug dosing on the morning of Day 1 will be performed at the same 
time (±30 minutes) as the study drug dosing occurred on Day -1 AM. 
Following application of the Day 1 eye drops, the following safety assessments are performed: 
• The following Visit Closure Procedures are performed prior to discharge: 
− Provide emergency numbers and trial instructions. 
− Schedule the Day 28 Visit. 
− Distribute study drug and dosing instructions. 
− Discharge subjects from site (subjects with continuing AEs are to remain under 
close observation until the Investigator determines that it is safe to discharge the 
subject from the site). 
9.2.5.2. 
Day 1 PM to Day 28 
• During the Treatment Period, all subjects will apply study drug twice daily to both 
eyes (the 1 study eye and the contralateral eye), every morning between 7:00 AM and 
9:00 AM and between 7:00 PM and 9:00 PM each evening. 
• Site personnel will make arrangements for telephone contact on the day before the 
planned Day 28 Visit to remind subjects not dose prior to arriving in the clinic on the 
Day 28 Visit; remind subjects to bring the study medications to the clinic on the Day 
28 Visit (the next day); and remind subjects to refrain from ingesting any caffeinated 
products in the morning of the Day 28 Visit from 5:00 AM to 10:15 AM.  
9.2.5.3. 
Day 28 Visit 
On Day 28 (±2 days), subjects will return to the investigative site for safety and efficacy 
assessments having refrained from applying any eye drops that morning or from ingesting 
caffeinated products from 5 AM to 10:15 AM.  
Throughout the study, activities that could impact the findings on the external eye examination 
(e.g., topical ophthalmic eye drop application) are performed after any of the external eye 
assessments.  Masked-IOP measurements are performed prior to any assessment that might make 
the subject anxious or uncomfortable (e.g., vital signs, ECGs, or blood sampling) so as not to 
affect the IOP results.   
The following procedures are performed during the Day 28 Visit: 
Prior to Masked-IOPs: 


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• Drug/dosing accountability reviewed (including time of last dose and general 
compliance).  
• BCVA assessed. 
• External eye* and slit lamp examinations. 
*Including hyperemia assessment (utilizing grading scale). 
Masked-IOPs: 
• Masked-IOPs between 7:00 AM and 8:40 AM (Following application of topical 
anesthetic and fluorescein or combined product [e.g. Fluress®]).  Note: This IOP 
measurement (as well as the other IOP measurements on this day) will be performed 
at the same time (±30 minutes) they were performed on Day -1. 
After Masked-IOPs: 
• Vital signs (supine position). 
The following procedures may be performed at any time during this visit: 
• AEs documented. 
• Concomitant medications reported. 
After completion of the initial assessments, the following Day 28 AM dosing-related procedures 
may proceed. 
• Site personnel to apply 1 drop of study drug between 7:40 AM and 9:00 AM to both 
eyes.  Note: Study drug dosing on the morning of the Day 28 Visit will be performed 
at the same time (±30 minutes) as the study drug dosing occurred on Day -1 AM. 
− This is the last dose that will be applied with the study drug kit that was 
assigned at Randomization. This kit will be collected from the subject and not 
re-distributed following this AM dose. 
Following application of the Day 28 eye drops, the following procedures are performed over the 
ensuing 8 hours post-dose: 
• Masked-IOPs are performed at 2, 4, and 8 hours (each ±30 minutes) after the morning 
dose. 
• Hyperemia assessment (utilizing grading scale) within 30 minutes prior to 4 hour IOP 
Measurement. 
Note:  Subjects may leave the site between the 4 hour and 8 hour post-dose IOP 
measurements. However, care should be taken to restrict subjects’ sodium and liquid intake 
so as not to impact their IOPs. In addition, subjects should return at least 15 minutes prior to 
the 8 hour IOP reading so as to allow the subjects to rest and re-acclimate to the office 
conditions. 
Following completion of all the Day 28 Visit activities, the following Visit Closure Procedures 
are performed: 
• Provide emergency numbers and trial instructions reviewed. 


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• Schedule the Day 56 Visit. 
• Distribute new study drug kit (Assigned by Interactive Response Technology) and 
dosing instructions. 
• Discharge subjects from site (subjects with continuing AEs are to remain under close 
observation until the Investigator determines that it is safe to discharge the subject 
from the site). 
9.2.5.4. 
Day 28 PM to Day 56 
• During the Treatment Period, all subjects will apply study drug twice daily to both 
eyes (the 1 study eye and the contralateral eye), every morning between 7:00 AM and 
9:00 AM and between 7:00 PM and 9:00 PM each evening. 
• Site personnel will make arrangements for telephone contact on the day before the 
planned End-of-Treatment Visit to remind subjects not dose prior to arriving in the 
clinic on the End-of-Treatment Visit; remind subjects to bring the study medications 
to the clinic on the End-of-Treatment Visit (the next day); and remind subjects to 
refrain from ingesting any caffeinated products in the morning of the End-of-
Treatment Visit from 5:00 AM to 10:15 AM. 
9.2.5.5. 
End-of-Treatment (Day 56) Visit 
On Day 56 (±2 days), subjects return to the investigative site for safety and efficacy assessments 
having refrained from applying any eye drops that morning or from ingesting caffeinated 
products from 5 AM to10:15 AM.   
Throughout the study, activities that could impact the findings on the external eye examination 
(e.g., topical ophthalmic eye drop application) are performed after any of the external eye 
assessments.  Masked-IOP measurements are performed prior to any assessment that might make 
the subject anxious or uncomfortable (e.g., vital signs, ECGs, or blood sampling) so as not to 
affect the IOP results.  
The following procedures are performed during the Day 56 Visit: 
Prior to Masked-IOPs: 
• Drug/dosing accountability reviewed (including time of last dose and general 
compliance).  
• BCVA assessed. 
• External eye* and slit lamp examinations. 
*Including hyperemia assessment (utilizing grading scale). 
Masked-IOPs: 
• Masked-IOPs between 7:00 AM and 8:40 AM (Following application of topical 
anesthetic and fluorescein or combined product [e.g. Fluress®]).  Note: This IOP 
measurement (as well as the other IOP measurements on this day) will be performed 
at the same time (±30 minutes) they were performed on Day -1. 


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After Masked-IOPs: 
• Vital signs (supine position). 
• Urine pregnancy test. 
The following procedures may be performed at any time during this visit: 
• AEs documented. 
• Concomitant medications reported. 
After completion of the initial assessments, the following Day 56 AM dosing-related procedures 
may proceed. 
• Site personnel to apply 1 drop of study drug between 7:40 AM and 9:00 AM to both 
eyes.  Note: Study drug dosing on the morning of Day 56 will be performed at the 
same time (±30 minutes) as the study drug dosing occurred on Day -1 AM. 
Following application of the Day 56 AM eye drops, the following procedures are performed over 
the ensuing 8 hours post-dose: 
• Masked-IOPs are performed at 2, 4, and 8 hours (each ±30 minutes) after the morning 
dose. 
• Hyperemia assessment (utilizing grading scale) within 30 minutes prior to 4 hour IOP 
Measurement. 
Note:  Subjects may leave the site between the 4 hour and 8 hour post-dose IOP 
measurements. However, care should be taken to restrict subjects’ sodium and liquid 
intake so as not to impact their IOPs. In addition, subjects should return at least 15 
minutes prior to the 8 hour IOP reading so as to allow the subjects to rest and re-
acclimate to the office conditions. 
Following completion of all the Day 56 activities, the following Visit Closure Procedures are 
performed: 
• Schedule the End-of-Study Visit. 
• Discharge subjects from site (subjects with continuing AEs are to remain under close 
observation until the Investigator determines that it is safe to discharge the subject 
from the site). 
As part of the rescue plan in Section 9.5, any subject whose mean IOP in either eye exceeds 34 
mmHg, at any timepoint or who an investigator judges there being significant clinical risk will 
complete collection of the 4 serial IOP measurements and be withdrawn from the study.  Please 
refer to Section 9.4 for complete instructions on withdrawal of subjects from the trial. 
9.2.6. 
Observation Period (7 ±1 days) 
9.2.6.1. 
Observation Period 
• During the Observation Period, no ocular medications are applied.  


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• Site personnel will make arrangements for telephone contact on the day before the 
End-of-Study Visit to remind subjects of their site visit the next day and to refrain 
from ingesting any caffeinated products in the morning of End-of-Study Visit 
between 5:00 AM to 10:15 AM. 
9.2.6.2. 
End-of-Study Visit (7 ±1 days) after EOT 
Seven (±1) days after the End-of-Treatment all subjects are required to return to the investigative 
site for End-of-Study activities.  
Throughout the study, activities that could impact the findings on the external eye examination 
(e.g., topical ophthalmic eye drop application) are performed after any of the external eye 
assessments.  Masked-IOP measurements are performed prior to any assessment that might make 
the subject anxious or uncomfortable (e.g., vital signs, ECGs or blood sampling) so as not to 
affect the IOP results.  Investigators and site personnel will perform study procedures in the 
appropriate order, as delineated in the clinical protocol.   
The following procedures are performed during the End-of-Study Visit: 
Prior to Masked-IOPs: 
• BCVA assessed. 
• External eye and slit lamp examinations. 
Masked-IOPs: 
• Masked-IOPs performed between 7:00 AM and 9:00 AM (Following application of 
topical anesthetic and fluorescein or combined product [e.g. Fluress®]). 
After Masked IOPs: 
• Visual field test (Must occur prior to dilation). 
• Fundus examination with pupillary dilation. 
• Vital signs (supine position). 
• 12-lead ECG performed. 
• Complete physical examination (excluding eye, breast, rectal, or pelvic 
examinations). 
• Collection of blood and urine samples for central clinical laboratory safety 
assessments. 
The following procedures may be performed at any time during this visit: 
• AEs documented. 
• Concomitant medications recorded. 
Visit Closure Procedures are performed after completion of the above procedures including: 
• Advise subjects to restart their routine (pre-trial) medication(s) per the discretion of 
the treating physicians. 


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• Provide appropriate medical follow-up to subjects with continuing AEs. 
• Subjects are discharged from the site. 
9.3. 
Study Procedure Details 
9.3.1. 
Subject Information and Consent Form 
Subject informed consent is obtained by the Investigator or his designee prior to study 
enrollment in accordance with the FDA Code of Federal Regulations (CFR) on GCP and ICH 
guidelines (see Title 21 CFR, Part 50, ICH [E6] for description of Informed Consent 
Procedures).  The Investigator’s responsibilities relating to informed consent are discussed in 
Section 15.3. 
9.3.2. 
Enrollment and Randomization 
This is a double-masked, multi-center clinical study.  All subjects who have signed the ICF and 
meet the entry criteria through Day 1 (AM) are eligible for enrollment, randomization, and 
treatment with the study drug.  
Treatment group assignment and randomization will occur on the Day 1 Visit utilizing a 
validated Interactive Response Technology. 
To mimic what is generally seen in clinical trials, the number of subjects with ocular 
hypertension as their diagnosis will be limited to approximately 30% of the total subjects 
enrolled.  Additionally, so the trial mirrors the general population demographics (so as to 
improve generalizability of the results) the proportion of African American subjects will be 
approximately 25% or less but not less than 12% of the total subjects enrolled. 
Any subject who completes 39 days in the Washout Period must either proceed the following 
day to the Placebo Run-In Period or be terminated from the trial.   
Any subject who completes the Placebo Run-In Period must either proceed to Day 1 or return to 
the Washout Period.  However, the days the subject was in Placebo Run-In must be applied to 
the Washout Period and such subjects still may not exceed the maximum of 39 days permitted 
for the Washout Period.  
Subjects who were terminated from the study solely because they had reached the maximum 
number of days permitted in the Washout Period or the Placebo Run-In Period but could not 
proceed into the next study period, may re-enter Screening after a 30-day waiting period for 
possible re-enrollment.  At the time of termination, such subjects are instructed to contact their 
primary ophthalmologist for treatment instructions. 
9.3.3. 
Masking Procedures 
All site personnel, and enrolled subjects are masked to the study drug assignments until the last 
subject has completed all study-related activities and the database has been locked.  All Sponsor 
personnel directly involved in the conduct of the study will also remain masked until after data 
lock.  


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In the event of an emergency in which unmasking is required at an investigative site, the 
emergency procedures found in Section 11.2 will be followed. 
9.3.4. 
Study Drug Administration 
Only subjects currently enrolled in the study with appropriately signed, dated, and witnessed 
informed consent and meeting the eligibility criteria may receive the study drug.  
Subjects who continue to meet the study enrollment criteria during the Day 1 Visit will receive 
the study drug.  Study drug is applied by trained site personnel, the subject, and/or the subject’s 
caregiver who was certified by the site Investigator.  The person administering the dose will 
allow the drop formed at the tip of the eyedropper to fall freely into the conjunctival sac (fornix).  
The drop should not be allowed to touch any part of the eye or its surrounding tissues before it is 
(they are) released from the eyedropper’s tip.  During the Treatment Period, study drug will be 
applied to both eyes.   
During administration of study drug, any solution that falls on the skin surrounding the eye is 
blotted away immediately and the skin cleansed with a cool wet wipe.  If the entire administered 
dose of study drug falls on the skin surrounding the eye (i.e., none of the liquid enters the eye), a 
new dose of study drug is applied to the conjunctival sac (fornix). 
Once the appropriate dose has been applied to the lower conjunctival sac (fornix) of the study 
eye, the Investigator or designee will allow the lower eyelid to gently return to its natural 
position.  The subject is instructed to gently close both eyes for a minimum of sixty (60) seconds.  
The person who applied the dose will then remove all excess liquid from the eyelids and 
surrounding skin of the dosed eye using an absorbent material (e.g., gauze or tissue). 
All used and unused study drugs must be returned to the site for drug accountability after each 
subject completes their participation in the trial (End-of-Study Visit). 
The post-dose time points of this protocol refer to the time when the study drug dosing has been 
completed. 
On days when AM pre-dose IOPs are measured, subjects will be asked not to ingest any 
caffeinated products from 5:00 AM through 10:15 AM that day.   
9.3.5. 
Demographics 
The birth date, gender, race and ethnicity of each subject will be documented in the Case Report 
Form (CRF). 
9.3.6. 
Medical and Ophthalmologic History  
Medical history, including any diseases, past surgeries, psychiatric illnesses and relevant medical 
history will be documented in the CRF, with particular attention given to cardiovascular 
conditions including hypertension, cardiac arrhythmias, and heart conduction disturbances. 
Ophthalmologic history will include ocular trauma and surgery, eye infections and inflammation, 
retinal vein occlusion, and acute or chronic vision disturbances. 
POAG is generally defined as a condition in which subjects have: (1) elevated IOPs and (2) 
abnormal findings on examination of the optic disc and/or a visual field defect that correlates 


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with the optic disc abnormalities and is consistent with POAG.  OHT is defined as a condition in 
which subjects have consistently elevated IOPs but fail to fulfill the above POAG definition.  
However, for the purposes of this study, the Investigator’s clinical diagnosis of POAG or OHT is 
adequate to meet this entry criterion. 
Each subject will be questioned regarding all anticipated elective medical procedures that may 
occur during the subject’s planned participation in the study and these must be documented in 
the subject’s medical record and the medical history section of the CRF.  
9.3.7. 
Medication History 
Medication history (past 45 days) will be documented during Screening.  Any medication 
received by the subject prior to their signing the ICF and through completion of the washout 
period will be captured as Medication History.  Any medication received by the subject 
following the start of the Placebo Run-In Period will be captured as Concomitant Medications.  
Any medication taken consistently by the subject for 30 days prior to Screening and is not a 
prohibited medication may be continued during the trial if appropriately documented and 
captured in the CRF. 
9.3.8. 
Concomitant Medications and Treatments 
All concomitant medications taken by subjects from the start of the Placebo Run-In Period 
through completion of the End-of-Study Visit, including all additions, subtractions, or 
adjustments of medications, vitamins, and/or herbal supplements, must be documented in the 
CRF.  
The Investigators and their designees are obligated to ensure the well-being of all subjects during 
this study.  Consequently, no medication or treatment will be withheld from a subject requiring 
medical intervention.  This may include treatments received by the subject prior to enrollment as 
well as in response to new medical conditions developed during the study.  The Investigator or 
designee must inform a subject when concomitant medical intervention or treatment is indicated 
and report this in the appropriate section of the CRF.  
9.3.9. 
Prohibited Medications 
Tobacco products, electronic cigarettes, cannabis (medical or recreational) over-the-counter or 
herbal medications, alternative medicines, or analgesics are all prohibited from start of Placebo 
Run-In Period through completion of the End-of-Study Visit, with the exception of: 
• ≤5 cigarettes daily,  
• Oral vitamin D calcium supplementation, multivitamins, and/or AREDS vitamins for 
ocular health taken consistently for at least 30 days prior to Screening, 
• Aspirin, acetaminophen, or ibuprofen taken consistently for approximately 30 days 
prior to Screening, with no anticipated dosing changes to take place during study 
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• Preservative free artificial tears, if taken consistently for at least 30 days prior to 
Screening and not administered within one hour of study medication AM or PM 
dosing.  Of note, cyclosporine containing agents such as Restasis® are NOT allowed. 
• Other vitamins, herbal supplements, or alternative medications taken consistently for 
at least 30 days prior to Screening AND approved by one of the medical monitors for 
each subject.  
9.3.10. 
Prohibited Activities 
Heavy exercise (e.g., running, heavy lifting, bicycling, power walking, kickboxing, rowing, and 
sit ups) and physical labor are prohibited from the start of the Placebo Run-In Period through the 
completion of the End-of-Study Visit, so as not to cause exercise-induced increases in serum 
creatinine phosphokinase (CPK) levels.  Moderate exercise (e.g., swimming and walking outside 
or on a treadmill) is permitted. 
Contact lenses may not be worn from the start of the Placebo Run-In Period through the 
completion of the End-of-Study Visit. 
9.3.11. 
Prohibited Foods 
More than 24 ounces of beer, 8 ounces of wine, or 4 ounces of liquor per day are prohibited from 
the start of the Placebo Run-In Period through completion of the End-of-Study Visit. 
Caffeinated products are prohibited (e.g., chocolate, coffee, tea, or cola) from 5 AM through 
10:15 AM on Placebo Run-In Day and Days -1, 1, 28, 56, and EOS Visit. 
9.3.12. 
Vital Signs, Height, and Weight 
Throughout the study, vital signs (resting blood pressure, pulse rate, temperature, and respiratory 
rate) will be obtained with the subject in a supine position after the subject has rested for 5 
minutes.  
Oral temperatures should not be obtained within 5 minutes of the ingestion of any food or drink 
in order to avoid their influencing the results. 
Respiratory rate and manually-obtained pulse/heart rates will be recorded following a minimum 
of 30 seconds of observation.  Pulse/heart rates may be measured electronically (for example, via 
an electronic blood pressure reader, monitor, or ECG).  However, the heart rate data from a 
scheduled ECG may not be used to obtain these vital sign data.   
The subject’s height and weight will be documented in the CRF during the Screening Visit.  
9.3.13. 
Physical Examination  
Two types of physical examinations will be performed during the trial: 
1. Complete physical examination includes skin, ears, nose, throat, lymph nodes, chest, 
heart, lungs, abdomen, as well as the neurological and musculoskeletal systems. 
2. Directed physical examination includes skin, throat, chest, heart, lung, and abdomen. 


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Neither type of physical examination includes an eye, breast, rectal, or pelvic examination.  Eye 
examinations are performed independent of the physical examinations.  
All abnormal findings must be recorded whether they are new or were recorded previously in the 
CRF.  For example, a surgical scar must be noted each time a physical examination is recorded.  
9.3.14. 
Laboratory Tests 
All Central Laboratory blood samples will be collected, processed and shipped as per the Central 
Laboratory’s Instruction Manual on the same day as sampling.  Samples will be obtained as per 
the time points listed in the Schedule of Assessments. 
9.3.14.1. Hematology, Coagulation Parameters, and Clinical Chemistry Profile 
Blood will be collected for hematology analysis including: 
• White blood cell count 
• Mean corpuscular volume  
• White blood cell differential in 
absolute numbers, not percentages 
• Mean corpuscular hemoglobin 
concentration 
• Hemoglobin 
• Red blood cell count 
• Hematocrit 
• Platelet count 
Blood for coagulation analysis including: 
• International normalized ratio 
• Partial thromboplastic time 
Blood for a clinical chemistry including: 
• ALT 
• Creatinine* 
• AST 
• Glucose 
• Albumin 
• Lactate dehydrogenase 
• Alkaline phosphatase 
• Inorganic phosphorus 
• Direct bilirubin 
• Potassium 
• Total bilirubin 
• Total protein 
• Blood urea nitrogen or urea 
• Sodium 
• Calcium and corrected calcium 
• Triglycerides 
• Total cholesterol 
• Uric acid 
• Chloride 
• Total CPK 
*estimated glomerular filtration rate (GFR) will be estimated using the formula used by the 
central laboratory. 
9.3.14.2. Urinalysis 
Urine samples will be collected and analysis will include: 
• Glucose 
• Erythrocytes 
• Protein 
• Leukocytes 


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• pH 
• Nitrites 
• Ketones 
 
9.3.14.3. Pregnancy Testing 
Samples for pregnancy testing will  be obtained from females of childbearing potential (as 
defined in Inclusion Criteria # 4) and will be performed on blood (during screening) and urine (at 
Day -1 and End-of-Treatment) samples. 
9.3.14.4. Determination of Clinical Significance 
The Investigators will use medical judgment when determining the clinical significance of any 
findings.   
Subjects with clinically significant abnormal findings at Screening, Washout, Placebo Run-In 
Day, Day -1, or Day 1 pre-dose are excluded from this clinical study.  
9.3.15. 
Electrocardiogram (12-Lead ECG) 
A standard, surface 12-lead ECG for RR, PR, QRS, and QT intervals, heart rate, and rhythm will 
be obtained.  ECGs in a digital format will be interpreted by a Board-Certified cardiologist at a 
central laboratory.  The QT interval results will be adjusted for rate using the Bazett (QTcB) and 
Fridericia (QTcF) corrections. 
Cardiac dysrhythmias will be documented by occurrence (date and time), severity, type, and 
duration.  Isolated premature ventricular contractions and supraventricular extrasystolic 
waveforms will not be recorded. 
Should an ECG recorded at any time after Screening demonstrate either a clinically significant 
change from the ECG obtained at screening or any new objective abnormality, the Investigator 
will immediately obtain an unscheduled ECG.   
9.3.16. 
Ophthalmologic Examinations and Measurements 
9.3.16.1. Ophthalmologic Procedures 
The following ophthalmologic procedures will be performed as part of this trial.  Only the 
personnel listed below may perform these activities. 
1. External eye and slit lamp examinations: This will include a pen light examination of the 
peri-orbital area (i.e., eyelids, eyelashes and conjunctivae) and a slit lamp examination of 
the eyelids, eyelashes, conjunctivae, sclerae, cornea, anterior chamber, anterior vitreous, 
iris, and lens.  This examination may be performed only by an optometrist or 
ophthalmologist.   
a. Hyperemia assessments are to be conducted on Day -1, Day 28, and Day 56 by a 
trained optometrist or ophthalmologist using a pen light and the sponsor provided 
hyperemia grading scale. Whenever possible, the same individual should perform 
hyperemia assessments for a subject throughout the trial. 


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2. Fundus examination (ophthalmoscopy/ funduscopy).  This will consist of optic nerve 
examination including (vertical) cup to disc ratio, retinal vasculature, macula assessment, 
and peripheral retinal assessment.  This examination may only be performed by an 
optometrist or ophthalmologist.  If possible, the same person must perform this activity 
throughout the study on any one particular subject. 
3. Gonioscopy:  Careful examination of the angle via gonioscopy will only be performed 
once at Screening as part of the internal eye examination to confirm that the subject’s 
angle is open (>10 degrees) and non-occludable. Schaeffer grading is required. If this 
procedure was performed within the past 180 days and documented in the subject’s 
medical record, this procedure need not be repeated (unless the Principal Investigator [PI] 
suspects a change).  This examination may be performed only by an optometrist or 
ophthalmologist. 
4. Masked IOPs: Instructions for the masked reading of IOPs are described below.  The slit 
lamp portion of the IOP measurement may be performed by a masked optometrist or 
ophthalmologist.  If possible, the same operator (ophthalmologist or optometrist) must 
perform these activities on the same Goldmann tonometer throughout the study on any 
one particular subject.  However, the person responsible for the pressure gauge IOP 
reader (see Section 9.3.16.2) may be a trained certified ophthalmic assistant (COA), 
certified ophthalmic technician (COT), nurse, or research coordinator. 
5. Modified ETDRS Best-corrected visual acuity (BCVA) will be performed based on the 
Early Treatment Diabetic Retinopathy Study (ETDRS) protocol.  This activity may be 
performed by an optometrist, ophthalmologist, or COT.  A well-trained and experienced 
nurse or research coordinator may also perform this activity. 
6. Visual Fields: The recommend visual fields include Humphrey (24-2 full threshold, 24-2 
SITA standard, 30-2 central threshold, [Note: 24-2 SITA fast not allowed]) and Octopus 
(GI dynamic strategy, GI normal strategy, 24-2 dynamic strategy, 24-2 normal strategy). 
If this procedure was performed within the past 90 days, and documented in the subject’s 
medical record, this procedure need not be repeated (unless the Principal Investigator [PI] 
suspects a change).  This may be performed by a trained certified ophthalmic assistant 
(COA), certified ophthalmic technician (COT), nurse, or research coordinator. 
7. Central Corneal Thickness will be performed utilizing an ultrasound pachymeter. If this 
procedure was performed within the past 365 days, and documented in the subject’s 
medical record, this procedure need not be repeated (unless the Principal Investigator [PI] 
suspects a change).  This examination may be performed only by an optometrist, 
ophthalmologist, or a trained certified ophthalmic technician (COT) 
8. Eye drop application:  This activity must be performed by an ophthalmologist, 
optometrist, COA, COT, or a research coordinator experienced in eye drop 
administration.  Qualified subjects (or their caregivers) may apply the eye drops. 
Note:  Whenever an external eye examination and/or BCVA are scheduled with IOP 
measurements, the external eye examination and BCVA will be performed before application of 
the topical anesthetic for the IOP measurements. 
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9.3.16.2. Instructions for Masked-IOP Readings via Goldmann Applanation Tonometry 
Topical anesthetic and fluorescein will be applied prior to performing the masked-IOP 
assessment described below. This can be a combined topical anesthetic and fluorescein product 
(such as Fluress®, Flurox™, etc) or administration of a topical anesthetic and fluorescein 
separately. 
Performance of the masked-IOP readings requires 2 trained personnel working together: (1) the 
tonometer operator responsible for positioning the subject and adjusting the tonometer; and (2) 
the IOP reader who reads the pressure gauge setting and records the IOP results.   
The masked-IOP measurements will be performed as follows: 
1. The tonometer operator must be an ophthalmologist or optometrist and will prepare the 
subject and the instrumentation.  The subject should be comfortably seated at the 
tonometer.  The subject should not be leaning, straining, stretching or stooping.  The 
temperature and lighting in the tonometry room should be as consistent as possible from 
visit to visit.  
2. The tonometer operator should not be able to read the IOP gauge from his position 
behind the tonometer.  If necessary, the gauge will be shielded.  
3. The IOP reader (any trained and experienced site personnel) sets the tonometer gauge to a 
setting between 10-20 mmHg. 
4. The tonometer operator adjusts the pressure in a masked fashion and instructs the IOP 
reader to record the pressure without removing his eyes from the slit lamp.  
5. The IOP reader records the measurement and resets the tonometer to a setting between10-
20 mmHg, avoiding the setting used above.  The tonometer operator will not be informed 
of the result obtained from the first pressure reading. 
6. The tonometer operator adjusts the pressure again in a masked fashion and instructs the 
IOP reader to record the second pressure without removing his eyes from the slit lamp.  
7. The IOP reader records the measurement. The tonometer operator will not be informed 
yet of the result obtained from the pressure readings. 
8. The IOP reader calculates the difference between the 2 IOP measurements obtained.   
9. If the 2 IOP readings differ by ≤2 mmHg, the IOP reader informs the tonometer operator 
that the readings are complete.  The tonometer operator may then remove his eyes from 
the instrument and be told the results.  However, if the first 2 IOP results differ by more 
than 2 mmHg, the IOP reader will again reset the tonometer to 10-20 mm Hg.  The 
tonometer operator then adjusts the pressure again in a masked fashion and instructs the 
IOP reader to record the third IOP measurement. 
Note: Goldmann Applanation Tonometer calibration will be checked monthly and recorded in a 
calibration log. 
9.4. 
Withdrawal of Subjects 
Subjects will be informed that they are free to withdraw from the study at any time.  


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The reason for any premature withdrawal must be explained in detail in the source document. 
A subject may be withdrawn from the study under the following conditions: 
• Subject withdraws consent. 
• Subject’s compliance to the protocol is poor, per discretion of the Investigator. 
• Any condition that, in the Investigator’s opinion, may cause risk to the subject (see 
also Section 9.5).  In this case, the Investigator will specify the reason for the 
subject’s withdrawal. 
Note: All effort will be made to capture the complete set of serial IOP measurements for 
the subject on the day of withdrawal. 
• Occurrence of a concomitant disease that violates the study protocol due to its 
severity or duration or due to changes in treatment being required. 
Any subject who withdraws or is withdrawn from the study should undergo the End-of-Study 
Visit procedures, preferably 7 (±1) days later, in order to assure the safety of the subject. 
The data handling of subjects who fail to complete all scheduled visits is described in the 
Section 12.3. 
9.5. 
Rescue Plan 
In order to ensure subject safety, careful attention should be paid at each visit to the subject’s 
IOP and general ophthalmologic condition. If any of the following occur, the subject should be 
withdrawn and begun on therapy per the Investigator’s judgement: 
• If subject’s IOP in either eye exceeds 34 mmHg at any timepoint during the trial.  
• At any time during the study the Investigator assesses there is a clinically significant 
risk to the subject’s safety.  
Due to each subject’s clinical condition being unique, this rescue plan does not recommend a 
specific recue therapy for subjects. If a subject meets one of the conditions specified in this 
rescue plan, the Investigator should use their clinical judgment and knowledge of the subject’s 
specific condition to institute the best treatment for that subject. For instance, if subject was on 
more than one drug or a fixed dose combination therapy prior to entry in the study, it may be 
determined that it is in the best interest of the prior subject to restart this therapy immediately to 
ensure a rapid return of the IOP into the target range for that subject. 


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10. 
TOLERABILITY AND SAFETY 
10.1. 
Adverse Events 
An AE is any unfavorable medical occurrence in a study subject that develops or worsens during 
the period of observation in the clinical study.  No causal relationship with the study medication 
or with the clinical study procedure is implied by the use of the term “adverse event.” AEs fall 
into the categories “non-serious” and “serious.” Seriousness is not the same as severity (see 
Section 10.2). 
Treatment-emergent Adverse Events (TEAEs) are AEs that occur following the first dose of 
study drug on Day 1 AM.  
Surgical procedures themselves are not AEs; they are therapeutic measures taken for the AE, and 
will be documented as such.  Planned hospital admissions and study-related procedures are also 
not AEs. 
10.2. 
Clarification of the Difference between “Severe” and “Serious” 
Severity describes the intensity of an event, irrespective of its medical significance (such as 
severe headache).  This is not the same as seriousness, which is based on ICH guidelines. 
Seriousness (not severity) defines SAE reporting obligations.  The severity of all AEs will be 
graded on a 3-point scale (mild, moderate, severe) and reported in detail on the CRF. 
• Mild: Discomfort noticed but no disruption of normal daily activity. 
• Moderate: Discomfort sufficient to reduce or affect daily activity. 
• Severe: Inability to work or perform normal daily activity. 
10.2.1. 
Laboratory Test and Diagnostic Procedure Abnormalities 
An abnormal result will not be recorded as an AE unless one or more of the below occurs: 
• The abnormal test is accompanied by symptoms. 
• The test result leads to an alteration or interruption in study medication. 
• The test result requires medical or surgical intervention (e.g., significant 
hyponatremia). 
• The test result is considered clinically significant by an Investigator. 
If such an event occurs, the test should be repeated and appropriately monitored (Section 10.2.2).   
10.2.2. 
Follow-up of Adverse Events 
All AE related symptoms and/or signs will be followed until there is a return to the baseline 
status, all associated parameters have returned to normal (or are no longer considered clinically 
significant), or no further improvement is anticipated.  Follow-up is mandatory, irrespective of 
causal relationship to the study drug(s).  SAEs will be monitored until resolution, as medically 
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10.2.3. 
Documentation and Reporting of Adverse Events by Investigator 
Instructions for the completion of AE reports in a clinical study are provided by the Sponsor.  
The following approach should be taken for documentation: 
• All AEs (whether serious or non-serious, or considered an alert term) must be 
documented on the AE page of the CRF. 
• Every attempt should be made to describe the AE in terms of a diagnosis.  If a clear 
diagnosis has been made, individual signs and symptoms will not be recorded unless 
they represent atypical or extreme manifestations of the diagnosis, in which case they 
should be reported as separate events.  If a clear diagnosis cannot be established, each 
sign and symptom must be recorded individually, as separate events.  
• An AE should only be recorded once, irrespective of the study period, with the event 
stop date being the date of resolution, resolution with sequelae, or otherwise.  If the 
same AE re-emerges after resolution, or the severity and/or the relatedness to study 
drug changes after the AE has been recorded in the CRF, a new event should be 
reported with the new description. 
• Relationship of the AE to each study drug must always be assessed by the 
Investigator, as indicated in the CRF and SAE Report form. 
• When appropriate, relevant supportive documents (e.g., medical reports, photographs) 
may be submitted to the Sponsor. 
• The period of observation for the collection of AEs extends from the time the subject 
signs ICF until the conclusion of the End-of-Study Visit. 
• If the Investigator is made aware of a drug-related SAE in a study subject after 
completion of the End-of-Study Visit, an SAE Report form should be completed.  If 
the study site has been closed, the Sponsor Medical Monitor or his designee should be 
contacted. 
10.3. 
Serious Adverse Events 
An SAE is any AE that, at any dose, results in at least one of the following outcomes: 
• Death.  Death is an outcome, not an event.  Where the cause of death is uncertain, the 
reported SAE should be the same as the term on the subject’s death certificate. 
• Is life-threatening.  Life-threatening means that the subject was at immediate risk of 
death at the time of the SAE; it does not refer to an AE or SAE that hypothetically 
might have caused death if it were more severe. 
• Requires or prolongs inpatient hospitalization. 
• Persistent or significant disability or incapacity. “Persistent or significant disability or 
incapacity” means that there is a substantial disruption of a person’s ability to carry 
out normal life functions. 
• A congenital anomaly or birth defect. 


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• A medically serious event based upon appropriate medical judgment.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
10.4. 
Special Interest Adverse Events and Overdoses 
There are no AEs of special interest in this clinical trial.  
Any overdose of the study drug is to be reported to the Sponsor in an expedited detailed manner.  
For example, if 2 drops of study drug are applied to an eye instead of 1 drop, this should be 
reported as an overdose.  In contrast, repeating an eye drop application due to uncertainty 
regarding the proper application of the first dose will not be considered an overdose.  
Any AEs or SAEs, as defined in Section 10.1 and Section 10.3, associated with an overdose will 
be reported as such. 
10.5. 
Reporting of Adverse Events 
10.5.1. 
Reporting of Serious Adverse Events by Investigators 
If the AE is serious, the Investigator must complete an SAE Report form, in addition to the AE 
page in the CRF. 
The SAE Report Form must be completed in accordance with instructions provided by the 
Sponsor or designee.  The completed form must be faxed or emailed to the Sponsor 
Pharmacovigilance designee within 24 hours of discovery of the SAE.  
If, for any reason, the Investigator cannot notify the Sponsor Pharmacovigilance designee via the 
appropriate form or if the Investigator suspects that using this method will delay the notification 
(e.g., during a holiday period), the Investigator may verbally notify the Sponsor Medical Monitor 
or Designee via telephone.  The SAE Report form must still be relayed at the earliest possible 
opportunity.  SAEs must be reported to the IRB according to IRB guidelines.  
The initial report must be as complete as possible, including details of the current illness and the 
SAE, and an assessment of the causal relationship between the event and the investigational 
product(s) or the study procedures. 
Information not available at the time of the initial report (e.g., an end date for the AE or 
laboratory values received after the report) must be documented as a follow-up on the SAE 
Report form. 
In addition, when a non-serious event becomes serious, details must be forwarded, within 24 
hours of Investigator awareness that an AE has become serious, to the Sponsor or designee on an 
SAE Report form, with the date of the seriousness upgrade as the SAE start date. 
All ancillary documentation (e.g., discharge letters, laboratory reports and consultations) must be 
sent to the Sponsor or designee.  In the event of an SAE resulting in death, post-mortem reports 
should be routinely sent to the Sponsor or designee. 
Any SAEs including death due to any cause, which occurs in any subject entered into treatment 
in this study or within 30 days following (self-reported by patient) cessation of treatment, 


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whether or not related to the investigation product, must be reported to the Sponsor within 24 
hours.  All subjects with SAEs must be followed-up for outcome. 
10.5.2. 
Reporting of Serious Adverse Events by Sponsor 
It is the Sponsor’s responsibility to ensure that all legal reporting requirements are met.  The 
Sponsor shall notify all applicable regulatory bodies and Investigators, while sites will notify 
IRBs, of any AE associated with the use of the drug that is both serious and unexpected as 
required by IRB regulations, and this will be done within applicable timelines.  
10.5.3. 
Periodic Reporting of Adverse Events by Sponsor 
The Sponsor will send a periodic safety summary to the Investigator and/or the local regulatory 
agencies as required by law and local regulations. 


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11. 
EMERGENCY PROCEDURES 
11.1. 
Emergency Sponsor Contacts 
In emergency situations, the Investigator must contact the Sponsor Medical Monitor or designee. 
11.2. 
Emergency Unmasking 
Should a serious safety concern arise and the Investigator feels it necessary to immediately 
obtain the code assignment of a specific subject, the Investigator may request the code 
assignment of only that specific subject from the electronic randomization system without 
obtaining prior permission from the Sponsor Medical Monitor or Designee.  The Investigator 
must contact the Sponsor Medical Monitor (or designee) by telephone within 12 hours of such 
circumstances. 
In all other cases, the Investigator must contact the Sponsor Medical Monitor (or designee) for 
unmasking approval.  A decision to unmask the assignment code of a study subject must be 
made jointly by the Investigator, and the Sponsor Medical Monitor or designee.  The decision to 
unmask a study subject will be documented in writing by the Sponsor Medical Monitor (or 
designee) before a subject’s treatment group assignment is unmasked. 
The time, date, reason(s) for the unmasking, and the actual treatment assignment must be 
documented in the subject’s source documents at the time of the unmasking.  
11.3. 
Emergency Treatment 
During a subject's participation in the study, the Investigator or institution will ensure that 
emergency medical care is provided to a subject for all AEs as required.  The Investigator or 
designee will inform a subject without delay whenever an emergent medical issue arises or if 
emergency medical intervention is required. 
Local ocular conditions that may be emergent are included in Section 9.5, Rescue Plan. 


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12. 
STATISTICAL PLAN 
12.1. 
Sample Size Determination  
To address the primary objective of this trial, based on an assumed SD of 3.3 mmHg, a sample 
size of 30 subjects in each group will provide an estimate of the effect on IOP with a 95% 
Confidence Interval with a ½ width (precision) of no greater than 1.2 mmHg. 
In order to compensate for an anticipated drop-out rate of 10%, approximately 33 subjects will 
be enrolled in each of the 5 treatment groups in order to complete the trial with approximately 
165 enrolled subjects and a total of 150 evaluable subjects. 
12.2. 
Analysis Populations 
12.2.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population is defined as all subjects who are randomized and who 
receive at least 1 dose of study drug (a modified ITT). 
All efficacy analyses will be performed on the ITT population.  For efficacy analysis, subjects 
will be analyzed in the treatment group to which they were randomized.   
12.2.2. 
Per-Protocol Population 
The Per-Protocol (PP) population is defined as all subjects who are included in the ITT 
population, who have at least 1 post dose IOP determination, and who were compliant.  Subjects 
with major protocol violations, identified prior to unmasking/unblinding the study, will be 
excluded from the PP population. 
Subjects who meet these criteria are “evaluable subjects”.  In regards to study dosing, a 
compliant subject is defined as one who after randomization missed no more than 3 non-
consecutive doses during the week preceding a scheduled site visit or 2 consecutive doses during 
the week preceding a scheduled site visit. 
Selected efficacy analyses will be performed on the PP population. 
12.2.3. 
Treated Population 
Treated population is defined as all subjects who receive at least one dose of study drug. For 
safety analysis, all subjects will be analyzed according to the treatment actually received. 
12.2.4. 
Washout Failure Population  
The Washout Failure Population will include all subjects who had a Washout Visit or Placebo 
Run-In Visit and did not receive study drug. 
All data collected in the electronic CRF (eCRF) for this population will be presented in the data 
listings. 


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12.3. 
Handling of Dropouts or Missing Data 
Subjects who withdraw or are withdrawn from the study after the study drug has been applied 
will not be replaced.  
The reason(s) for any premature withdrawal must be explained in detail in the CRF and source 
documents. 
12.4. 
Statistical Analyses 
All analyses will be presented by treatment group.  Continuous variables will be described as the 
mean, median, standard deviation and range of n observations.  Where applicable standard error 
of the means (SE) will be presented.  Categorical data will be described with contingency tables 
including frequency and percent.  A detailed statistical analysis plan will be developed prior to 
unmasking study data.  Statistical analysis and data descriptions will be carried out using SAS 
statistical analysis software (SAS Institute, Inc., Cary, NC).  
12.5. 
Demographic and Baseline Characteristics 
The comparability of the dose groups will be summarized by the evaluation of the demographic 
information, including age, gender, race and ethnicity, and primary diagnosis for all subjects. 
12.6. 
Efficacy 
12.6.1. 
Efficacy Endpoints 
• Mean Daily IOP-change from diurnal baseline (average of the 4 diurnal changes from 
baseline calculated during a dosing interval) calculated at the Week 4 visit and the 
Week 8 visit. 
• Mean Daily IOP (average of the 4 serial IOPs taken during a dosing interval) 
calculated at the Week 4 visit and the Week 8 visit. 
• Mean Daily IOP-change from study baseline (average of the 4 changes from study 
baseline calculated during a dosing interval) calculated at the Week 4 visit and the 
Week 8 visit. 
• Mean IOP at 8AM, 10AM, 12PM, and 4PM for the subject's ‘study' eye calculated at 
the end of each of the 4 weeks of treatment for each of the doses/combinations tested. 
• IOP change from diurnal baseline [this is the time-matched subtraction of each of the 
4 IOP timepoints of the circadian curve post randomization from the pre-
randomization circadian curve] calculated at the end of the 4 weeks of treatment for 
each of the doses/combinations tested. 
• IOP change from study baseline [this calculates the change in IOP from the 8AM  
Day 1 baseline IOP] calculated at the end of the 4 weeks of treatment for each of the 
doses/combinations tested. 


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12.6.2. 
Efficacy Analyses 
The primary analysis will be performed on the ITT population.  These analyses will be repeated 
based on the per-protocol population.  The primary efficacy analysis will be based on the study 
eye.  All the efficacy analyses will be assessed for each of the different treatment groups: 
• Trabo 6.0% + LP 0.005%  
• Trabo 6.0% + LP 0.0025% 
• Trabo 3.0% + LP 0.05% 
• LP 0.005% 
• LP 0.0025% 
IOP measurements will be evaluated by presenting descriptive statistics by treatment group, visit, 
and time point.  For the efficacy endpoints means and 95% CI will be computed.  In addition, 
adjusted means (adjusts for differences in baseline values) and 95% CI, will be computed based 
on an Analysis of Covariance (ANCOVA) model with treatment as the independent variable and 
baseline IOP as the covariate. 
The effect of AM dosing vs PM dosing will be assessed using within subject comparisons. 
12.7. 
Safety 
12.7.1. 
Safety Analyses 
The tolerability and safety of trabodenoson will be assessed based on AEs, findings of physical 
examinations, vital signs, clinical laboratory test results, 12-lead ECG tracings, BCVA, bilateral 
complete external and internal eye examinations with a standardized masked grading of 
conjunctival hyperemia, IOPs, drug exposure, concomitant medications, and 
withdrawals/terminations.  These findings will be summarized by treatment group. AEs will be 
categorized by System Organ Class (SOC) and Preferred Terms using the Medical Dictionary for 
Regulatory Activities (MedDRA).  The incidence of AEs as well as the severity and relationship 
to study drug will be summarized by treatment group. 
12.7.2. 
Pharmacodynamic Assessments 
In order to provide a robust assessment of potential systemic effects of therapy, vital signs 
(resting blood pressure, pulse rate, temperature, and respiratory rate) and laboratory 
measurements (e.g., ECGs) will be descriptively analyzed as pharmacodynamic markers.   


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13. 
CLINICAL SUPPLIES 
13.1. 
Storage and Handling of Ophthalmic Study Drug and Matched 
Placebo Product 
All Study Drug and Placebo will be sent to the clinical study site where it will be stored at 2-8 
°C.  Subjects will store the study drug in the refrigerator and shake it vigorously prior to dosing 
(instructions located in the Pharmacy Manual).  Storage, labeling, handling, returns and 
accountability are described in detail in the study’s Pharmacy Manual.  
13.2. 
Dose Verification and Drug Accountability 
All details of the drug receipt, storage, preparation, randomization, dispensation and returns (or 
destruction) will be contained within the Pharmacy Binder.  This includes inventory and 
dispensing logs, temperature monitoring and drug storage locations, etc. maintained by the 
Pharmacist (or a trained designee). 


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14. 
STUDY DOCUMENTATION AND RECORDS RETENTION 
14.1. 
Data Collection Methods 
Electronic Data Capture (EDC) will be utilized in this trial. The EDC system is fully validated 
and conforms to Title 21 Code of Federal Regulations (CFR) Part 11 and the Guidance for 
Industry on Computerized Systems Used in Clinical Trials requirements.    
The trained Investigational site staff will enter the data required by the protocol into the eCRFs 
from source documents (e.g., medical records and study-specific data capture forms as needed) 
into the EDC system.  All information on the eCRFs must be traceable to these source 
documents.  Instances of missing or uninterpretable data will be discussed with the study site for 
resolution.  The study site is responsible for providing missing data and resolutions to the data 
queries and for correcting the eCRFs as appropriate.  Electronic CRFs must be reviewed, signed, 
and dated by the Investigator.  Training for each site on the use of the EDC will be conducted 
and documented.  All original laboratory, and ECG reports will be kept with the subject source 
documentation and a copy will be transmitted to the Sponsor (or designee), if required.   
General compliance will be assessed at each study visit. 
14.2. 
Monitoring 
Inotek (or designee) will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor to 
inspect the drug storage area, study drug stocks, drug accountability records, subject charts and 
study source documents, and other records relative to study conduct. 
Before an investigational site can enter a subject into the study, a representative of Inotek will 
visit the investigational study site to: 
• Determine the adequacy of the facilities; 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Inotek or its representatives.  This 
will be documented in a Clinical Study Agreement between Inotek and the 
Investigator. 
During the study, a monitor from Inotek or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the Investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, data are being 
accurately recorded in the case report forms, and investigational product 
accountability checks are being performed. 
• Perform source data verification.  This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, and other 
records relevant to the study.  This will require direct access to all original records for 
each subject (e.g., clinic charts). 


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• Record and report any protocol deviations not previously identified. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Inotek (or designee) and those SAEs that met criteria 
for reporting have been forwarded to the IRB. 
Prior to study start, the Investigator will be informed of the anticipated frequency of the 
monitoring visits.  The Investigator will also receive a notification prior to each monitoring visit 
during the course of the study.  It is expected that the Investigator and/or his/her sub 
Investigator(s) and other appropriate staff are available on the day of the visit in case any 
questions arise. The monitor will be available between visits if the Investigator(s) or other staff 
needs information or advice. 
14.3. 
Data Retention 
All relevant correspondence (e.g., with the Sponsor, CRO, IRB, etc.) relating to this clinical 
study conduct will be maintained in the appropriate file at the site. 
The Investigator must retain all records, including the source documents, ICFs, central laboratory 
reports including ECGs, and all other study-related documentation at the study site for a period 
of at least 2 years following the date the last marketing application is approved for the study drug 
for the indication for which it is being investigated, or 2 years after the date that the FDA has 
been notified that all clinical investigation of the drug has been discontinued, whichever is 
greater, unless notified otherwise in writing by the Sponsor.  These documents will, however, be 
retained for a longer period if required by the applicable regulations or if requested by the 
Sponsor.  The Investigator must contact the Clinical Operations Department of the Sponsor and 
gain written approval prior to destroying any records.  No study documents will be destroyed or 
moved to a new location without prior written approval of the Sponsor.  If the Investigator 
relocates, retires, or withdraws from a clinical study for any reason, all records required for the 
study will be transferred to an agreed-upon designee, e.g., another Investigator. 


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15. 
CLINICAL STUDY ADMINISTRATION, ETHICS, AND 
CONDUCT 
15.1. 
Good Clinical Practice 
GCP is an important ethical and scientific quality standard for designing, conducting, recording 
and reporting studies that involve the participation of human subjects.  Compliance with this 
standard provides public assurance that the rights, safety and well-being of study subjects are 
protected.  
15.2. 
Confidentiality 
15.2.1. 
Study Confidentiality 
All information regarding the nature of the investigation provided by the Sponsor or its designee 
to the Investigator and his / her staff or designees (except for information required by law or 
regulations to be disclosed to the IRB, the subject, and/or the appropriate regulatory authorities) 
must be maintained in confidence by the Investigator and his / her staff or designees. 
15.2.2. 
Subject Anonymity 
The anonymity of participating subjects must be maintained.  Subjects will be identified by their 
initials and subject number on eCRFs and other documents submitted to the Sponsor.  
Documents not submitted to the Sponsor include those that identify the subject (e.g., the signed 
ICF), and must be maintained in strict confidence by the Investigator, except as necessary to 
allow auditing by the IRB, Sponsor or its designee, FDA, and/or equivalent authorities. 
15.2.3. 
Financial Disclosure 
Prior to the start of the study, Investigators will release sufficient and accurate financial 
information that permits the CRO/Sponsor to demonstrate that an Investigator and all personnel 
listed on the FDA Form 1572 have no personal or professional financial incentive regarding the 
future approval or disapproval of the study medication such that his or her research might be 
biased by such incentive. 
15.3. 
Subject Information and Informed Consent 
Before being enrolled in the clinical study, subjects must consent to participate after the nature, 
scope, and possible consequences of the clinical study have been explained in a form 
understandable to them. 
An informed consent document that includes information about the study will be prepared and 
given to the subject.  This document will contain all the elements required by the ICH E6 
Guideline for GCP and any additional elements required by local regulations.  The document 
must be in a language understandable to the subject and must specify who informed the subject.  
Where required by local law, the person who informs the subject must be a physician. 
All ICFs must contain the minimum elements as mandated by the FDA and ICH guidelines and 
will be subject to the Sponsor’s (or designee’s) approval as well as the IRB’s approval.  The 


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Sponsor (or designee) may submit ICFs to a central IRB for review and approval or favorable 
opinion contingent upon the prior Investigator permission and review.   
The Investigator will not undertake any measures or procedures specifically required of a subject 
for the clinical study until valid consent has been obtained. 
The Investigator should inform the subject’s primary physician about the subject’s participation 
in the study if the subject has a primary physician and if the subject agrees to the primary 
physician being informed, as per the site’s standard operating procedures. 
If an amendment to the protocol changes the subject participation schedule in scope or activity, 
or increases the potential risk to the subject, the ICF must be revised, submitted to the IRB for 
review and approval or favorable opinion.  The revised ICF must be used to obtain consent from 
a subject currently enrolled in the study if he or she is affected by the amendment.  The revised 
ICF must be used to obtain consent from any new subjects who are enrolled into the study after 
the date of the approval or favorable opinion of the amendment. 
15.4. 
Study Closure 
Completion or premature termination of the study will be reported by the Sponsor to the 
regulatory agency and by the Sponsor or by the Investigator to the IRB as required by local 
regulations or by the IRB.  Once the database is locked, and all efforts are made to settle all 
outstanding queries, site closeout will occur.  Study materials must be returned, disposed of or 
retained, as directed by the Sponsor.  
15.5. 
Early Termination of the Clinical Trial 
The Sponsor may at any time terminate this clinical trial.  In the event of premature termination 
of the study, the Sponsor will notify the Investigators in writing.  Notification will include 
instructions regarding subjects in the study at the time of termination.  The Investigators or 
designee must immediately confirm receipt of this notification in writing.  The Sponsor and the 
Investigators will then agree to a timely closure of the site by the Study Monitor(s) assigned by 
the Sponsor to the site.  Drug accountability and data collection procedures discussed in 
Section 12.6 will be followed.  
15.6. 
Termination of an Investigative Site 
The Sponsor may at any time terminate a study site.  Early termination of an investigative site 
should occur after verbal communication with the site. 
Reasons for such actions include: 
• Violations of GCP and/or regulatory guidelines. 
• Investigator malfeasance, disbarment, or inappropriate behavior. 
• Protocol or contract violation. 
• Threat to the proper conduct, reliability, safety, or timely conclusion of the study. 
• Failure to meet enrollment goals 


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16. 
INVESTIGATOR'S OBLIGATIONS 
16.1. 
General 
The Investigator agrees that the study will be conducted in accordance with the clinical protocol, 
FDA’s GCP guidelines, ICH guidelines, and the Declaration of Helsinki (see Section 19.1).  The 
Investigator will conduct all aspects of this study in accordance with all governmental, state and 
local laws. 
The Investigator must sign and return the Investigator Signature Page of the protocol and/or 
amendments (if applicable) and provide to the Sponsor a current signed and dated curriculum 
vitae (CV).  Each Sub-Investigator and study member must provide the Sponsor with a current 
CV, and license, if applicable.  For studies conducted under an IND, the Investigator must sign 
and return a completed Form FDA 1572, “Statement of Investigator,” to the Sponsor or its 
designee. 
The Investigator must make study data accessible to the study monitors, Clinical Research 
Associate, IRB, FDA, and/or equivalent government regulatory authorities. 
Prior to performing any study procedures on subjects, the Investigator will provide a copy of the 
most current, IRB-approved ICF to the potential participant to read.  The Investigator will 
discuss the study protocol (explain the nature, purpose, procedures, possible risks, benefits, and 
duration) with the potential participant.  The potential participant must be given ample time and 
opportunity to read the information and to enquire about details of the study.  During and after 
the discussions, the Investigator will answer all protocol or procedural questions the potential 
participant may have.  Once the Investigator is assured that the potential participant understands 
the implications of participating in the study, the potential participant or his/her legal authorized 
representative will be asked to give consent to participate in the study by signing and dating the 
ICF.  Likewise, the person obtaining the consent is required to sign and date the ICF.  A signed 
copy of the ICF must be provided to the subject.  
The original ICF will be kept at the investigational site.  The subject’s medical record should 
include a statement that the subject has accepted to participate in this investigational study by 
signing the ICF. 
16.2. 
Institutional Review Board 
Before initiation of the study, the Investigator or designee must obtain approval of the clinical 
protocol and ICF from the IRB complying with the provisions specified in FDA CFR, Title 21, 
Part 56, ICH Guidelines, and all governmental, state and local laws. 
A copy of the written IRB approval of the protocol, ICF and any other documentation (such as 
advertising) as appropriate must be provided to the Sponsor or its designee prior to initiation of 
the study.  The approval letter must identify the IRB name and address, the clinical protocol by 
title and/or protocol number, and the date approval was granted. Furthermore, the approval letter 
must contain a statement that the IRB complies with the FDA CFR, Title 21, Part 56, and ICH 
Guidelines for a study conducted under an IND, or other applicable government regulations for 
studies not conducted under an IND. 


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The Investigator is responsible for supplying the IRB with the data required for continued review 
of this study at intervals not exceeding one year, or at intervals otherwise specified by the IRB.  
The Investigator shall supply the Sponsor with written documentation of this continued review.  
When necessary, an extension or renewal of the IRB approval must be obtained and this shall 
also be forwarded to the Sponsor. 
A list of the IRB members will be forwarded to the Sponsor in accordance with local regulations. 
The IRB and the regulatory authorities will be provided with any amendments for their review 
and/or approval.  A yearly status report on the progress of the study will be submitted by the 
Investigator to the IRB per their regulations. 
16.3. 
Protocol Adherence 
The Investigator and his/her designees are required to adhere to the protocol.  While deviations 
from the protocol are discouraged, they may be necessary in order to eliminate an immediate 
hazard to subjects or to facilitate adherence to protocol procedures.  
Emergency departures from the protocol that eliminate an apparent immediate hazard to a 
subject and that are deemed crucial for the safety and well-being of a particular subject may be 
instituted for that subject only.  The Investigator or other attending physician will contact the 
Sponsor as soon as possible in the case of such a departure.  These departures do not require pre-
approval by the IRB; however, the Sponsor and the IRB must be notified in writing as soon as 
possible after the departure has been made.  In addition, the Investigator will document in the 
subject’s eCRF the reasons for protocol deviation and the ensuing events. 
16.4. 
Protocol Amendments 
Amendments may include the following: changes that affect the safety of subjects, or changes 
that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosages, assessment variable(s), the number of subjects treated, or the subject-selection 
criteria.  Such changes will be prepared as a protocol amendment by the Sponsor.  Protocol 
amendments must undergo IRB approval prior to implementation.  Should the ICF require 
changes, the revised ICF must be approved also according to the same procedure. 
16.5. 
Audits and Inspections 
The Investigator will permit study-related monitoring, audits and inspections by the IRB, the 
Sponsor or its designee, government regulatory bodies, and quality assurance groups of all study-
related documents.  This includes direct access to source documents, regulatory documents, data 
collection instruments, study data, etc.  The Investigator will ensure that all study-related 
facilities (e.g., pharmacy, laboratories, etc.) are maintained in accordance with GCP guidelines. 
Participation as an Investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable quality assurance offices. 


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17. 
USE OF DATA AND PUBLICATIONS 
All information concerning the product as well as any matter concerning the activities and trade 
secrets of the Sponsor, such as clinical indications for the drug, its formula, methods of 
manufacture and other scientific data relating to it, that have been provided by the Sponsor and 
are unpublished, are confidential and shall remain the sole property of the Sponsor.  The 
Investigator will agree to use the information only for the purposes of carrying out this study and 
for no other purpose unless prior written permission from the Sponsor is obtained. 
In addition, the Sponsor has full ownership of the eCRFs that were completed as part of the 
study. 
By signing the clinical study protocol, the Investigator agrees that the results of the study may be 
used for the purposes of national and international drug registration, publication, and information 
for medical and pharmaceutical professionals.  The authorities will be notified of the 
Investigator's name, address, qualifications and extent of involvement.  The Sponsor will ensure 
that a final report on the study is prepared. 
As required by local regulations or by the IRB, a summary of the clinical study will be submitted 
by the Sponsor to the regulatory authorities and by the Sponsor or Investigator to the IRB. 
The Investigator (or Sub-Investigator) may be required to sign a statement in the clinical study 
report confirming that, to the best of his or her knowledge, the above report accurately describes 
the conduct and results of the study. 
 


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18. 
REFERENCES 
 
1. 
Ocular Hypertension Treatment Study (OHTS): National Eye Institute;  [cited 2007]. 
Available from: https://www.nei.nih.gov/glaucomaeyedrops/background. 
2. 
Perkins ES. Recent advances in the treatment of glaucoma. Transactions of the 
ophthalmological societies of the United Kingdom. 1966;86:199-210. PubMed PMID: 5226572. 
3. 
Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, et al. The 
Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular 
hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Archives 
of ophthalmology. 2002 Jun;120(6):701-13; discussion 829-30. PubMed PMID: 12049574. 
4. 
Primary open angle glaucoma. Preferred practice pattern. San Francisco: American 
Academy of Opthalmology, Glaucoma Panel; 2000. p. 1-36. 
5. 
Draft Report of the Ocular Epidemiology Strategic Planning Panel.  Epidemiological 
Research: From Populations Through Interventions to Translation.: National Eye Institute;  [cited 
2007]. Available from: http://www.nei.nih.gov/strategicplanning/draft.asp#6. 
6. 
Cioffi GA, Van Buskirk EM. Glaucoma basics & frequently asked questions  [cited 
2006]. Available from: http://www.americanglaucomasociety.net/patients/faqs/. 
7. 
Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, Pokharel GP, et al. 
Global data on visual impairment in the year 2002. Bulletin of the World Health Organization. 
2004 Nov;82(11):844-51. PubMed PMID: 15640920. Pubmed Central PMCID: 2623053. 
8. 
Riordan-Eva P, Vaughan D. Eye. In: Tierney LJ, McPhee S, Papadakis M, editors. 
Current medical diagnosis & treatment. 40th ed. New York: Lange Medical Books/McGraw-
Hill; 2001. p. 185-216. 
9. 
Raber S, Mandema JW, Lee H, Nickens, DJ. A Model-Based Dose-Response Meta-
Analysis of Ocular Hypotensive Agents as a Drug Development Tool to Evaluate New Therapies 
in Glaucoma. J Ocul Pharmacol Therapeut 2015; 31: 189-97. 
10. 
Zhang WY, Po AL, Dua HS, Azuara-Blanco A. Br J Ophthalmol 2001;85:983-990. 
11. 
Avila MY, Stone RA, Civan MM. A1-, A2A- and A3-subtype adenosine receptors 
modulateintraocular pressure in the mouse. British J. of Pharm. 2001;134:241-245. 
12. 
Husain S, Shearer TW, Crosson CE. Mechanisms linking adenosine A1 receptors and 
extracellularsignal-regulated kinase 1/2 activation in human trabecular meshwork cells. J 
Pharmacol Exp Ther.2007;320(1):258-65. 
 


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19. 
APPENDICES 
19.1. 
Declaration of Helsinki 
The World Medical Association 
Declaration of Helsinki 
World Medical Association Declaration of Helsinki: Recommendations Guiding Medical 
Doctors in Biomedical Research Involving Human Subjects 
Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964 and as revised 
by the World Medical Assembly in Tokyo, Japan in October 1975, 35th World Medical 
Assembly in Venice, Italy in October 1983, and in the 41st World Medical Assembly Hong 
Kong in September 1989. 
Introduction 
It is the mission of the physician to safeguard the health of the people.  His or her knowledge and 
conscience are dedicated to the fulfillment of this mission. 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act only in the patient's interest when providing 
medical care which might have the effect of weakening the physical and mental condition of the 
patient." 
The Purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic and prophylactic procedures and the understanding of the etiology and pathogenesis 
of disease. 
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve 
hazards. This applies especially to biomedical research. 
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
In the field of biomedical research a fundamental distinction must be recognized between 
medical research in which the aim is essentially diagnostic or therapeutic for a patient, and 
medical research, the essential object of which is purely scientific and without implying direct 
diagnostic or therapeutic value to the person subjected to the research. 
Special caution must be exercised in the conduct of research which may affect the environment, 
and the welfare of animals used for research must be respected. 
Because it is essential that the results of laboratory experiments be applied to human beings to 
further scientific knowledge and to help suffering humanity, the World Medical Association has 
prepared the following recommendations as a guide to every physician in biomedical research 
involving human subjects.  They should be kept under review in the future.  It must be stressed 
that the standards as drafted are only a guide to physicians all over the world.  Physicians are not 
relieved from criminal, civil and ethical responsibilities under the laws of their own countries. 
I. Basic Principles  


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Biomedical research involving human subjects must conform to generally accepted scientific 
principles and should be based on adequately performed laboratory and animal experimentation 
and on a thorough knowledge of the scientific literature.  
10. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted for 
consideration, comment and guidance to a specially appointed committee independent of 
the investigator and the sponsor provided that this independent committee is in 
conformity with the laws and regulations of the country in which the research experiment 
is performed. 
11. Biomedical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  
The responsibility for the human subject must always rest with a medically qualified 
person and never rest on the subject of the research, even though the subject has given his 
or her consent. 
12. Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject. 
13. Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others.  Concern for the interests of the subject must always prevail over the 
interests of science and society. 
14. The right of the research subject to safeguard his or her integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject and to 
minimize the impact of the study on the subject's physical and mental integrity and on the 
personality of the subject. 
15. Physicians should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable.  
Physicians should cease any investigation if the hazards are found to outweigh the 
potential benefits. 
16. In publication of the results of his or her research, the physician is obliged to preserve the 
accuracy of the results.  Reports of experimentation not in accordance with the principles 
laid down in this Declaration should not be accepted for publication. 
17. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail.  He or she should be informed that he or she is at liberty to 
abstain from participation in the study and that he or she is free to withdraw his or her 
consent to participation at any time.  The physician should then obtain the subject's 
freely-given informed consent, preferably in writing. 
18. When obtaining informed consent for the research project, the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress.  In that case the informed consent should be obtained by a 


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physician who is not engaged in the investigation and who is completely independent of 
this official relationship. 
19. In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation.  Where physical or mental incapacity 
makes it impossible to obtain informed consent, or when the subject is a minor, 
permission from the responsible relative replaces that of the subject in accordance with 
national legislation.  Whenever the minor child is in fact able to give a consent, the 
minor's consent must be obtained in addition to the consent of the minor's legal guardian. 
20. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with. 
II. Medical Research Combined with Professional Care (Clinical Research) 
In the treatment of the sick person, the physician must be free to use a new diagnostic and 
therapeutic measure, if in his or her judgment it offers hope of saving life, reestablishing health 
or alleviating suffering. 
1. The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods. 
2. In any medical study, every patient — including those of a control group, if any — 
should be assured of the best proven diagnostic and therapeutic method.  
3. The refusal of the patient to participate in a study must never interfere with the physician-
patient relationship. 
4. If the physician considers it essential not to obtain informed consent, the specific reasons 
for this proposal should be stated in the experimental protocol for transmission to the 
independent committee (I,2). 
5. The physician can combine medical research with professional care, the objective being 
the acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the patient. 
 
III. Non-Therapeutic Biomedical Research Involving Human Subjects (Non-Clinical 
Biomedical Research) 
In the purely scientific application of medical research carried out on a human being, it is the 
duty of the physician to remain the protector of the life and health of that person on whom 
biomedical research is being carried out. 
1. The subjects should be volunteers — either healthy persons or patients for whom the 
experimental design is not related to the patient's illness. 
2. The investigator or the investigating team should discontinue the research if in his/her or 
their judgment it may, if continued, be harmful to the individual. 
3. In research on man, the interest of science and society should never take precedence over 
considerations related to the well-being of the subject. 

SAP_000.pdf: 
Statistical Analysis Plan 
Inotek Protocol IPC-02-2015 
Version 1.1 
INC Research 1007502 
 
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 Document 
Type: 
Template 
Document ID: 
03.007A.02 
Issue Date:            01 SEP 2015 
Effective Date:    29 SEP 2015 
 
Sponsor Name: 
Inotek Pharmaceuticals Corporation 
Protocol Number and Title: 
 
IPC-02-2015 
A Phase II, Randomized, Double-masked Study 
to Evaluate the Efficacy, Safety and 
Tolerability of Topical Ocular Administration of 
Fixed-Dose Combinations of Trabodenoson and 
Latanoprost in Subjects with Ocular 
Hypertension or Primary Open-Angle Glaucoma 
Protocol Version and Date: 
Protocol Amendment 2.0 28 March 2016 
IPC-02-2015 LCVA 1.0 06 October 2016 (sub-
study protocol) 
 
 
 
 
INC Research Project Code: 
1007502 
Author: 
Fang Zhu, Senior Biostatistician 
 
 
SAP Version: 
Version 1.1 
SAP Version Date:  
14 June 2017 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Inotek Pharmaceuticals. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Inotek Pharmaceuticals.  However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, INC Research should be notified 
promptly. 


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Revision History 
 
 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
0.1 
04-Nov-2016 
Fang Zhu 
1st draft SAP 
0.2 
21-Mar-2017 
Fang Zhu 
Update based on sponsor comments 
0.3 
14-Apr-2017 
Fang Zhu 
Update based on sponsor comments 
1.0 
19-May-2017 
Fang Zhu 
Update based on sponsor comments 
1.1 
14-June-2017 
Fang Zhu 
Update based on sponsor comments 
 
 
 
 
 
 




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Table of Contents 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................ 7 
2. 
PURPOSE ....................................................................................................... 9 
2.1. 
Responsibilities ................................................................................................................... 9 
2.2. 
Timing of Analyses .............................................................................................................. 9 
3. 
STUDY OBJECTIVES ................................................................................... 10 
3.1. 
Primary Objective .............................................................................................................. 10 
3.2. 
Secondary Objectives ....................................................................................................... 10 
3.3. 
sub-study ............................................................................................................................ 10 
3.4. 
Brief Description ................................................................................................................ 10 
3.4.1. 
Inclusion Criteria .............................................................................................................. 11 
3.4.2. 
Exclusion Criteria ............................................................................................................. 12 
3.5. 
Determination of Sample Size .......................................................................................... 16 
3.6. 
Treatment Assignment & Blinding ................................................................................... 16 
3.7. 
Administration of Study Medication ................................................................................ 17 
3.8. 
Study Procedures and Flowchart ..................................................................................... 18 
4. 
ENDPOINTS .................................................................................................. 21 
4.1. 
Primary Efficacy Endpoint ................................................................................................ 21 
4.2. 
Secondary Efficacy Endpoints ......................................................................................... 21 
4.3. 
Safety Endpoints ................................................................................................................ 21 
4.4. 
SUB-STUDY endpoints ...................................................................................................... 21 
5. 
ANALYSIS POPULATION ............................................................................ 23 
5.1. 
Intent-to-treat Population .................................................................................................. 23 
5.2. 
Per-Protocol Population .................................................................................................... 23 


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5.3. 
Safety Population ............................................................................................................... 23 
5.4. 
Protocol Violation or Deviations ...................................................................................... 23 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 25 
6.1. 
General Methods ................................................................................................................ 25 
6.2. 
Key Definitions ................................................................................................................... 25 
6.3. 
Missing Data ....................................................................................................................... 26 
6.4. 
Visit Windows ..................................................................................................................... 27 
6.5. 
Subgroups .......................................................................................................................... 27 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 28 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 28 
7.2. 
Demographic and Other Baseline Characteristics ......................................................... 28 
7.3. 
Medical and Ophthalmologic History .............................................................................. 29 
7.4. 
Medication History and Concomitant Medications ........................................................ 29 
8. 
EFFICACY ..................................................................................................... 30 
8.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 30 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses .............................................................. 31 
8.2.1. 
Daily IOP.......................................................................................................................... 31 
8.2.2. 
Daily IOP –change from Study Baseline ......................................................................... 32 
8.2.3. 
Mean IOP at 8AM, 10AM, 12PM and 4PM ...................................................................... 32 
8.2.4. 
IOP Change from Diurnal Baseline ................................................................................. 32 
8.2.5. 
IOP Change from Study Baseline ................................................................................... 33 
8.3. 
EXPLORATORY ANALYSES ............................................................................................. 33 
8.4. 
LCVA sub-study endpoints and analyses ....................................................................... 33 
8.5. 
Safety .................................................................................................................................. 34 
8.6. 
Extent of Exposure ............................................................................................................ 34 
8.7. 
Treatment Compliance ...................................................................................................... 35 


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8.8. 
Adverse Events .................................................................................................................. 35 
8.9. 
Laboratory Evaluations ..................................................................................................... 35 
8.10. 
Vital Signs ........................................................................................................................... 37 
8.11. 
ECG ..................................................................................................................................... 37 
8.12. 
PHYSICAL Examination .................................................................................................... 37 
8.13. 
EYE ExaminationS, IOP Assessment, BCVA AND LCVA .............................................. 38 
8.14. 
Other Safety ........................................................................................................................ 40 
9. 
INTERIM ANALYSES .................................................................................... 41 
10. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 42 
11. 
REFERENCE LIST .................................................................................... 43 
12. 
PROGRAMMING CONSIDERATIONS ...................................................... 44 
12.1. 
General Considerations .................................................................................................... 44 
12.2. 
Table, Listing, and Figure Format .................................................................................... 44 
12.2.1. 
General ........................................................................................................................ 44 
12.2.2. 
Headers ....................................................................................................................... 44 
12.2.3. 
Display Titles ............................................................................................................... 45 
12.2.4. 
Column Headers ......................................................................................................... 45 
12.2.5. 
Body of the Data Display ............................................................................................. 46 
12.2.6. 
Footnotes .................................................................................................................... 48 
13. 
QUALITY CONTROL ................................................................................. 49 
 
 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
 
Abbreviation 
Description 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice-daily 
BMI 
Body Mass index 
CI 
Confidence Interval  
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
EOS 
End of Study 
EOT 
End of Treatment  
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Estimated Glomerular Filtration Rate 
ICH 
International Conference on Harmonization 
IOP 
Intraocular Pressure 
INR 
International Normalized Ratio 
ITT 
Intent-to-Treat 
LBBB 
Left Bundle Branch Block 
LCVA 
Low Contrast Visual Acuity 
LSmeans 
Least squared means 


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Abbreviation 
Description 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimeters of Mercury 
MMRM 
Mixed effect model repeat measurement 
OHT 
Ocular Hypertension 
OU 
Each Eye 
POAG 
Primary Open-Angle Glaucoma 
PP 
Per Protocol  
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
QD 
Once Daily  
QTcB 
Bazett Corrected QT Interval 
QTcF 
Fridericia Corrected QT Interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International System of Units 
SLT 
Selective Laser Trabeculoplasty 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table, Listing and Figure 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
WF 
Washout Failure 
WPW 
Wolff-Parkinson-White syndrome 
YAG 
Yttrium Aluminium Garnet 
 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives.   
2.1. 
RESPONSIBILITIES 
INC Research will perform the statistical analyses and is responsible for the production 
and quality control of all tables, figures and listings. 
2.2. 
TIMING OF ANALYSES 
The final analysis of safety and efficacy is planned after all subjects complete the final 
study visit or terminate early from the study. At that time, the database will be locked, 
the study will be unmasked, and then final analyses will be performed.  
 
 


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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the efficacy of different topical ocular 
doses of trabodenoson (3.0% and 6.0%) when added to latanoprost (0.005% or 0.0025%), 
one drop daily to both eyes over two consecutive 4 week periods.   
All subjects were dosed (in a masked manner) with AM active drug during Weeks 1 – 4, 
and with PM active drug during Weeks 5 - 8. 
3.2. 
SECONDARY OBJECTIVES 
The secondary objectives are to evaluate the tolerability and safety of different doses 
of trabodenoson (3.0% and 6.0%) when added to latanoprost (0.005% or 0.0025%), one 
drop daily to both eyes over two consecutive 4 week periods.   
3.3. 
SUB-STUDY 
The analyses for protocol “Low Contrast Visual Acuity (LCVA) Sub-study for IPC-02-
1015”, run on a subset of subjects from IPC-02-2015, is included in this SAP. 
3.4. 
BRIEF DESCRIPTION 
This is a phase II, randomized, double-masked study to evaluate the efficacy and 
tolerability of topical ocular delivery of fixed-dose combinations of trabodenoson and 
latanoprost in subjects with Ocular Hypertension (OHT) or Primary Open-Angle 
Glaucoma (POAG). 
All subjects who meet the study’s enrollment criteria following Screening will undergo 
washout of all prohibited medications (if washout is needed), including their routine 
glaucoma medications. During the Placebo Run-In Period, placebo (vehicle control 
matched to trabodenoson) is applied twice daily to both eyes in all subjects. During the 
Treatment Period, study drug is applied to both eyes for a total of 8 weeks. Each 
subject will be assigned 4 weeks of AM and 4 weeks of PM dosing in a masked manner. 
The Treatment Period will be followed by an Observation Period of approximately 7 
days wherein no study eye drops are instilled. 
These periods are described in detail in the study protocol (Section 9.2). 
To mimic what is generally seen in clinical trials, the number of subjects with ocular 
hypertension as their diagnosis will be limited to approximately 30% of the total 
subjects enrolled. Additionally, so the trial mirrors the general population demographics 
(so as to improve generalizability of the results) the proportion of African American 
subjects will be approximately 25% or less but not less than 12% of the total subjects 
enrolled. 


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The purpose of the study is to assess the efficacy, tolerability, and safety of binocular 
topical application of different doses of trabodenoson (3.0% and 6.0%) when combined 
with latanoprost (0.005% or 0.0025%) one drop daily over two consecutive 4 week 
periods in subjects with POAG or OHT. Data collection will include efficacy (masked- 
Intraocular Pressures [IOPs]), local (ophthalmic) and systemic tolerability and safety 
assessments. 
Approximately 40 sites in the United States (US) will participate in this trial.  
The following is a schematic of the trial treatment plan. Please note that Screening, 
Washout, and Placebo Run-In Periods can vary in length and therefore are presented as 
ranges throughout the protocol instead of specific days. 
 
 
The reason(s) for any premature withdrawal must be explained in detail in the CRF and 
source documents. 
3.4.1. 
Inclusion Criteria 
1. Subject provides written informed consent prior to any study-related procedure not 
part of normal medical care. 
2. Subject has the diagnosis of OHT or POAG (subjects with secondary, exfoliative, 
and/or pigmentary glaucomas are excluded from the trial). 


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3. Subject with at least 1 eye that meets each of the following criteria in the same eye: 
(1) mean 8AM IOP ≥25 and ≤34 on Placebo Run-In Visit, Day -1, and Day 1 (AM predose) 
mmHg; and (2) mean IOP ≥21 mmHg on Day -1 at 8 hours post-dose (~4PM). IOP is taken 
by Goldmann Applanation Tonometry and is not corrected for central corneal thickness. 
(If one eye fails this criterion but the second eye meets this criterion and all other 
enrollment criteria are met, the subject can be randomized). 
4. Subject is aged 18 years or older; If female, subject must not be pregnant or nursing, 
and is either: 
    a. Not of childbearing potential, defined as postmenopausal for at least 1 year or     
surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy; or 
    b. Of childbearing potential and meets at least 1 of the following: 
i. Is practicing an effective method of contraception (e.g., a. double barrier 
method, b. oral/parenteral contraceptives plus barrier, c. intrauterine device 
plus barrier), or 
ii. Has a vasectomized partner (at least 90 days post vasectomy procedure), or 
iii. Is practicing abstinence from sexual intercourse. 
Subjects must be willing to practice the chosen contraceptive method or remain 
abstinent during the conduct of the study and for at least 1 month after last dose of 
study medication. 
Non-vasectomized males (with a partner of childbearing potential) are required to 
practice effective birth control methods (e.g., abstinence, use of condom [or other 
barrier device] along with partner’s oral/parenteral contraceptives) during the conduct 
of the study and for at least 1 month after last dose of study medication. 
3.4.2. 
Exclusion Criteria 
1. Subject has clinically significant abnormalities in their medical history or from the 
results of the physical examinations, vital signs, or clinical laboratory tests performed 
at Screening or during the Placebo Run-in period that may put the subject at risk in this 
trial or cause the subject not to complete the trial per protocol by the Investigator’s 
judgment ((Examples of clinically significant laboratory results include: both aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) > 2 times upper limit of 
normal (ULN) or either >3.0 times ULN, Total bilirubin > 2.0 times ULN, BMI > 40 kg/M2, 
Hemoglobin A1C > 8.0%, or creatinine clearance <50 ml/min). 
Note: Subject with creatinine clearance <50 ml/min may still be eligible upon review 
and written approval by the Inotek Medical Monitor or his designee (a Board-certified 


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physician) following review of the current medications, laboratory values, and medical 
history. 
2. Subject has any new clinically significant field loss within the past year in either eye, 
or any non-glaucoma ophthalmologic disease that might exacerbate during the trial. 
3. Subject’s Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual 
Acuity (BCVA) Snellen equivalent is worse than 20/80 in either eye. 
4. Subject has a vertical cup-to-disc ratio >0.8 or an IOP in either eye above 34 mm Hg 
at any examinations prior to Day 1 dosing in either eye. 
5. Subject has a central corneal thickness <490 μm or >610 μm at Screening in both 
eyes. (If only one eye is excluded based upon this criterion but the second eye does not 
meet this exclusion or any other exclusion criteria, the subject can be included). 
6. Subject is currently on any drug that in the opinion of the Investigator might affect 
IOP including oral or ocular glucocorticoids. (Low to moderate stable doses [no change 
for 30 days] of nasal or dermatologic steroids are permitted). 
7. Subject received oral/systemic beta-blocker within 28 days of screening. 
8. Subject has history of clinically significant trauma to the globe of both eyes. (If only 
one eye is excluded based upon this criterion but the second eye does not meet this 
exclusion or any other exclusion criteria, the subject can be included). 
9. Subject has had ocular or orbital surgery (conventional or laser, such as Selective 
Laser Trabeculoplasty [SLT] or Argon Laser Trabeculoplasty) to both eyes (If only one 
eye is excluded based upon this criterion but the second eye does not meet this 
exclusion or any other exclusion criteria, the subject can be included). 
However, the following procedures are not exclusionary: 
    a. At least 1 year prior to Screening: retinal laser, cataract extraction (no surgical 
complications such as capsular rupture or vitreous loss), peripheral iridotomy (with 
otherwise open angle per Exclusion Criteria #25) and other extraocular (e.g., tear duct, 
pterygial, or palpebral) surgeries. 
    b. At least 180 days prior to Screening: uncomplicated YAG laser capsulotomy. 
10. Subject has any ocular abnormality that in the opinion of the Investigator might 
preclude reliable applanation tonometry in either eye. 
11. Subject has a fundus in either eye that in the opinion of the Investigator cannot be 
well-visualized with pupillary dilation.  
12. Subject has a history of or current retinal condition that, in opinion of the 


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Investigator, could affect BCVA (i.e., diabetic retinopathy, central or branch retinal 
vein occlusion, cystoid macular edema, etc). 
13. Subject cannot, or is unwilling to, function without contact lenses from Placebo 
Run-In Visit through the completion of the End-of-Study Visit.  
14. Subject uses oral sympathomimetics (e.g., pseudoephedrine) within 14 days of start 
of Placebo Run-In Period, or the Investigator feels may be required during the study. 
15. Subject used inhaled bronchodilators and/or inhaled steroids more than once per 
week on the average in the past 90 days, or the Investigator feels may be required 
during the study. 
16. Subject uses dipyridamole, theophylline, or other adenosine antagonist medication 
within 4 days of the start of the Placebo Run-In Period, or the Investigator feels may be 
required during the study. 
17. Subject used any of the following drugs (alone or in combination) for treatment of 
ophthalmologic illness: 
 
    a. Parasympathomimetics or carbonic anhydrase inhibitors within 4 days of the start 
of the Placebo Run-In Period. 
b. Sympathomimetics or alpha adrenergic agonists within 14 days of the start of the 
Placebo Run-In Period. 
c. Topical ocular beta-blockers with 28 days of the start of the Placebo Run-In 
Period. 
    d. Prostaglandins, prostamides or prostanoids within 35 days of the start of the 
Placebo Run-In Period. 
18. Subject has any acute or chronic ophthalmologic illness requiring use of any non-IOP 
lowering ocular medication at screening and throughout study conduct (specific tear 
supplements are allowed as described in Protocol Section 9.3.9). 
19. Subject has a history of significant cardiac rhythm disturbance or a complete left 
bundle branch block (LBBB). (Examples of significant rhythm disturbances include PR 
intervals above 220 msecs, history of 2nd or 3rd degree blocks, acquired or congenital 
long QT syndrome, atrial fibrillation or other atrial arrhythmia, ventricular arrhythmia, 
bradycardia (<50 bpm), or ventricular pre-excitation (WPW). Subjects with PR intervals 
between 221 msec and 240 msec (inclusive) may only be enrolled following receipt of 
the written approval of the Inotek Medical Monitor or his designee (a Board-certified 
physician) so as to ensure an opportunity to review, as necessary, the subject’s ECG, 
medication and medical history with the study cardiologist.) 
20. Subject has clinically significant corneal and/or conjunctival findings (including 


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clinically significant hyperemia) related to any recurrent or chronic conditions including 
allergic conjunctivitis, blepharitis, or keratoconjunctivitis sicca that might recur or 
worsen during the study and confound the ophthalmologic safety data. 
21. Subject has a closed or occludable angle on gonioscopy (chamber angle less than 10 
degrees), a history of angle-closure, or any non-POAG glaucoma (including neovascular 
glaucoma) in both eyes at Screening (if only one eye is excluded based upon this 
criterion but the second eye does not meet this exclusion or any other exclusion 
criteria, the subject can be included). 
22. Subject has history of, or current, uveitis or any other inflammatory intraocular 
disease of either eye, unless the inflammatory process was caused by a topical 
ophthalmic medication that was stopped and has been in full remission for at least 1 
year. 
23. Subject received any investigational device or product within 30 days prior to the 
start of the Placebo Run-In Period or has ever been rejected on medical or psycho-social 
grounds from participation in a clinical trial.  
24. Subject has a history of allergy to more than 3 structurally unrelated medications, 
unless approved in writing by the Sponsor Medical Monitor (or their designees, a 
Board-certified physician). 
25. Subject has a history of significant sensitivity to latanoprost, trabodenoson, 
benzalkonium chloride, EDTA, or any of the other study drug excipients, or to local 
anesthetics or topical ophthalmic anesthetics such as lidocaine or to fluorescein. 
26. Subject is unable to discontinue the use of prohibited medications delineated in 
Protocol Section 9.3.9 from the start of the Placebo Run-In Period through completion 
of the End-of-Study Visit. 
27. Subject is unable to limit their daily consumption to ≤ 24 ounces of beer, ≤ 8 ounces 
of wine, or ≤ 4 ounces of liquor from the start of the Placebo Run-In Period through 
completion of the End-of-Study Visit. 
28. Subject has any recent (acute) or chronic medical, psychiatric, drug or alcohol, or 
social problem that might in the opinion of the Investigator: (1) interfere with the 
subject’s performance or completion of the trial; (2) obfuscate the subject’s study 
data; or (3) render the subject unable to understand the nature, scope, and possible 
consequences of the study. Or subject is likely to be noncompliant with the protocol 
(e.g., uncooperative attitude; a history of significant mental depression, panic attacks, 
or manic episodes; inability to return for all planned visits, and/or unlikelihood of 
completing the study). 
29. Subject is involved in any aspect of trial conduct including, Investigator, 
Sub-Investigator, other site staff, and/or immediate family members (first degree 


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relative, spouse, adoptees, legal dependents) or employee of Inotek. 
3.5. 
DETERMINATION OF SAMPLE SIZE 
To address the primary objective of this trial, based on an assumed SD of 3.3 mmHg, a 
sample size of 30 subjects in each group will provide an estimate of the effect on IOP 
with a 95% Confidence Interval with a ½ width (precision) of no greater than 1.2 mmHg. 
In order to compensate for an anticipated drop-out rate of approximately 10%, 
approximately 33 subjects will be enrolled in each of the 5 treatment groups in order to 
complete the trial with approximately 165 enrolled subjects and a total of 150 
evaluable subjects. 
3.6. 
TREATMENT ASSIGNMENT & BLINDING 
Treatment group assignment and randomization will occur on the Day 1 Visit utilizing a 
validated Interactive Response Technology.  Subjects will be randomized in equally 
allocated groups (1:1:1:1:1) to 1 of the following 5 treatment arms: 
1) trabodenoson 6.0% / latanoprost 0.005% QD and Placebo QD, instilled OU for a 
total of 8 weeks.  
2) trabodenoson 3.0% / latanoprost 0.005% QD and Placebo QD, instilled OU for a 
total of 8 weeks. 
3) trabodenoson 6.0% / latanoprost .0025% QD and Placebo QD, instilled OU for a 
total of 8 weeks. 
4) latanoprost 0.005% QD and Placebo QD, instilled OU for a total of 8 weeks. 
5) latanoprost 0.0025% QD and Placebo QD, instilled OU for a total of 8 weeks. 
All site personnel and enrolled subjects will be masked to the study drug assignments 
until the last subject has completed all study-related activities and the database has 
been locked.  All Sponsor personnel directly involved in the conduct of the study will 
also remain masked until after data lock. Subjects will receive 4 weeks of AM active 
drug dosing and 4 weeks of PM active drug dosing. AM and PM dosing will also be 
masked.  
(Note that all subjects will be dosed, in a masked manner, with AM active drug during 
Weeks 1 – 4, and with PM active drug during Weeks 5-8). In the event of an emergency 
in which unmasking is required at an investigative site, the emergency procedures 
detailed in the clinical study protocol will be followed (Protocol Section 11.2).  


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3.7. 
ADMINISTRATION OF STUDY MEDICATION 
From Day 1 through Day 56, subjects will receive 1 drop of study drug, twice daily, in 
each eye (OU). No prohibited medications are permitted during this period. Of note, the 
one study eye, as defined in Section 6.5.4 of the protocol, will be determined on Day 1. 
AM vs PM Dosing is masked utilizing Placebo in addition to the active drug product. 
During the Treatment Period, study drug (Active and Placebo) eye drop applications will 
occur twice daily, in the morning (between 7:00 AM - 9:00 AM) and in the evening 
(between 7:00 PM – 9:00 PM).  
 


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Table 1: Binocular Dosing Regimen of Each Treatment Group 
 
 
Study Period 
 
Screening 
Washout 
Period 
Placebo 
Run-In 
Treatment 
Period 
Observation 
Period 
Randomized 
Group: 
Range: 
1 to 14 days  
Range: 
4  to 39 days  
Range: 
5 to 9 days  
28 ±2 
days (Day 
1 to 
Day 28) 
28 ±2 days 
(Day 29 to 
Day 56) 
7 ±1 days 
 
Trabo 6.0% / 
LP 0.005% 
QD & Placebo 
QD 
Continue 
routine 
medications 
& ensure 
subject 
meets 
general 
study entry 
criteria. 
No 
prohibited 
medications 
are allowed. 
Placebo 
BID 
 
No 
prohibited 
medication
s are 
allowed. 
Study 
Drug 
Dosing 
BID 
(Active or 
Placebo) 
 
 
 
 
 
 
Study Drug 
Dosing BID 
(Active or 
Placebo) 
 
No 
prohibited 
medications 
are allowed. 
Trabo 3.0% / 
LP 0.005% 
QD & Placebo 
QD 
Trabo 6.0% / 
LP .0025% 
QD & Placebo 
QD 
LP 0.005% 
QD & Placebo 
QD 
LP 0.0025% 
QD & Placebo 
QD 
 
3.8. 
STUDY PROCEDURES AND FLOWCHART 
A full description of the study visit schedule can be found in the study protocol.  Table 2 
below presents the schedule of assessments for the study. 


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Table 2: 
Schedule of Assessments 
Study Period: 
Screening 
Period 
Range 
Washout and Placebo Run-in Period:  
Washout Range: 4 to 39 Days f 
Placebo Run-in Range: 5 to 9 Days 
Treatment Period:  
Day 1 to Day 56 (± 2) 
Observation 
Period:  
7 Days (± 1)  
after EOT 
 
Visit: 
Procedure: 
1 to 14 
Days  
Washout 
Visit e  
Placebo 
Run-In 
Visit a 
Day -1 a 
Day 1 a 
Day 28 a 
(± 2) 
End-of- Treatment 
(EOT) Visit 
Day 56 a 
(± 2) 
End-of-Study 
(EOS) Visit g 
7 Days (± 1) 
after EOT 
Informed consent procedures 
√ 
 
 
 
 
 
 
 
Demographics and medical history 
√ 
 
 
 
 
 
 
 
Medication History / Concomitant medications 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Enrollment criteria and/or safety data review 
√ 
√ 
√ 
√ 
√ 
 
 
 
Subject randomization 
 
 
 
 
√ 
 
 
 
Physical examination, complete (C) or directed 
(D) 
√C 
 
 
 
√D 
 
 
√C 
Height / weight 
√ 
 
 
 
 
 
 
 
Clinical laboratory tests (Central Lab) 
√ 
 
√ 
 
 
√ 
 
√ 
Pregnancy test for females, central (C) or at the 
site (S) 
√C 
Serum 
 
 
√S 
Urine 
 
 
√S 
Urine 
 
Adverse events review /reporting 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Modified ETDRS-BCVA test 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Low Contrast Visual Acuity (LCVA) Testi 
 
 
 
√ 
 
√ 
√ 
 
External eye examination h 
√ 
 
√ h 
√ h 
√ 
√ h 
√ h 
√ 
Slit Lamp examination 
√ 
 
√ 
√ 
√ 
√  
√  
√ 
Masked-IOPs  
√ 
 
√ 
4√ 
√ 
4√ 
4√ 
√ 
Dilated Fundus examination 
√ 
 
 
 
 
 
 
√ 
Vital signs 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
12-Lead ECG 
√ 
 
√ 
 
 
 
 
√ 


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Study Period: 
Screening 
Period 
Range 
Washout and Placebo Run-in Period:  
Washout Range: 4 to 39 Days f 
Placebo Run-in Range: 5 to 9 Days 
Treatment Period:  
Day 1 to Day 56 (± 2) 
Observation 
Period:  
7 Days (± 1)  
after EOT 
 
Visit: 
Procedure: 
1 to 14 
Days  
Washout 
Visit e  
Placebo 
Run-In 
Visit a 
Day -1 a 
Day 1 a 
Day 28 a 
(± 2) 
End-of- Treatment 
(EOT) Visit 
Day 56 a 
(± 2) 
End-of-Study 
(EOS) Visit g 
7 Days (± 1) 
after EOT 
Gonioscopy c 
√ 
 
 
 
 
 
 
 
Central corneal thickness d 
√ 
 
 
 
 
 
 
 
Visual field testb 
√  
 
 
 
 
 
 
√ 
Drug/Dosing accountability 
 
 
 
√ 
√ 
√ 
√ 
 
Washout prohibited medication 
 
√ 
√ 
√ 
 
 
 
 
Study drug dosing 
 
 
 
 
BID 
BID 
QAM 
 
Placebo Run-In dosing 
 
 
BID 
BID 
 
 
 
 
a  On Placebo Run-In Visit and Days -1, 1, 28 and 56 all procedures will take place at the Investigational site.  
b Measurements can be historical values within 90 days. 
c Measurements can be historical values within 180 days.   
d Measurements can be historical values within 1 year. 
e Upon conclusion of all Screening Period activities, subjects who still meet the study enrollment criteria are invited to attend a Washout Period Visit (if washout 
is needed). This visit may be accomplished in person at the investigative site or by phone. 
f Minimum length of washout required is described in Table 5.  
g End-of-Study Visit is calculated as 7 Days (± 1) after the actual occurrence of the EOT Visit. 
h Hyperemia assessments performed on Placebo Run-in Visit, Day -1, Day 28, and Day 56. 
i The Low Contrast Visual Acuity (LCVA) test is only to be conducted on POAG subjects enrolled in the IPC-02-2015 LCVA Sub-study. 
 


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4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
Daily IOP-change from diurnal baseline (average of the 4 diurnal changes from baseline 
calculated during a dosing interval) calculated at the Week 4 visit and the Week 8 visit. 
4.2. 
SECONDARY EFFICACY ENDPOINTS 
The secondary efficacy endpoints include: 
1. Daily IOP (average of the 4 serial IOPs taken during a dosing interval) calculated at the 
Week 4 visit and the Week 8 visit. 
2. Daily IOP-change from study baseline (average of the 4 changes from study baseline 
calculated during a dosing interval) calculated at the Week 4 visit and the Week 8 
visit. 
3. Mean IOP at 8AM, 10AM, 12PM, and 4PM for the subject's ‘study' eye calculated at the 
Week 4 and Week 8 visit for each of the doses/combinations tested. 
4. IOP change from diurnal baseline [this is the time-matched subtraction of each of the 
4 IOP timepoints of the circadian curve post randomization from the 
pre-randomization circadian curve] calculated at the Week 4 and Week 8 visit each of 
the doses/combinations tested.  
5. IOP change from study baseline [this calculates the change in IOP from the 8AM Day 1 
baseline IOP] calculated at the end of the Week 4 and Week 8 visit for each of the 
doses/combinations tested.  
4.3. 
SAFETY ENDPOINTS  
Clinical and laboratory evaluations including results of the bilateral eye examinations tests 
(e.g., IOPs, BCVA, visual fields, central corneal thickness, and conjunctival hyperemia 
grading), vital signs, physical examinations, clinical laboratory tests, 12-lead ECGs, AEs, 
concomitant medications, withdrawals/ terminations, and drug exposure will be used to 
assess tolerability and safety. 
4.4. 
SUB-STUDY ENDPOINTS 
The analysis of data from the Low Contrast Visual Acuity (LCVA) Sub-study (protocol IPC-02-
2015-LCVA) is included under this statistical analysis plan: 
Primary Sub-study Efficacy Endpoint: 
Change from Day -1 baseline in monocular (study eye only) Letter Score using the SLOAN 2.5% 
visual acuity chart at Day 56. 
 


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Secondary Sub-study Efficacy Endpoint 
1. Change from Day-1 baseline in binocular (both eyes together) Letter Score using the 
SLOAN 2.5% visual acuity chart at Days 28 and 56. 
2. Comparison of LCVA between pooled latanoprost alone arms and pooled fixed-dose 
combination arms at Days -1, 28 and 56. 


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5. 
ANALYSIS POPULATION 
The study populations include Intent-to-Treat (ITT), the Per-Protocol (PP), and the Safety 
population. The primary analysis will be performed using the Intent-to-Treat Population. All 
decision rules regarding any exclusion of a subject from Intent-to-Treat, Per-Protocol, and 
safety populations will be made and documented before locking the study database and 
unmasking this study. 
5.1. 
INTENT-TO-TREAT POPULATION 
The Intent-to-Treat (ITT) population is defined as all subjects who are randomized and who 
receive at least 1 dose of study drug (a modified ITT). 
All efficacy analyses will be performed on the ITT population. For efficacy analysis, subjects 
will be analyzed in the treatment group to which they were randomized. 
5.2. 
PER-PROTOCOL POPULATION  
The Per-Protocol (PP) population is defined as all subjects who are included in the ITT 
population, who have at least 1 post dose IOP determination, and who were compliant with 
all critical study criteria.  Subjects with major protocol violations that could potentially 
impact efficacy results will be identified prior to unmasking/unblinding the study, and will be 
excluded from the PP population. 
 
 
In regards to study dosing, a compliant subject is defined as one who after randomization 
missed no more than 2 study doses during the week preceding a scheduled site visit or any of 
the 3 doses immediately preceding a scheduled site visit. 
 
Selected efficacy analyses will be performed on the PP population.  
 
5.3. 
SAFETY POPULATION  
Safety population is defined as all subjects who receive at least one dose of study drug. For 
safety analysis, all subjects will be analyzed according to the treatment actually received 
 
5.4. 
PROTOCOL VIOLATION OR DEVIATIONS 
The Investigator and his/her designees are required to adhere to the protocol. While 
deviations from the protocol are discouraged, they may be necessary in order to eliminate an 
immediate hazard to subjects or to facilitate adherence to protocol procedures.  
If protocol violations do occur as outlined in the criteria below, then the data from complete 
individual subjects, individual visits or individual evaluations may be excluded from selected 
analyses. The finalization of protocol violations and excluded data will be made prior to the 
randomization code being revealed. 
All protocol violations will be presented in a data listing. 


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Violation Criteria 
Subjects who meet any of the following violation criteria may be listed and presented in the 
study report: 
• 
Non-compliance with inclusion criteria 
• 
Non-compliance with exclusion criteria 
• 
Non-compliance with randomization  
• 
Non-compliance with study drug treatment - A compliant subject is defined 
as one who after randomization missed no more than 2 study doses during 
the week preceding a scheduled site visit or any of the 3 doses immediately 
preceding a scheduled site visit.  
• 
Non-compliance with Informed Consent  
• 
Non-compliance with handling of the investigation Product  
• 
Prohibited Concomitant Treatment  
• 
Non-compliance with the Visit Window  
• 
Non-compliance with Study Procedure for the Washout period.  
• 
Receipt of incorrect randomized study drug 
 
Other reasons for violation may be added to this list, but will be done so prior to unmasking 
of the study.  
Deviations from the procedures listed in the protocol that do not fit the definition of a 
violation are called protocol deviations. Deviations from the protocol will be documented on 
an ongoing basis by the study monitors, project manager, and other study personnel.  
Prior to the time of database lock, prior to unmasking and while the protocol violations are 
being reviewed, the project manager will forward all relevant documentation highlighting 
protocol deviations to the appropriate members of the project team. These deviations will be 
included in the protocol violation document for agreement and will be listed with the 
protocol violations in the clinical study report (CSR). 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
All analyses will be presented by treatment group and dosing regimen (AM dosing, Week 1 – 
Week 4; PM dosing, Week 5 – Week 8). Summary statistics for continuous variables will be 
described by number of subjects (n), mean, median, standard deviation (SD) and minimum 
and maximum. For continuous efficacy variables, the standard error of the mean (SE) may 
also be reported. Categorical variables will be summarized using counts and percentages. All 
data collected will be included in the data listings. 
 
Statistical analysis and data descriptions will be carried out using SAS statistical analysis 
software (SAS Institute, Inc., Cary, North Carolina, USA) version 9.3 or higher. 
 
Summary statistics and analyses will be displayed for the following treatment groups: 
• 
trabodenoson 6.0% / latanoprost 0.005% QD 
• 
trabodenoson 3.0% / latanoprost 0.005% QD 
• 
trabodenoson 6.0% / latanoprost .0025% QD 
• 
latanoprost 0.005% QD  
• 
latanoprost 0.0025% QD  
Unless otherwise noted, the baseline value will be considered to be the most recent 
non-missing value (or mean value in the case of IOP) obtained prior to the first dose of study 
drug.  
 
6.2. 
KEY DEFINITIONS 
Mean IOP: “Mean IOP” is the average of the 2 or 3 IOP measurements per eye performed at 
each time point. 
 
Study Eye: The study eye will be an eye that meets all the following criteria: (1) mean 8AM 
IOP on Placebo Run-In Visit, Day -1, and Day 1 (AM predose) of 
≥2
5 and ≤34  mmHg; and 
(2) mean IOP ≥21 mmHg on Day -1 at 8 hours post-dose (~4PM).  If both eyes meet the above 
IOP criteria then the eye with the highest mean 8AM IOP on Day 1 will be designated as the 
‘study’ eye. In the event that the mean IOPs in both eyes are equivalent, the right eye will 
arbitrarily be designated as the ‘study’ eye.  If only 1 eye meets all the Study Enrollment 
Criteria, that eye will automatically be designated as the ‘study’ eye. 
 
First Dose Date: The first dose date is defined as the date on which the first drop of study 
drug in treatment period is taken. 
 
Last Dose Date: The last dose date is defined as the date on which the last drop of study drug 
in treatment period is taken. 
 
Baseline:  
• 
The study baseline is the last valid mean IOP prior to the first drop of the study drug 
(8AM on Day 1) . 
• 
The diurnal baseline is defined the mean IOP at the respective time point (8AM, 10AM, 
12PM and 4PM) on Day -1 for analyzing time-matched change. 


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Study Day: The study day is the current event date relative to the first dose date in the 
treatment period. That is, the study day = the current event date – first dose date +1 if the 
current event date is on or after the first dose date. Otherwise, the study day = the current 
event date – first dose date. That is, the first dose date is Study Day 1, the day preceding the 
first dose date is Study Day –1. 
 
6.3. 
MISSING DATA 
Subjects who withdraw or are withdrawn from the study after the study drug has been 
applied will not be replaced.  
The reason(s) for any premature withdrawal must be explained in detail in the CRF and source 
documents.  
Complete missing or partial date will be presented in the listings as reported on CRFs. Missing 
or incomplete onset dates for adverse events and concomitant medications will be imputed as 
needed in order to determine treatment emergence or determine the prior and concomitant 
medications. 
If an AE has a completely missing onset date, then the AE will be considered a TEAE unless a 
non-missing stop date indicates otherwise. In cases where severity is missing for TEAEs, the 
AE will be considered to be the highest degree of severity: Severe. In cases where relationship 
information is missing for TEAEs, the AE will be considered to be related. A medication with a 
completely missing start date is considered a prior medication. A medication with a 
completely missing stop date is considered a concomitant medication.  
 
If an adverse event or a medication has a partial start or stop date, the following rules will be 
used to determine whether it is an AE or a TEAE, or a prior or concomitant medication.  
Table 3: Partial Date Imputation for TEAE Determination 
 
Partial Missing Start or 
Stop Date 
 
Imputed Start Date 
Imputed Stop Date 
Missing month and day, 
and the year is present 
 
January 1 of that year or first 
dose date if the year is the same 
as the year of first dose date 
 
December 31 of that 
year 
Missing day, but year and 
month are present 
 
First day of that month or first 
dose date if the year and month 
are the same as the year and 
month of first dose date 
 
Last day of that month 
Missing month, but year 
and day are present 
Missing 
month 
imputed 
as 
January 
Missing month imputed 
as December 
 
The imputed date is only used for determining TEAEs, prior and concomitant medications.  
The collected partial dates will be reported in the listings.    
 


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6.4. 
VISIT WINDOWS 
The analyses will be based on visit designation. Visit dates are required within specified time 
windows relative to Day 1 Visit (see Table 2: Schedule of Assessments). The visits out of the 
visit window are considered protocol deviations, but the measurements at these visits are also 
included in the analyses. If there is more than one measurement within the same visit 
designation, then the observation recorded at the time closest to the target day will be used. 
When there is more than one measurement on the same day, the latest observation will be 
used in the analyses. 
 
For subjects withdrawing early, the end of study data collected (Early Termination visit) will 
be mapped to the next planned visit for summarization and analysis. 
 
6.5. 
SUBGROUPS 
Subgroup analyses will include:  
• 
Primary diagnosis – POAG versus OHT. 
• 
Day 1 pre-dose baseline IOP – Baseline >26 mmHg versus Baseline ≤26 mmHg. 
• 
Washout vs. No Washout. 
• 
Race: African Americans versus non-African Americans.  
• 
Baseline corneal thickness: ≥490 microns and ≤555 microns, >555 microns and ≤610 
microns. 
 
 


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
The reason for any premature withdrawal must be explained in detail in the source 
document. 
A subject may be withdrawn from the study under the following conditions: 
• Subject withdraws consent. 
• Subject’s compliance to the protocol is poor, per discretion of the Investigator. 
• Any condition that, in the Investigator’s opinion, may cause risk to the subject (also see  
Protocol Section 9.5). In this case, the Investigator will specify the reason for the subject’s 
withdrawal. 
Note: All effort will be made to capture the complete set of serial IOP measurements for the 
subject on the day of withdrawal. 
• Occurrence of a concomitant disease that violates the study protocol due to its severity or 
duration or due to changes in treatment being required. 
Any subject who withdraws or is withdrawn from the study should undergo the End-of-Study 
Visit procedures, preferably 7 (±1) days later, in order to assure the safety of the subject.  
The number of subjects receiving study treatment, including the washout and placebo run-in 
failures and the number of subjects who completed or discontinued the study and the reasons 
for any premature discontinuation from the study will be summarized by randomized 
treatment group. A by-subject listing of early withdrawal and study population will also be 
provided.  
7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
All baseline and demographic characteristics will be summarized by treatment group. This will 
include age, sex, race, ethnicity, primary ophthalmic diagnosis, height, weight, body mass 
index (BMI), Study baseline IOP (mean IOP at 8AM on Day 1) and Diurnal Baseline (average of 
the diurnal IOP measurement on Day -1). 
Age will be calculated as of the screening visit date using SAS functions as 
floor((intck('month',date_of_birth,visit_date) - (day(visit_date) < day(date_of_birth))) / 12) ; 
BMI will be calculated as BMI (kg/m2) = Weight(kg)/[Height(m)^2]. 
All information collected at baseline and for demographics will be provided in data listings. 


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7.3. 
MEDICAL AND OPHTHALMOLOGIC HISTORY  
Medical history, including any diseases, past surgeries, psychiatric illnesses and relevant 
medical history will be documented in the CRF, with particular attention given to 
cardiovascular conditions including hypertension, cardiac arrhythmias, and heart conduction 
disturbances.  
Ophthalmologic history will include ocular trauma and surgery, eye infections and 
inflammation, retinal vein occlusion, and acute or chronic vision disturbances. 
POAG is generally defined as a condition in which subjects have: (1) elevated IOPs and (2) 
abnormal findings on examination of the optic disc and/or a visual field defect that correlates 
with the optic disc abnormalities and is consistent with POAG.  
OHT is defined as a condition in which subjects have consistently elevated IOPs but fail to 
fulfill the above POAG definition. However, for the purposes of this study, the Investigator’s 
clinical diagnosis of POAG or OHT is adequate to meet this entry criterion. 
Each subject will be questioned regarding all anticipated elective medical procedures that 
may occur during the subject’s planned participation in the study and these must be 
documented in the subject’s medical record and the medical history section of the CRF. 
All medical and ophthalmologic history will be documented in the eCRF and will be 
summarized by treatment group. 
All information collected at screening for medical and ophthalmologic history will be provided 
in data listings. 
7.4. 
MEDICATION HISTORY AND CONCOMITANT MEDICATIONS 
Medication history (past 45 days) will be documented during Screening. Any medication 
received by the subject prior to their signing the ICF and through completion of the washout 
period will be captured as Medication History. Any medication received by the subject 
following the start of the Placebo Run-In Period will be captured as Concomitant Medications. 
All concomitant medications taken by subjects from the start of the Placebo Run-In Period 
through completion of the End-of-Study Visit, including all additions, subtractions, or 
adjustments of medications, vitamins, and/or herbal supplements, must be documented in 
the CRF. 
Concomitant medications will be summarized by treatment group, and presented by WHO 
Drug Dictionary Anatomic-Therapeutic-Chemical Code (ATC) level 3 with the highest 
occurrence in the overall column. Within each ATC level 3 group, prior and concomitant 
medications will be displayed by Preferred Term (standard medication name) in decreasing 
order in the overall column.  
All medications (prior and concomitant medications) will be listed by subject. 
 


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8. 
EFFICACY 
All efficacy data will be presented by randomized treatment group and dosing regimen (AM 
dosing, Week 1 – Week 4 when randomized treatment is used during AM; PM dosing, Week 5 – 
Week 8 when randomized treatment is used during PM). 
The confidence interval and the adjusted means will be computed for the study eye. IOP 
measurements will be summarized separately for the study eye and non-study eye using 
descriptive statistics.   
For the study eye, all the efficacy end points (both primary and secondary) will be evaluated 
by presenting descriptive statistics (n, mean, median, standard deviation and range) by 
treatment group, and visit. Empirical SE of the means and 90% and 95% CI’s (assume standard 
normal distribution) will also be computed. In addition adjusted means (adjusts for 
differences in baseline values) and 90% and 95% CI’s, will be computed based on an Mixed 
effect Model Repeated Measure (MMRM)  model with treatment, visit, and the interaction of 
treatment and visit as the independent variables and baseline IOP as the covariate.  All 
efficacy analyses will be performed on the ITT population and PP population. 
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary efficacy endpoint is the daily IOP-change from diurnal baseline (average of the 4 
diurnal changes from baseline calculated during a dosing interval) calculated at the Week 4 
(after 4 weeks of AM dosing regimen) visit and the Week 8 visit (after 4 weeks of PM dosing 
regimen). The four IOP measurements from Day -1 are used as the diurnal baseline for the 
analyses at both Week 4 and Week 8.  
The daily IOP-change at Day 28 (AM dosing regimen) from diurnal baseline is calculated as 
average of the following diurnal changes:  
Day 28 8AM IOP Change = Day 28 8AM IOP minus Day -1 8AM IOP  
Day 28 10AM IOP Change =Day 28 10AM IOP minus Day -1 10AM IOP  
Day 28 12PM IOP Change =Day 28 12PM IOP minus Day -1 12PM IOP 
Day 28 4PM IOP Change=Day 28 4PM IOP minus Day -1 4PM IOP 
The daily IOP-change at Day 56 from diurnal baseline will be defined similarly. 
The daily IOP-change at Day 28 and Day 56 from diurnal baseline will be analyzed using Mixed 
effect Model Repeated Measure (MMRM) model with Daily IOP-change from diurnal baseline as 
the dependent variable, and treatment, visit, and the interaction of treatment and visit as 
factors, and Daily IOP at Day -1(average IOP of the four serial time points on Day -1) as a 
covariate.  Taking into consideration the correlation of these visits, as well as intra-visit, the 
covariance structure will be assumed to be unstructured. In the event convergence cannot be 
attained, alternative structures will be attempted in the following order: Toeplitz, compound 
symmetry, and then autoregressive. Least squared means (LS means) will be estimated from 
the model by time point and treatment. LS means for each treatment group at Day 28 and 
Day 56 will be estimated using LS means from the MMRM model. The comparison of the 


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treatments are exploratory by nature, therefore multiplicity will not be controlled for. The 
following pair-wise treatment comparisons will be made between treatment groups: 
 
• 
Trabodenoson 6.0%/ Latanoprost 0.005% vs Latanoprost 0.005% only; 
• 
Trabodenoson 6.0%/ Latanoprost 0.0025% vs Latanoprost 0.0025% only; 
• 
Trabodenoson 3.0%/ Latanoprost 0.005% vs Latanoprost 0.005% only. 
• 
All three groups of Trabodenoson / Latanoprost vs. Latanoprost 0.005% 
• 
Trabodenoson 6.0%/ Latanoprost 0.005% AND Trabodenoson 3.0%/ Latanoprost 0.005%      
vs. Latanoprost 0.005%. 
 
The distribution of the data will be visually examined, and the residuals from the MMRM 
model will be investigated for normality using the univariate Shapiro-Wilk W-test. The 
primary endpoint, as well as parameters that do not meet the assumptions of a normal 
distribution will also be analyzed using a non-parametric version of the MMRM model above, 
utilizing ranked IOP post-baseline data.  The Median, Q1, and Q3 will be summarized for each 
treatment group and combined treatment group and the p-values will be presented for the 
pairwise treatment differences of LS mean differences of rank at each visit.   
 
The effect of AM dosing vs PM dosing will be analyzed by examining the within subject 
difference between the AM dosing (or Day 28) and PM dosing (or Day 56) within each 
treatment. The LS mean will be estimated from the model by the visit and treatment 
interaction.  The within subject correlation will be adjusted by the covariance matrix used in 
the model.   
 
The daily IOP change from diurnal baseline will be descriptively summarized for the following 
subgroups: 
• 
Primary diagnosis – POAG versus OHT. 
• 
Day 1 pre-dose baseline IOP – Baseline >26 mmHg versus Baseline ≤26 mmHg. 
• 
Washout vs. No Washout. 
• 
Race: African Americans versus non-African Americans.  
• 
Baseline corneal thickness: ≥490 microns and ≤555 microns, >555 microns and ≤610 
microns. 
 
8.2. 
SECONDARY EFFICACY ENDPOINT(S) AND ANALYSES 
The following secondary analyses will be performed. 
8.2.1. 
Daily IOP 
Daily IOP, the average of the 4 serial IOPs taken during a dosing interval, will be calculated at 
the Week 4 visit (Day 28 – after 4 weeks of AM dosing regimen) and the Week 8 visit (Day 56 – 
after 4 weeks of PM dosing regimen).  


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Daily IOP=average of IOP at 8AM, 10AM, 12PM, and 4PM.  
Daily IOP at Day 28 (AM dosing) and Day 56 (PM dosing) will be analyzed using a similar MMRM 
model as section 8.1, with Daily IOP as the dependent variable, treatment, visit, and the 
interaction of treatment and visit as factors, and Daily IOP at Day -1 (average IOP of the four 
serial time points on Day -1) as a covariate. 
The mean daily IOP vs visit day will be plotted by treatment group.  
8.2.2. 
Daily IOP –change from Study Baseline 
A change from study baseline (8AM Day 1 predose IOP) analysis will be performed.    
The endpoint at Day 28 (after 4 weeks of AM dosing) is calculated as the average of the 
following:  
Day 28 8AM IOP Change from study baseline =Day 28 8AM IOP minus Day 1 8AM PRE-DOSE IOP 
Day 28 10AM IOP Change from study baseline = Day 28 10AM IOP minus Day 1 8AM PRE-DOSE 
IOP  
Day 28 12PM IOP Change from study baseline = Day 28 12PM IOP minus Day 1 8AM PRE-DOSE 
IOP  
Day 28 4PM IOP Change from study baseline =Day 28 4PM IOP minus Day 1 8AM PRE-DOSE IOP  
 
The endpoint at Day 56 will be calculated similarly. 
Daily IOP –change from study baseline on Day 28 and Day 56 will be analyzed using the same 
MMRM model, with Daily IOP as the dependent variable, treatment, visit, and the interaction 
of treatment and visit as factors, and study baseline (Day 1 8AM pre-dose IOP) as a covariate. 
8.2.3. 
Mean IOP at 8AM, 10AM, 12PM and 4PM   
A mean IOP at each time point will be calculated for the subject’s study eye at the end of 
week 4 and week 8 for each treatment group.   
Mean IOP at each time point on Day 28 and Day 56 will be analyzed using the same MMRM 
model, with the IOP from the diurnal baseline as the dependent variable, treatment, visit, 
and the interaction of treatment and visit as a factor, and diurnal baseline of the 
corresponding time point as a covariate.   
The mean IOP at 8AM, 10AM, 12PM and 4PM vs visit day will be plotted by treatment, for Day 
28 and Day 56. 
8.2.4. 
 IOP Change from Diurnal Baseline   
IOP change from diurnal baseline analysis, the time-matched subtraction of each of the 4 IOP 
time points of the circadian curve post randomization from the pre-randomization circadian 
curve, will be calculated at the end of the 4 weeks of treatment (Day 28 AM dosing, and Day 


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56, PM dosing) for each of the doses/combinations tested.  
IOP change from diurnal baseline will be analyzed using the same MMRM model as section 
8.2.3, with diurnal baseline of the corresponding time point on Day -1 as a covariate.   
8.2.5. 
IOP Change from Study Baseline 
IOP change from study baseline, calculated as the change in IOP from 8AM Day 1 baseline IOP, 
is computed at the end of the 4 weeks of treatment (Day 28 AM dosing, and Day 56 PM dosing) 
for each of the doses/combinations tested. 
IOP Change from study baseline at 8AM will be analyzed using the same MMRM model as 
section 8.2.3, with Day 1 pre-dose IOP at 8AM as a covariate.  
8.3. 
EXPLORATORY ANALYSES 
An analysis of the primary endpoint, daily IOP change from diurnal baseline, will be 
performed excluding subjects considered to be “non-responders” to latanoprost. “Non-
responders” will be defined as subjects with a daily IOP improvement from diurnal baseline of 
< 2 mmHg at Day 28 and Day 56. 
Summary statistics by treatment group will be presented, and pairwise treatment 
comparisons, as well as the analysis of the effect of AM dosing vs PM dosing will be performed 
as described in section 8.1.      
8.4. 
LCVA SUB-STUDY ENDPOINTS AND ANALYSES 
Analyses for LCVA will be presented by treatment group.  Continuous variables will be 
described as the mean, median, standard deviation and range of n observations.  Where 
applicable standard error of the means (SE) will be presented.  Categorical data will be 
described with contingency tables including frequency and percent.  
Demographic data and baseline characteristics will be descriptively summarized by dose group 
for this sub-study population. 
Primary LCVA Endpoint: 
• 
Change from Day -1 baseline in monocular (study eye only) Total Letter Score using the 
SLOAN 2.5% visual acuity chart at Day 56. 
Secondary LCVA Endpoints: 
• 
Change from Day -1 baseline in binocular (both eyes together) Total Letter Score using the 
SLOAN 2.5% visual acuity chart at Days 28 and 56. 
• 
Comparison of the LCVA Total Letter Score between pooled latanoprost alone arms and 
pooled fixed-dose combination arms at Days -1, 28 and 56. 
All LCVA total letter score will be summarized for the ITT population, and by primary 
diagnosis.  The LCVA analyses of change from baseline will be performed on the ITT 


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population, POAG subjects.  The analysis for LCVA will be assessed for each of the different 
treatment groups: 
• 
Trabo 6.0% + LP 0.005%  
• 
Trabo 6.0% + LP 0.0025% 
• 
Trabo 3.0% + LP 0.05% 
• 
LP 0.005% 
• 
LP 0.0025% 
LCVA Letter Scores will be evaluated by presenting descriptive statistics for the change from 
baseline by treatment group and visit.  Means and 90% and 95% Confidence Intervals (CI) will 
be computed.   
Secondary analyses will be performed using the same methods as above for: 
• 
the change from baseline in binocular LCVA Total Letter Score; 
• 
the change from baseline in monocular LCVA Total Letter Score, pooling the 
latanoprost alone dose arms and pooling the fixed-dose combination arms (in addition, 
for the pooled dose groups, adjusted means and 95% CI will be computed based on an 
Analysis of Covariance (ANCOVA) model with treatment as the independent variable 
and baseline LCVA as the covariate). 
Baseline is defined as the Day -1, pre-dose LCVA Letter Scores. 
Listings and descriptive summaries will include all LCVA sub-study subjects. Analyses will 
include only POAG subjects. 
 
8.5. 
SAFETY 
The tolerability and safety of trabodenoson will be assessed based on AEs, findings of physical 
examinations, vital signs, clinical laboratory test results, 12-lead ECG tracings, BCVA, 
bilateral complete external and internal eye examinations with a standardized masked 
grading of conjunctival hyperemia, IOPs, drug exposure, concomitant medications, and 
withdrawals/terminations. These findings will be summarized by treatment group. The Safety 
population is used as the analysis population for all the safety analyses. AEs will be 
categorized by System Organ Class (SOC) and Preferred Terms using the Medical Dictionary for 
Regulatory Activities (MedDRA, version 18.1). The incidence of AEs as well as the severity and 
relationship to study drug will be summarized by treatment group. 
8.6. 
EXTENT OF EXPOSURE 
Exposure to study treatment will be summarized by treatment group. Duration of treatment 
will be defined as: 
 
Duration = (last dose date minus first dose date) plus 1. 
If last dose date is missing, end-of-study date will be used.  


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The duration of treatment will be summarized using descriptive statistics. 
8.7. 
TREATMENT COMPLIANCE 
The compliance will be expressed as a percentage and calculated as the number of doses 
taken divided by the number expected to have been taken times 100. The compliance with 
study medication will be summarized using descriptive statistics. 
8.8. 
ADVERSE EVENTS 
AEs will be categorized by System Organ Class (SOC) and Preferred Terms using the Medical 
Dictionary for Regulatory Activities (MedDRA version 19.1).  
 
AE summary tables will focus on treatment emergent adverse events (TEAEs), defined  
as AEs that occur following the first dose of study drug on Day 1 AM. The data listings will 
include all AEs. Non-treatment emergent AEs will be flagged in the listings;  
 
The following AE subsets will be summarized by SOC, PT, and treatment group: 
 
• 
Treatment emergent AEs 
• 
Treatment emergent serious adverse events (SAE) 
• 
Adverse events leading to study withdrawal  
 
Treatment emergent AEs will also be summarized by SOC, PT, maximum severity (mild, 
moderate, severe), and treatment group. A summary of treatment emergent AEs by SOC, PT, 
maximum relationship (not related, related) to study drug, and treatment group will also be 
provided. A separate listing of serious adverse events and listing of adverse events leading to 
study drug discontinuation will also be provided.  
 
8.9. 
LABORATORY EVALUATIONS 
The following laboratory tests will be performed for this study: 
Hematology: 
• 
White Blood Cell Count 
• 
Hematocrit 
• 
Red Blood Cell Count 
• 
White Blood Cell 
Differential in absolute 
numbers, not percents 
• 
Mean Corpuscular 
Volume 
• 
Platelet Count 
• 
Hemoglobin 
• 
Mean Corpuscular 
Hemoglobin 
Concentration 
 
Coagulation analysis: 
• 
International Normalized Ratio (INR) 


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• 
Partial Thromboplastin Time (PTT) 
Clinical chemistry: 
• 
ALT 
• 
Total cholesterol 
• 
Sodium 
• 
AST 
• 
Chloride 
• 
Triglycerides  
• 
Albumin 
• 
Creatinine 
• 
Uric acid  
• 
Alkaline phosphatase 
• 
Glucose 
• 
Total CPK 
• 
Direct bilirubin 
• 
Lactate 
dehydrogenase 
• 
Glomerular filtration 
rate (GFR) will be 
estimated using the 
formula used by the 
central laboratory 
• 
Total bilirubin 
• 
Inorganic phosphorus 
• 
Blood urea nitrogen or 
urea 
• 
Potassium 
• 
Calcium and corrected 
calcium 
• 
Total protein 
Urinalysis: 
• 
Glucose 
• 
Leucocytes 
• 
Ketones 
• 
Erythrocytes 
• 
pH 
 
• 
Protein 
• 
Nitrites 
 
Findings from the central laboratory data will be summarized by lab parameter, study visit, 
and treatment group using descriptive statistics. Categorical and numeric variables will be 
presented separately. 
Absolute parameter value will be summarized at Baseline. Baseline is defined as the last non-
missing value before the first dose of study medication. Day 28 and EOS. Changes from 
Placebo-Run-in visit to Day 28 and EOS will also be summarized.  
Shift tables presenting the change, relative to the normal range, from baseline to post Day 1 
visits will be provided. 
Only scheduled laboratory results will be summarized. All laboratory results (i.e., scheduled 
and unscheduled) will be listed. Results outside predefined normal ranges will be flagged in 
the data listing.


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8.10. 
VITAL SIGNS  
Vital signs will be assessed at Screening, Placebo Run-In Visit, Day -1, Day 1, Day 28, 
Day 56 and EOS. Results for resting systolic and diastolic blood pressure, pulse rate, 
temperature and respiratory rate will be summarized by study visit and treatment 
group. Changes from baseline in blood pressure, pulse rates and respiratory rates will be 
summarized by visit and treatment. Height and weight will be assessed during the 
screening period. Summary statistics of height and weight will be presented together 
with the baseline parameters. Baseline is defined as the last non-missing value before 
the first dose of study medication. 
Vital sign measurements will be presented for each subject in a data listing. 
 
8.11. 
ECG  
ECGs will be assessed at Screening, Placebo Run-In Visit, and EOS. A standard, surface 
12-lead ECG for RR, PR, QRS, and QT intervals, heart rate, and rhythm will be obtained. 
ECGs in a digital format will be interpreted by a Board-Certified cardiologist at a central 
laboratory. The QT interval results will be adjusted for rate using the Bazett (QTcB) and 
Fridericia (QTcF) corrections. 
The quantitative (interval measurements) along with changes from baseline will be 
summarized by visit and treatment group. Baseline is defined as the last non-missing 
value before the first dose of study medication. QT, QTcB, and QTcF in the categories 
below will be summarized using frequency and percentage: 
1) > 450 for male and 470 for female; 
2) >500; 
3) Change > 60; 
4) Change between 30-60 (inclusive); 
5) Change <30. 
The overall ECG interpretation (normal / abnormal, clinically significant / abnormal, 
not clinically significant) collected on the CRF will be summarized by treatment group.  
All data obtained from the ECGs will be listed. 
8.12. 
PHYSICAL EXAMINATION  
Two types of physical examinations will be performed during the trial: 
1. Complete physical examination includes skin, ears, nose, throat, lymph nodes, chest, 
heart, lungs, abdomen, as well as the neurological and musculoskeletal systems. 


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2. Directed physical examination includes skin, throat, chest, heart, lung, and 
abdomen. 
Neither type of physical examination includes an eye, breast, rectal, or pelvic 
examination. Eye examinations are performed independent of the physical 
examinations. 
Complete physical examination occurs during screening and at the end of study visit.  
Directed physical examination occurs on Day 1.  
A separate listing of all abnormal findings for complete physical examination and 
directed physical examination will be provided.  
8.13. 
EYE EXAMINATIONS, IOP ASSESSMENT, BCVA AND LCVA 
Safety assessments of the eye include: 
 
1. External eye and slit lamp examinations: This will include a pen light 
examination of the peri-orbital area (i.e., eyelids, eyelashes and conjunctivae) 
and a slit lamp examination of the eyelids, eyelashes, conjunctivae, sclerae, 
cornea, anterior chamber, anterior vitreous, iris, and lens. Hyperemia 
assessments are to be conducted at Placebo Run-In, Day -1, Day 28, and Day 56 
at pre-dose and 8 hours post dose. A score of ‘0’ means hyperemia and a 
non-zero value means hyperemia. The incidence of hyperemia will be tabulated 
at Day -1, Day 28 and Day 56 for both pre-dose and post-dose.  Change in 
incidence of hyperemia from Day -1 to Day 28 and Day 56 will be presented in a 
shift table by comparing Day -1 time-matched incidences. Frequency of 
abnormal results from the examinations will be summarized by treatment, visit, 
timing relative to study drug dosing, and eye (study eye or non-study eye).   
 
2. Dilated Fundus examination (ophthalmoscopy/ funduscopy) will be performed at 
the screening period and end of study visit. The examination consists of optic 
nerve examination including (vertical) cup to disc ratio, optic nerve head, 
retinal vasculature, macula assessment, and peripheral retinal assessment.  
Abnormal findings will be listed.  Cup to disc ratio will also be summarized by 
descriptive statistics by treatment group, visit and eye (study and non-study). 
Frequency of visibility and abnormal results from the examinations will be 
summarized by treatment, visit, timing relative to study drug dosing, and eye 
(study eye or non-study eye).  
3. Masked IOPs: The Masked IOPs will be measured at Screening, Placebo Run-In 
Visit, Day -1, Day 1, Day 28 and Day 56 and EOS.  
 
4. Gonioscopy will be performed once at Screening in order to confirm that the 
subject’s angle (>10 degrees) is open and non-occludable. Schaeffer grading is 


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required. If this procedure was performed within the past 180 days and 
documented in the subject’s medical record, this procedure need not be 
repeated (unless the Principal Investigator [PI] suspects a change).Binary 
findings (open versus closed/narrow), Schaeffer grade, and other pathology 
findings will be listed and no statistical analyses will be performed.  
 
5. Best corrected visual acuity test (BCVA) will be performed via a modified Early 
Treatment Diabetic Retinopathy Study (ETDRS) protocol at Screening, Placebo 
Run-In Visit, Day -1, Day 1, Day 28, Day 56 and EOS. Descriptive statistics will 
be provided for BCVA. Total letter scores will be tabulated by treatment group, 
visit, and eye (study and non-study eye).BCVA total letter score, Snellen 
equivalent, refraction left and right eye will be listed for each subject.  
 
6. Low Contrast Visual Acuity (LCVA) will be performed in a subset of subjects 
enrolled in the LCVA sub-study, using 2.5% Contrast Sloan Letter Charts at 
Placebo Run-In Visit, Day -1, Day 28 and Day 56. Descriptive statistics will be 
provided for LCVA. Total letter scores will be tabulated by treatment group, 
visit, eye (study and non-study eye), and for both eyes together (binocular). 
LCVA total letter score will be listed for each subject.  
 
7. Visual Fields: The recommend visual fields include Humphrey (24-2 full 
threshold, 24-2 SITA standard, 30-2 central threshold, [Note: 24-2 SITA fast not 
allowed]) and Octopus (GI dynamic strategy, GI normal strategy, 24-2 dynamic 
strategy, 24-2 normal strategy). If this procedure was performed within the past 
90 days, and documented in the subject’s medical record, this procedure need 
not be repeated (unless the Principal Investigator [PI] suspects a change). Visual 
fields will only be performed at Screening and the End of Study visit. Mean 
deviation (dBel) and p value will be summarized by treatment, visit and eye. 
For the end of study visit, the frequency of clinically significant progression will 
be tabulated by eye and treatment. A listing of visual field program used, mean 
deviation (dBel) and P value by subject will be provided.  
 
8. Central Corneal Thickness will be performed utilizing an ultrasound 
pachymeter. If this procedure was performed within the past 365 days, and 
documented in the subject’s medical record, this procedure need not be 
repeated (unless the Principal Investigator [PI] suspects a change). A listing of 
the findings will be provided.  
 
For all summaries, non-study eye findings will also be summarized for comparison with 
the study eye. 
 
 


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8.14. 
OTHER SAFETY 
Samples for pregnancy testing will only be obtained from enrolled females of 
childbearing potential (as defined in Inclusion Criteria #4) and will be performed on 
blood (during Screening) and urine (at Day -1 and Day 56(EOT)) samples.   
 


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9. 
INTERIM ANALYSES 
There is no planned interim analysis. 


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10. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
• 
Washout failure population is defined in the protocol, but not used. It is thus 
removed from the SAP. 
• 
90% confidence intervals have been included, in addition to the 95% confidence 
intervals. 
• 
An exploratory analysis on daily IOP change from diurnal baseline, excluding 
“non-responders” to latanoprost has been added. 
• 
The LCVA analysis will only be performed on the ITT population due the small 
sample size in the Per-Protocol Population. 
 


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11. 
REFERENCE LIST 
 
 


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12. 
PROGRAMMING CONSIDERATIONS 
The following conventions will be followed for this study. 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® 9.3 or later (SAS® Institute Inc., Cary, NC, USA) Computer-generated table, listing 
and figure output will adhere to the following specifications.   
12.1. 
GENERAL CONSIDERATIONS 
• 
One SAS program can create several outputs. / A separate SAS program will be 
created for each output. 
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow ICH E3 guidance 
 
12.2. 
TABLE, LISTING, AND FIGURE FORMAT 
12.2.1. 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 8  
• 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and 
programmer-supplied formats, as appropriate. 
 
12.2.2. 
Headers 
• 
All output should have the following header at the top left of each page: 


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<Sponsor Name> Protocol XXX (     
          
Draft/Final Run <date> 
• 
All output should have Page n of N at the bottom right corner of each page. TLFs 
should be internally paginated in relation to the total length (i.e., the page number 
should appear sequentially as page n of N, where N is the total number of pages in 
the table). 
• 
The date and time of table and listing creation should appear bottom. The source 
listing number for table will appear bottom left.  
• 
The SAS program name should appear on each page. 
 
12.2.3. 
Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination. A decimal system (x.y and x.y.z) should be 
used to identify TLFs with related contents. The title is in the top left portion of 
table and listing. A table or listing number followed by the title of table or listing 
will be presented. The analysis set should be identified on the line immediately 
following the title. The title and table designation are single spaced. A solid line 
spanning the margins will separate the display titles from the column headers. There 
will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
 
12.2.4. 
Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values may be presented under the total column or in separate p-value column (if 
applicable). Within-treatment comparisons may have p-values presented in a row 
beneath the summary statistics for that treatment. 
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
• 
The order of treatments in the tables and listings will be Placebo first in the case of 
placebo controlled studies and Active comparators first in the case of active 
comparator trials, followed by a total column (if applicable). 


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12.2.5. 
Body of the Data Display 
12.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
 
12.2.5.2. Table Conventions 
• 
Units will be included where available 
• 
All tables have their source listing referenced in a footnote 
• 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
• 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
• 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
• 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, standard 
deviations and standard error should be printed out to 2 more significant digits than 
the original values. The minimum and maximum should report the same significant 
digits as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Std Error 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 


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Maximum 
XXX 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the 
p-value should be less than 0.0001 then present as <0.0001. If the p-value is 
returned as >0.999 then present as >0.999 
• 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to 
display values that round down to 0.0.  A common convention is to display as '<0.1', 
or as appropriate with additional decimal places. Unless otherwise noted, for all 
percentages, the number of subjects in the analysis set for the treatment group who 
have an observation will be the denominator. Percentages after zero counts should 
not be displayed and percentages equating to 100% should be presented as 100%, 
without any decimal places.  
• 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC with the highest occurrence in the active treatment group 
in decreasing order, assuming all terms are coded. Within the body system, drug 
class and SOC, medical history (by preferred term), drugs (by ATC1 code), and 
adverse events (by preferred term) should be displayed in decreasing order. If 
incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values which cannot be estimated 
should be reported as “-”. 
• 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
• 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
• 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 
 
12.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 


Statistical Analysis Plan 
Inotek Protocol IPC-02-2015 
Version 1.1 
INC Research 1007502 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 48 of 49 
• 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
• 
Units will be included where available. The unit associated with a variable will be 
presented only once within parentheses either below or next to that variable in the 
heading portion. 
• 
In the case that a subject’s record has been continued to the next page, an 
appropriate identification (eg., subject ID number) must be presented at the 
beginning of that page.  
 
12.2.5.4. Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
 
12.2.6. 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
• 
Subject specific footnotes should be avoided, where possible. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page.  
• 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan 
Inotek Protocol IPC-02-2015 
Version 1.1 
INC Research 1007502 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 49 of 49 
13. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 03.010 
and 03.013 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the 
proper clinical trial output by checking for their logic, efficiency and commenting and 
by review of the produced output.