Clinical trial NCT02754596
Conditions: Glaucoma Open-angle
Sponsor: Glaukos Corporation
Start date: 2016-03-29; Completion date: 2020-07-21
Enrollment: 154 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized trial comparing two elution doses of the Travoprost Intraocular implant to timolol ophthalmic solution.

Detailed description:
This is a randomized trial comparing two elution doses of the Travoprost Intraocular implant to timolol ophthalmic solution in patients with open-angle glaucoma. Study assessments will include IOP and medication use as well as safety parameters.

Arms: arm 1: This implant will be surgically implanted and elute travoprost, a prostaglandin. arm 2: This implant will be surgically implanted and elute travoprost, a prostaglandin. arm 3: Timolol, a beta blocker, will be dosed twice daily
Interventions: intervention 1: Travoprost Intraocular Implant, high elution intervention 2: Travoprost Intraocular Implant, low elution intervention 3: Timolol Maleate Ophthalmic Solution, 0.5%
Intervention descriptions: intervention 1: Surgical implant placed within the eye to elute travoprost. intervention 2: Surgical implant placed within the eye to elute travoprost intervention 3: Instillation of one drop of timolol in the study eye twice daily

Protocol documents:
Prot_000.pdf: 
PROSPECTIVE, RANDOMIZED PHASE II STUDY 
COMPARING TWO ELUTION RATES OF GLAUKOS 
TRAVOPROST INTRAOCULAR IMPLANTS TO 
TIMOLOL MALEATE OPHTHALMIC SOLUTION, 
USP, 0.5%
PROTOCOL #GC-009 
DOCUMENT CONTROL # AND REVISION #: CR-0412-2015 REV 2 
DATE:  SEPTEMBER 16, 2016 
Sponsor: 
GLAUKOS CORPORATION 
229 Avenida Fabricante │ San Clemente, CA  92672 │ (949) 367-9600 
NCT02754596


 
CLINICAL PROTOCOL 
Date: 
 
Phase: 
 
Protocol No.: 
September 16, 2016 
Phase II Study 
GC-009 
 
CR-0412-2015 Rev 2 
CONFIDENTIAL 
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TABLE OF CONTENTS 
SUMMARY 
.............................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................10 
1. 
INTRODUCTION ....................................................................................................11 
2. 
OBJECTIVE ...........................................................................................................12 
3. 
CLINICAL HYPOTHESES .....................................................................................12 
4. 
STUDY DESIGN......................................................................................................12 
4.1.  Description of Study Design  ...............................................................................12 
4.2.  Discussion of Study Design   ...............................................................................14 
5. 
STUDY MEASURES ...............................................................................................14 
5.1.  EFFICACY MEASURE ......................................................................................14 
5.2.  SAFETY MEASURES ........................................................................................14 
6. 
MATERIALS ...........................................................................................................15 
6.1.  STUDY MEDICATIONS ....................................................................................15 
6.1.1. Test Articles ...............................................................................................15 
6.1.2. Control Articles ..........................................................................................17 
6.1.3. Other Articles .............................................................................................17 
7. METHODS 
 ...........................................................................................................18 
7.1.  SUBJECTS ..........................................................................................................18 
7.2.  ELIGIBILITY REQUIREMENTS ......................................................................18 
7.2.1. Inclusion Criteria .......................................................................................18 
7.2.1.1. 
Screening Inclusion Criteria ............................................................18 
7.2.1.2. 
Baseline Inclusion Criteria ..............................................................20 
7.2.2. Exclusion Criteria ......................................................................................20 
7.2.2.1. 
Screening Exclusion Criteria ...........................................................20 
7.2.2.2. 
Baseline Exclusion Criteria .............................................................23 
7.2.3. Criteria for Subject Exit Prior to Study Completion ..................................23 
7.2.3.1. 
Prior to Randomization ...................................................................23 
7.2.3.2. 
After Randomization .......................................................................24 
7.2.3.2.1. Subject Lost to Follow-Up .......................................................24 
7.2.4. Study Termination .....................................................................................24 
7.3.  PROCEDURES ..................................................................................................24 
7.3.1. Duration Of Study ......................................................................................24 
7.3.2. Methods To Monitor Subject Compliance .................................................24 
7.3.3. Enrollment..................................................................................................25 
7.3.4. Screening Phase .........................................................................................25 
7.3.4.1. 
Visit 1 (Screening) ...........................................................................25 
7.3.4.2. 
Visit 2 (Baseline) .............................................................................26 
7.3.5. Treatment Phase .........................................................................................27 
7.3.5.1. 
Visit 3 (Operative Exam) ................................................................27 
7.3.5.2. 
Visit 4 (Day 1-2 Exam) ...................................................................28 
7.3.5.3. 
Visit 5 (Week 1-2 Exam) .................................................................29 




 
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9.6.1. General Principles of Data Analysis ..........................................................46 
9.6.2. Subject Enrollment and Disposition ..........................................................47 
9.6.3. Subject Demographic and Baseline Characteristics ..................................47 
9.6.4. Efficacy Analyses ......................................................................................48 
9.6.4.1.Primary Efficacy Analysis ...................................................................48 
9.6.4.2.Sensitivity Analysis .............................................................................48 
9.6.4.3.Analysis of Covariates .........................................................................49 
9.6.4.4.Subgroup Analysis ...............................................................................49 
9.6.4.5.Exploratory Analyses ...........................................................................49 
9.6.5. Safety Analyses ..........................................................................................49 
9.6.5.1.Study Drug Exposure ...........................................................................50 
9.6.5.2.Surgical Complications ........................................................................50 
9.6.5.3.Adverse Events ....................................................................................50 
9.6.5.4.Best Spectacle Corrected Visual Acuity (BSCVA) .............................50 
10. ADVERSE EVENTS ................................................................................................51 
10.1.  Possible Adverse Events from Implantation of Model G2TR
 or Model 
G2TR-
          .................................................................................................52 
10.2.  Possible Adverse Events from Travoprost or Timolol ......................................52 
10.3.  Serious Adverse Event .......................................................................................52 
10.4.  Unexpected Adverse Event ................................................................................53 
10.5.  Non-Serious Adverse Event ...............................................................................54 
10.6.  Intercurrent Events Prior to Randomization ......................................................54 
10.7. Follow-up After Adverse Events ........................................................................54 
11. MAINTAINING THE MASK ..................................................................................54 
12. INFORMED CONSENT ..........................................................................................55 
13. INSTITUTIONAL REVIEW ....................................................................................55 
14. CONFIDENTIALITY/PUBLICATION OF THE STUDY ......................................55 
15. STATEMENT OF COMPLIANCE ..........................................................................56 
16. RECORD KEEPING ................................................................................................56 
16.1.  Source Documents .............................................................................................56 
16.2.  Data Collection  .................................................................................................56 
16.3.  Study Supply Accountability .............................................................................57 
16.4.  Record Retention ...............................................................................................57 
17. BIBLIOGRAPHY ..................................................................................................58 
18. APPENDIX A – SCHEDULE OF VISITS AND ASSESSMENTS ........................59 
19. APPENDIX B – OBLIGATIONS OF INVESTIGATORS......................................60 
20. APPENDIX C – ELEMENTS OF INFORMED CONSENT ...................................61 
21. APPENDIX D - DECLARATION OF HELSINKI..................................................63 
22. APPENDIX E – GLAUKOS TRAVOPROST INTRAOCULAR IMPLANT 
SURGICAL INSTRUCTIONS ..........................................................................................68 
23. APPENDIX F –1 TRAVATAN PACKAGE INSERT AND APPENDIX F-2 
TIMOLOL PACKAGE INSERT………………………………………………………...70 
24. APPENDIX G – ARTIFICIAL TEARS PACKAGE INSERT ................................81 


 
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25. APPENDIX H – ASSIGNING SUBJECT NUMBERS AND KITS ........................82 
26. APPENDIX I – PROCEDURES FOR EXAMINATIONS ......................................83 
26.1.  Pregnancy Test   .................................................................................................83 
26.2.  Visual Acuity     .................................................................................................83 
26.2.1.  Pinhole Visual Acuity ...............................................................................83 
26.2.2.  Manifest Refraction and Best Spectacle Corrected Visual Acuity 
(ETDRS)   .................................................................................................83 
26.3.  Pachymetry…… ................................................................................................84 
26.4.  Gonioscopy…… ................................................................................................84 
26.5.  Slit-lamp Biomicroscopy ...................................................................................84 
26.6.  Intraocular Pressure (IOP) .................................................................................86 
26.6.1. Standard IOP Measurement .......................................................................86 
26.6.2. Diurnal IOP Measurement .........................................................................86 
26.7.  Ophthalmoscopy ................................................................................................86 
26.8.  Visual Field ….. .................................................................................................87 
26.9.  Specular Microscopy .........................................................................................87 
26.10. Conjunctival Hyperemia, Iris, Eyelash and Periorbital Assessments and 
Photographs and Blood Sampling ... ................................................................88 
26.10.1. 
Conjunctival Hyperemia ......................................................................88 
26.10.2. 
Iris (Color) Assessment ........................................................................88 
26.10.3. 
Eyelash (Length and Density) Assessment ..........................................89 
26.10.4. 
Periorbital Assessment .........................................................................89 
26.10.5. 
Blood Sampling ...................................................................................89 
 
 
 
 




 
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Objective: 
To compare the safety and initial efficacy of intraocular implants containing travoprost at 
two different elution rates versus Timolol Maleate Ophthalmic Solution, USP, 0.5% 
(timolol) in reducing elevated intraocular pressure in subjects with open-angle glaucoma 
(OAG) or ocular hypertension (OHT).  
 
 
Clinical Hypotheses: 
‐ 
Intraocular implants containing travoprost are at least as effective as timolol in 
achieving lowered intraocular pressure (IOP) in subjects with open-angle 
glaucoma (OAG) or ocular hypertension (OHT) 
‐ 
Intraocular implants containing travoprost are well-tolerated 
 
Study Population: 
Approximately 150 subjects diagnosed with OAG or OHT will be randomized. Subjects 
must meet all entry criteria at the Screening Visit. Subjects on 0 medications at the 
Screening Visit must have an IOP of 
 in the study eye, and then complete a 
3-day waiting period and return for a Baseline exam. Subjects on 1-3 medications must 
complete a required medication washout/waiting period. At the Baseline visit, all subjects 
must have mean diurnal IOP of 
 in the study eye, and meet all other entry 
criteria. 
 
Structure: 
parallel groups 
 
Multicenter: 
Yes 
 
Masking: 
‐ Observer-masked (IOP readings, assessments of 
symptomatology) 
‐ Subject-masked 
 
Method of Subject Assignment: 
After the 4:00 pm IOP measurement at Visit 2 (Baseline), qualified subjects will be 
scheduled to undergo treatment with the G2TR-
 implant, the G2TR-
 implant, or 
timolol in a ratio of 1:1:1. 
 
Randomization: 
Yes 
 
Estimated Total Sample Size: 
Approximately 150 subjects 
 
Statistical Rationale Provided: 
Not Applicable 




 
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Study Variables and Statistical Analysis: 
Efficacy Variable 
The primary efficacy variable will be the IOP at 1 week through 12 weeks. Refer to the 
Statistical Analysis Section for the statistical analysis methodology. 
 
Safety Variables 
Surgical complications and adverse events will be summarized. 
 
Ocular safety variables, i.e. best spectacle-corrected visual acuity, biomicroscopy 
findings, gonioscopy findings, ophthalmoscopy findings (including cup/disc ratio), 
pachymetry, visual field test evaluation and endothelial cell parameters, will be 
summarized. In addition, changes from baseline in conjunctival hyperemia, periorbital 
measurements, iris (color) and eyelashes (density and length) will be analyzed, if 
feasible. 
 
Blood plasma testing will be performed to assess systemic exposure to the implant study 
medication (travoprost free acid).  
 
Analysis Populations 
Refer to Statistical Analysis Section (Section 9). 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation/Term 
Definition 
AA 
Alpha agonist 
AREDs 
Alpha agonist 
AE 
Adverse event 
BAK 
Benzalkonium chloride 
BB 
Beta blocker 
BSCVA 
Best spectacle corrected visual acuity 
CAI 
Carbonic anhydrase inhibitor 
CRF 
Case report form 
ECD 
Endothelial cell density 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
ICH 
International Conference on Harmonization 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LogMAR 
Logarithm of the minimum angle of resolution 
MA 
Medical Affairs 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimeters of mercury 
OAG 
Open-angle glaucoma 
OHT 
Ocular hypertension 
OTC 
Over the counter 
PG 
Prostaglandin 
PVG 
Pharmacovigilance 
SAE 
Serious adverse event 
SOC 
System organ class 
TEAC 
Treatment Emergent Adverse Event 
VF 
Visual field 
 
 
 


 
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1. INTRODUCTION 
Glaucoma is a group of eye diseases characterized by progressive, irreversible and 
largely asymptomatic vision loss caused by optic nerve damage, which is most 
commonly associated with elevated levels of intraocular pressure. Glaucoma is a 
chronic condition that progresses slowly over long periods of time and can have a 
devastating impact on a patient's vision and quality of life. Reducing intraocular 
pressure is the only proven treatment for glaucoma.  
 
Treatment for open-angle glaucoma (OAG) has started traditionally with topical 
ocular hypotensive medical therapy.  Development of more effective medications has 
increased the popularity of this approaches as initial treatment compared to more 
invasive incisional or drainage device surgery. Furthermore, the more benign 
medication treatments preserve the ocular tissues in the event that more invasive 
surgical approaches are eventually required. 
 
The various topical ocular medications available to reduce IOP include miotics, β-
adrenergic receptor antagonists (β-blockers), carbonic anhydrase inhibitors (CAIs), α-
adrenergic receptor agonists (α-agonists), and prostaglandin analogues (PGs). The 
PGs are a class of ocular hypotensive agents that have been proven effective in 
lowering IOP in subjects with OAG or OHT. Advantages of this class of medications 
over other classes is that the systemic side effects associated with α-agonists (e.g., dry 
mouth, drowsiness) and β-blockers (e.g., depression, fatigue, bradycardia) do not 
appear to be associated with PGs.  Furthermore, the ocular side effects typically 
associated with a-agonists (e.g., allergic reactions), and cholinergic agents (e.g., 
reduced vision), do not seem to manifest with the use of PGs. 
 
In spite of these apparent advantages, PGs have been shown to be associated with 
side effects such as ocular hyperemia, iris hyperchromia, periorbital atrophy, 
increased eyelash growth, general ocular surface discomfort and headache.1-5 These 
side effects and other factors including cost, compliance, and the difficulty of proper 
instillation, hinder the proper use of topical medications.6,7 Some patients may 
possess or develop an intolerance to topical medications. 
 
The Travoprost Intraocular Implant was developed to remove or minimize the 
problem of patient compliance with prescription medication. This clinical protocol 
will evaluate two versions of the Travoprost Intraocular Implant: Model G2TR-
 
and Model G2TR-
. The implants are identical except that they are designed to 
elute travoprost at two different elution rates. For the purposes of this protocol, Model 
G2TR-
 is the high elution rate implant and Model G2TR-
 is the low elution 
rate implant).  
 
































 
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7.3.5.  Treatment Phase 


 
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7.3.5.2. 
Visit 4 (Day 1-2 Exam, 1-2 days) 


 
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7.3.5.3. 
Visit 5 (Week 1-2 Exam, 10 days ± 3) 
 
7.3.5.4. 
Visit 6 (Week 4 Exam, 28 days ± 3) 


 
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7.3.5.5. 
Visit 7 (Week 6 Exam, 42 days ± 3) 


 
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7 3 5 7  
Visit 9 (Month 6 Exam  182 days ± 14) 
7.3.5.8. 
Visit 10 (Month 9 Exam, 274 days ± 14) 


 
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7.3.5.10. Visit 12 (Month 15 Exam, 455 days ± 30) 


 
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7.3.5.11. Visit 13 (Month 18 Exam, 547 days ± 30) 


 
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7 3 5 12  Visit 14 (Month 21 Exam  637 days ± 30) 




 
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7.3.5.15. Visit 17 (Month 30 Exam, 910 days ± 60) 


 
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7.3.5.16. Visit 18 (Month 33 Exam, 1000 days ± 60) 
 
 
7.3.5.17. Visit 19 (Month 36 Exam, 1095 days ± 60) 






















 
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number of ETDRS will be summarized using the statistics for the continuous 
variables. 
 
Additionally, the number and percentage of subjects will be summarized for each of 
the three treatment groups based on the following VA categories: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. ADVERSE EVENTS 
Adverse events will be monitored throughout the course of the study, and reported 
on an adverse event (AE) form. Any significant change in a 
subject's condition from baseline, regardless of causality, is to be 
considered an adverse event, unless the change is determined to be 
a continuation of a pre-existing condition that is documented in the 
subject's medical history. However, a clinically significant increase 
in frequency or worsening in severity of a pre-existing condition 
may indicate an adverse event. In addition, a clinically significant 
laboratory finding may also indicate an adverse event.  Lack of 
efficacy of the study treatment for the condition being investigated 
is not an adverse event. Subjects should be asked using a general, 
non-direct question if there has been any change in how they feel 
from the previous visit (e.g., "How have you felt since the last 
visit?"). Direct questioning and examination should then be 
performed as appropriate.  If an adverse event occurs, then an AE 
form must be completed including a description of the event, 
seriousness, severity, onset and duration, action taken, outcome, 
and relationship to study medication.  A separate AE Form must be 
completed for each adverse event. All items on the AE form must 
be completed. 
 
If an adverse event is ongoing at the time of study exit, then the investigator should 
perform reasonable follow-up efforts as necessary (e.g., telephone contact, post-study 
office visit) to determine the outcome of the event. 
 










 
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15. STATEMENT OF COMPLIANCE 
This study will be conducted in compliance with the protocol, good clinical practices 
(GCP), International Conference on Harmonization (ICH) guidelines, the Declaration of 
Helsinki, and applicable regulatory requirements. 
 
16. RECORD KEEPING 
16.1. Source Documents 
The clinical investigator must maintain detailed source documents on all study subjects. 
Source documents include subject medical records, hospital charts, clinic charts, 
investigator subject study files, as well as the results of diagnostic tests (e.g., laboratory 
tests, visual field test printouts). 
 
The following minimum information should be entered into the subject's medical 
record: 
‐ 
The date the subject entered the study and the subject number 
‐ 
The study protocol number and the name of Glaukos 
‐ 
The date that informed consent was obtained 
‐ 
Evidence that the subject meets study eligibility requirements (e.g., medical 
history, study procedures and/or evaluations) 
‐ 
The dates of all study related subject visits 
‐ 
Evidence that required procedures and/or evaluations were completed 
‐ 
Use of any concurrent medications 
‐ 
Documentation of study medication accountability, including a copy of study 
medication labels 
‐ 
Occurrence and status of any adverse events 
‐ 
The date the subject exited the study, and a notation as to whether the subject 
completed the study or was discontinued, including the reason for 
discontinuation 
 
 
 
16.2. Data Collection  
The clinical investigator must maintain detailed records on all enrolled subjects.  Data for 
enrolled subjects will be collected with an electronic data capture system. The electronic 
database, which is Title 21 CFR Part 11 compliant, will be managed by a data 
management vendor. Access to the database will be granted to authorize study personnel 
based on their role after training; and the access will be password-protected. The data 
clarification process will be managed within the electronic data capture system by either 
system-generated or manually generated electronic queries. Accuracy of data will be 
verified by 100% source data verification at regular intervals, and all corrections to data 
will be made in the database. 


 
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Exit forms are completed for all enrolled subjects, regardless of their final study status 
(e.g., subject discontinuation, study termination). 
 
16.3. Study Supply Accountability 
The principal investigator is responsible for ensuring that an inventory is conducted upon 
receipt of the clinical supplies and that the clinical study supplies are received and stored 
as instructed. The receipt of clinical supplies should be completed, signed, and returned 
as directed by Glaukos (or designee). A copy must be maintained at the site for the 
investigator's records. The principal investigator will keep a current record of the 
inventory and dispensing of all study medications. This record will be made available to 
the Glaukos monitor (or designee) for the purpose of accounting for all clinical supplies. 
Any significant discrepancy and/or deficiency must be recorded with an explanation. All 
supplies sent to the investigator must be accounted for and in no case will study 
medications be used in any unauthorized situation. 
 
It is the responsibility of the principal investigator to return any used and unused supplies 
to the Glaukos monitor (or designee) at the conclusion of the study. 
 
16.4. Record Retention 
All records relating to the conduct of this study are to be retained by the investigator until 
notified by Glaukos that the records may be destroyed. 
 
The investigator will allow representatives of Glaukos' monitoring team (or designee), 
the governing institutional review board, the Food and Drug Administration (FDA), and 
other applicable regulatory agencies to inspect all study records, CRFs, and 
corresponding portions of the subject's office and/or hospital medical records at regular 
intervals throughout the study. These inspections are for the purpose of verifying 
adherence to the protocol, completeness, and exactness of the data being entered onto the 
CRF, and compliance with FDA or other regulatory agency regulations. 
 
 




 
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19. APPENDIX B - OBLIGATIONS OF INVESTIGATORS 
 
In summary, the clinical investigator has agreed to the following obligations: 
‐ 
Obtaining informed consent from every subject prior to enrollment in the 
study and maintaining records of consent as part of the study records. 
‐ 
Obtaining approval from the Institutional Review Board (IRB) before 
enrolling any subject; submitting verification of the approval to the Sponsor; 
submitting periodic progress reports (at least annually) and final report to IRB. 
‐ 
Approving the protocol and conducting the study according to the protocol 
and applicable regulations; informing the Sponsor of all deviations from the 
protocol. 
‐ 
Informing the IRB of all protocol amendments/modifications; sending the 
Sponsor a copy of the letter from the IRB approving the 
amendment/modification. 
‐ 
Reporting to the Sponsor and the IRB any adverse experiences that occur in 
the course of the investigation. 
‐ 
Keeping careful and accurate records of all clinical study data (study records 
must be considerably more exact and complete than those kept in ordinary 
medical practice); maintaining records of all materials submitted to the IRB 
and of all action by the IRB regarding the study. 
‐ 
Making study records available for inspection by the sponsor (Glaukos) and 
representatives of the Food and Drug Administration; keeping records until 
notified by the Sponsor that they may be destroyed. 
‐ 
Maintaining proper control and documentation of all test and control articles. 
‐ 
Submitting the following records and reporting to the Sponsor (See I, II, and 
III). 
 
I. 
Prior to the Beginning of the Study 
‐ 
A signed Form FDA-1572 or Statement of Investigator. 
‐ 
A current curriculum vitae (CV) if not submitted to Glaukos previously or 
if updated. 
‐ 
CVs for all sub-investigators listed on the 1572. 
‐ 
A letter from the Institutional Review Board (IRB) indicating that the 
protocol was approved, including the name and address of the IRB. 
‐ 
A copy of the consent form approved by IRB. 
‐ 
A list of current members of the IRB. 
 
II. 
While the Study is in Progress 
‐ 
Acknowledgment of receipt of the test and control articles; documentation 
of disposition of all test and control articles. 
‐ 
Original Case Report Forms for each subject enrolled in the study. 


 
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‐ 
Information regarding all deviations from the protocol. 
‐ 
Information regarding all adverse medical events occurring to a subject 
while enrolled in the study. 
‐ 
Annual progress report (if study is ongoing for more than one year). Letter 
from the IRB indicating approval of the annual progress report. 
 
III. 
Once the Study is Completed 
‐ 
Disposition of all used and/or unused test and control articles, as well as 
documentation of all drug accountability. 
‐ 
A final study report (if requested). 
 
20. APPENDIX C - ELEMENTS OF INFORMED CONSENT 
I. 
Elements of Informed Consent 
The following information must be provided to each subject in obtaining 
informed consent. If written consent is being obtained, the subject (or subject's 
legal representative) should be provided with a copy of the signed written 
informed consent. 
 
1. State that the study involves RESEARCH. 
 
A. Explain the PURPOSE of the research. 
B. State the expected DURATION of the subject's participation. 
C. Describe the PROCEDURES to be followed. 
D. Identify any EXPERIMENTAL procedures. 
 
2. Describe any reasonably foreseeable RISKS OR DISCOMFORTS to the subject. 
 
3. Describe any BENEFITS to the subject or to others that may reasonably be 
expected from the research. 
 
4. Note appropriate ALTERNATIVE procedures or courses of treatment, if any that 
might be advantageous to the subject. 
 
5. 
a. Describe the extent, if any, to which CONFIDENTIALITY of records 
identifying the subject will be maintained. 
b. Note that the Food and Drug Administration MAY INSPECT the records. 
 
6. For research involving more than minimal risk, explain if any COMPENSATION 
or medical treatments are available should injury occur. If so, explain (a) what 
they consist of, OR (b) where further information may be obtained. 
 


 
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7. 
a. Tell whom to contact for ANSWERS to pertinent questions about (a) the 
research, and (b) research subjects’ rights. 
b. Tell whom to contact in the event of a research-related INJURY to the 
subject. 
 
8. State that: 
a. Participation is VOLUNTARY, 
b. Refusal to participate will involve NO PENALTY or loss of benefits to 
which the subject is otherwise entitled, and 
c. The subject MAY DISCONTINUE participation at any time without penalty 
or loss of benefits to which the subject is otherwise entitled. 
 
II. 
Additional Elements of Informed Consent 
 
When appropriate, one or more of the following elements of information shall also be 
provided to each subject: 
 
1. 
A statement that particular treatment or procedure may involve risks to the 
subject (or to the embryo or fetus, if the subject is or may become pregnant) 
which are currently unforeseeable. 
2. 
Anticipated circumstances under which the subject's participation may be 
terminated by the investigator without regard to the subject's consent. 
3. 
Any additional costs to the subject that may result from participation in the 
research. 
4. 
The consequences of a subject's decision to withdraw from the research and 
procedures for orderly termination of participation by the subject. 
5. 
A statement that significant new findings developed during the course of the 
research, which may relate to the subject's willingness to continue participation, 
will be provided to the subject. 
6. 
The approximate number of subjects involved in the study. 
 
The informed consent requirements in these regulations are not intended to preempt any 
applicable Federal, State, or local laws which require additional information to be 
disclosed for informed consent to be legally effective. 
 
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
Federal, State, or local law. 
 
REFERENCE: 21 CFR Part 50.25 - PROTECTION OF HUMAN SUBJECTS, Elements 
of informed consent. 
 
 


 
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21. APPENDIX D - DECLARATION OF HELSINKI 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical principles for medical research involving human subjects 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended 
by the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 48th WMA General Assembly, Somerset West, Republic of South 
Africa, October 1996 and the 52nd WMA 
General Assembly, Edinburgh, Scotland, October 2000 
 
A. INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as 
a statement of ethical principles to provide guidance to physicians and other 
participants in medical research involving human subjects. Medical research 
involving human subjects includes research on identifiable human material or 
identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the 
people. The physician’s knowledge and conscience are dedicated to the 
fulfillment of this duty. 
3. 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." 
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
5. In medical research on human subjects, considerations related to the well-
being of the human subject should take precedence over the interests of 
science and society. 
6. The primary purpose of medical research involving human subjects is to 
improve prophylactic, diagnostic and therapeutic procedures and the 
understanding of the aetiology and pathogenesis of disease. Even the best 
proven prophylactic, diagnostic, and therapeutic methods must continuously 
be challenged through research for their effectiveness, efficiency, accessibility 
and quality. 


 
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7. In current medical practice and in medical research, most prophylactic, 
diagnostic and therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all 
human beings and protect their health and rights. Some research populations 
are vulnerable and need special protection. The particular needs of the 
economically and medically disadvantaged must be recognized. Special 
attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for 
those who will not benefit personally from the research and for those for 
whom the research is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory 
requirements for research on human subjects in their own countries as well as 
applicable international requirements. No national ethical, legal or regulatory 
requirement should be allowed to reduce or eliminate any of the protections 
for human subjects set forth in this Declaration. 
 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
1. It is the duty of the physician in medical research to protect the life, health, 
privacy, and dignity of the human subject. 
2. Medical research involving human subjects must conform to generally 
accepted scientific principles, be based on a thorough knowledge of the 
scientific literature, other relevant sources of information, and on adequate 
laboratory and, where appropriate, animal experimentation. 
3. Appropriate 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. 
4. The design and performance of each experimental procedure involving human 
subjects should be clearly formulated in an experimental protocol. This 
protocol should be submitted for consideration, comment, guidance, and 
where appropriate, approval to a specially appointed ethical review 
committee, which must be independent of the investigator, the sponsor or any 
other kind of undue influence. This independent committee should be in 
conformity with the laws and regulations of the country in which the research 
experiment is performed. The committee has the right to monitor ongoing 
trials. The researcher has the obligation to provide monitoring information to 
the committee, especially any serious adverse events. The researcher should 
also submit to the committee, for review, information regarding funding, 
sponsors, institutional affiliations, other potential conflicts of interest and 
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5. The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that there is compliance with the 
principles enunciated in this Declaration. 
6. Medical 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 consent. 
7. Every medical research project involving human subjects should be preceded 
by careful assessment of predictable risks and burdens in comparison with 
foreseeable benefits to the subject or to others. This does not preclude the 
participation of healthy volunteers in medical research. The design of all 
studies should be publicly available. 
8. Physicians should abstain from engaging in research projects involving human 
subjects unless they are confident that the risks involved have been adequately 
assessed and can be satisfactorily managed. Physicians should cease any 
investigation if the risks are found to outweigh the potential benefits or if 
there is conclusive proof of positive and beneficial results. 
9. Medical research involving human subjects should only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
subject. This is especially important when the human subjects are healthy 
volunteers. 
10. Medical research is only justified if there is a reasonable likelihood that the 
populations in which the research is carried out stand to benefit from the 
results of the research. 
11. The subjects must be volunteers and informed participants in the research 
project. 
12. The right of research subjects to safeguard their integrity must always be 
respected. Every precaution should be taken to respect the privacy of the 
subject, the confidentiality of the patient’s information and to minimize the 
impact of the study on the subject's physical and mental integrity and on the 
personality of the subject. 
13. In any research on human beings, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail. The subject 
should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal. After ensuring 
that the subject has understood the information, the physician should then 
obtain the subject's freely given informed consent, preferably in writing. If the 


 
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consent cannot be obtained in writing, the non-written consent must be 
formally cumented and witnessed. 
14. When obtaining informed consent for the research project the physician 
should be particularly cautious if the subject is in a dependent relationship 
with the physician or may consent under duress. In that case the informed 
consent should be obtained by a well-informed physician who is not engaged 
in the investigation and who is completely independent of this relationship. 
15. For a research subject who is legally incompetent, physically or mentally 
incapable of giving consent or is a legally incompetent minor, the investigator 
must obtain informed consent from the legally authorized representative in 
accordance with applicable law. These groups should not be included in 
research unless the research is necessary to promote the health of the 
population represented and this research cannot instead be performed on 
legally competent persons. 
16. When a subject deemed legally incompetent, such as a minor child, is able to 
give assent to decisions about participation in research, the investigator must 
obtain that assent in addition to the consent of the legally authorized 
representative. 
17. Research on individuals from whom it is not possible to obtain consent, 
including proxy or advance consent, should be done only if the 
physical/mental condition that prevents obtaining informed consent is a 
necessary characteristic of the research population. The specific reasons for 
involving research subjects with a condition that renders them unable to give 
informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee. The protocol should state 
that consent to remain in the research should be obtained as soon as possible 
from the individual or a legally authorized surrogate. 
18. Both authors and publishers have ethical obligations. In publication of the 
results of research, the investigators are obliged to preserve the accuracy of 
the results. Negative as well as positive results should be published or 
otherwise publicly available. Sources of funding, institutional affiliations and 
any possible conflicts of interest should be declared in the publication. 
Reports of experimentation not in accordance with the principles laid down in 
this Declaration should not be accepted for publication. 
 
 
 
 
 
 


 
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C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
1. The physician may combine medical research with medical care, only to the 
extent that the research is justified by its potential prophylactic, diagnostic or 
therapeutic value. When medical research is combined with medical care, 
additional standards apply to protect the patients who are research subjects. 
2. The benefits, risks, burdens and effectiveness of a new method should be 
tested against those of the best current prophylactic, diagnostic, and 
therapeutic methods. This does not exclude the use of placebo, or no 
treatment, in studies where no proven prophylactic, diagnostic or therapeutic 
method exists. 
3. At the conclusion of the study, every patient entered into the study should be 
assured of access to the best proven prophylactic, diagnostic and therapeutic 
methods identified by the study. 
4. The physician should fully inform the patient which aspects of the care are 
related to the research. The refusal of a patient to participate in a study must 
never interfere with the patient physician relationship. 
5. In the treatment of a patient, where proven prophylactic, diagnostic and 
therapeutic methods do not exist or have been ineffective, the physician, with 
informed consent from the patient, must be free to use unproven or new 
prophylactic, diagnostic and therapeutic measures, if in the physician’s 
judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, these measures should be made the object of 
research, designed to evaluate their safety and efficacy. In all cases, new 
information should be recorded and, where appropriate, published. The other 
relevant guidelines of this Declaration should be followed. 
 


 
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22. APPENDIX E – GLAUKOS TRAVOPROST INTRAOCULAR IMPLANT 
SURGICAL INSTRUCTIONS 
 
Do not use the implant if the Tyvek lid on the blister tray has been opened or the 
packaging appears damaged.  In such cases, the sterility of the implants may be 
compromised. 
 
Surgical Instructions 
1. The eye should be anesthetized using general, retrobulbar, peribulbar, or 
topical anesthesia per standard hospital or ambulatory surgery center 
procedures. 
2. It is recommended that the implant surgery be performed from the temporal 
side, using a temporal clear corneal incision, to provide clear access for the 
surgical instruments.  The implant will be implanted through the trabecular 
meshwork on the nasal side.  
3. Create a clear corneal incision at the temporal limbus location using an 
instrument of the surgeon’s choice. 
4. A cohesive viscoelastic is added to the anterior chamber as needed to improve 
visualization of the angle, and to maintain IOP for use of the gonioscope.  
5. A gonioscope is placed on the cornea and the surgical microscope and the 
patient are positioned as needed to visualize the angle, through the 
gonioprism, on the nasal side of the eye.  Tilting the patient’s head as far as 
practical away from the surgeon, and also tilting the microscope toward the 
surgeon will help viewing of the angle. 
6. The angle is inspected using a gonioprism to ensure good visualization at the 
nasal implant location.   
7. Remove the G2TR
 or G2TR-
on its inserter from the blister tray. 
Inspect the implant on the tip of the inserter. 
8. When ready for implantation, remove safety clip which holds trigger in place. 
Keep finger on trigger button to ensure it remains in the forward position and 
doesn’t prematurely release implant. 
9. Insertion of Model G2TR-
 or G2TR-
  
a. Deepen the anterior chamber with additional viscoelastic to aid in 
chamber maintenance as needed. 
b. Enter the anterior chamber with the implant using supplied inserter. 
c. Advance to the pupillary margin before replacing the goniolens onto 
the eye. 
d. Care must be taken to avoid contact with the lens or cornea. 
e. Advance to the anterior chamber angle and approach the trabecular 
meshwork.   
f. Press the distal end of the implant directly into and through trabecular 
meshwork until the barb at the tip securely penetrates the sclera at the 
outer wall of Schlemm’s canal, and the base of the cylindrical 


 
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reservoir is firmly in contact with and compressing the trabecular 
meshwork. 
g. During scleral penetration, it may be necessary to apply firm and 
focused responsive pressure against the sclera on the outside of the eye 
to react against the penetration and keep the tissue from collapsing 
around the sharp tip of the implant thereby preventing penetration. 
h. Once the tip barb of the implant is securely embedded in sclera, 
carefully slide the trigger button rearward to open the jaws of the 
gripper and thus release the implant from the inserter.  Back the 
inserter away from the implant without allowing it to pull the implant 
of position. 
i. Withdraw the insertion instrument from the eye. 
 
10. High-magnification examination is performed to confirm that the implant is in 
proper position (i.e., the proximal end rests in the anterior chamber with an 
unobstructed membrane) and securely attached with the tip barb thoroughly 
embedded in sclera. 
11. It is normal for an edge of the implant to make contact with iris, but most of 
the membrane should be unobstructed by iris. 
12. The anterior chamber is irrigated and aspirated with balanced salt solution 
(BSS) through the corneal wound to remove all viscoelastic.  The surgeon 
may press down on the posterior edge of the incision as needed to facilitate 
complete removal of viscoelastic. 
13. The anterior chamber is inflated with saline solution as needed to achieve 
physiologic pressure. 
 
Do not use the implant if the Tyvek lid on the blister tray has been opened or the 
packaging appears damaged.  In such cases, the sterility of the implants may be 
compromised. 
 
 


















 
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24. APPENDIX G – ARTIFICIAL TEARS PACKAGE INSERT 
 
 
 




 
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25. APPENDIX H – ASSIGNING SUBJECT NUMBERS AND KITS  
Subject and kit numbers will be dispensed using in accordance with detailed 
instructions provided separately. The investigator or his/her designee must access the 
electronic data base to obtain details of subject randomization and kit use. 
 
 
 
 
















 
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baseline, Week 1-2 (10 day ± 3), Week 12 and Month 12 examinations, blood 
samples will be obtained from each study subject at a lab in close proximity to the 
investigational site. 
 
 

SAP_001.pdf: 






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Statistical Analysis Plan 06JAN2022 
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Table of Contents 
Statistical Analysis Plan Approval Signatures ............................................................................2 
Table of Contents ...........................................................................................................................4 
List of Abbreviations .....................................................................................................................6 
Version History ..............................................................................................................................8 
1.
Introduction .....................................................................................................................9 
2.
Objectives and Study Design .......................................................................................10 
2.1. 
Objectives, Endpoints, and Estimands ............................................................................10 
2.2. 
Study Design ...................................................................................................................12 
2.3. 
Assessment Schedule ......................................................................................................14 
2.4. 
Sample Size Determination ............................................................................................14 
3.
Analysis Sets ..................................................................................................................16 
4.
General Statistical Considerations ..............................................................................17 
4.1. 
Definition of Variables ...................................................................................................17 
4.1.1. 
Baseline ...........................................................................................................................17 
4.1.2. 
Change and Percent Change from Baseline ....................................................................17 
4.1.3. 
Study Days ......................................................................................................................17 
4.2. 
Analysis Windows ..........................................................................................................18 
4.3. 
Adjustment for Covariates ..............................................................................................18 
4.4. 
Handling Missing Data ...................................................................................................18 
4.4.1. 
Handling of Missing Data/Intercurrent Events for Efficacy 
Variables .........................................................................................................................18 
4.4.2. 
Imputation of Incomplete Medication/AE Dates ............................................................18 
4.5. 
Multiple Study Centers ...................................................................................................19 
5.
Demographic and Baseline Characteristic Analyses .................................................20 
5.1. 
Subject Disposition .........................................................................................................20 
5.2. 
Protocol Deviations.........................................................................................................20 
5.3. 
Demographic and Baseline Characteristics ....................................................................20 
5.4. 
Medical and Surgical History .........................................................................................21 
5.5. 
Prior and Concomitant Medications/Procedures ............................................................21 
6.
Efficacy Analyses ..........................................................................................................22 
6.1. 
Primary Efficacy Endpoints Analysis .............................................................................22 
6.1.1. 
Definition of Endpoints...................................................................................................22 
6.1.2. 
Statistical Hypotheses .....................................................................................................22 
6.1.3. 
Handing of Missing Data/Intercurrent Events for Efficacy 
Variables .........................................................................................................................22 
6.1.4. 
Multiplicity Adjustment ..................................................................................................25 
6.1.5. 
Primary Analysis .............................................................................................................25 
6.1.6. 
Sensitivity Analyses ........................................................................................................26 
6.1.7. 
Summary of Planned Analyses .......................................................................................28 
6.1.8. 
Subgroup Analyses .........................................................................................................30 
6.2. 
Secondary Efficacy Endpoints Analyses ........................................................................30 


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6.3. 
Other Efficacy Endpoints Analyses ................................................................................31 
7. 
Safety Analyses ..............................................................................................................33 
7.1.1. 
Extent of Exposure ..........................................................................................................33 
7.1.2. 
Adverse Events ...............................................................................................................33 
7.1.3. 
Best Spectacle Corrected Visual Acuity (BSCVA) ........................................................34 
7.1.4. 
Slit Lamp Examination and Implant Assessment ...........................................................34 
7.1.5. 
Gonioscopy .....................................................................................................................36 
7.1.6. 
Ophthalmoscopy .............................................................................................................37 
7.1.7. 
Visual Field .....................................................................................................................37 
7.1.8. 
Vertical Cup-to-Disc Ratio .............................................................................................37 
7.1.9. 
Pachymetry .....................................................................................................................38 
7.1.10. Specular Microscopy ......................................................................................................38 
7.1.11. Conjunctival Hyperemia Assessment .............................................................................38 
7.1.12. Iris Color, Eyelash and Periorbital Assessments ............................................................39 
8. 
Other Analyses ..............................................................................................................40 
8.1.1. 
Plasma Sample ................................................................................................................40 
9. 
Interim Analysis ............................................................................................................40 
11. 
Supporting Documentation ..........................................................................................45 
12. 
References ......................................................................................................................48 
 


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List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BSCVA 
Best Spectacle Corrected Visual Acuity 
C/D 
Cup-to-Disc 
CI 
Confidence Interval 
COV 
Coefficient of Variation  
CRF 
Case Report Form 
CS 
Compound Symmetry 
dB 
Decibels  
ECD 
Endothelial Cell Density 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
ICE 
Intercurrent Events 
IOP 
Intraocular Pressure 
ITT 
Intent-To-Treat 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MCMC 
Monte Carlo Markov Chain 
MNAR 
Missing Not At Random 
mmHg 
Millimeters of Mercury 
MMRM 
Mixed Model for Repeated Measures 
NRI 
Non-Responder Imputation 
OAG 
Open-Angle Glaucoma 
OC 
Observed Case 


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OHT 
Ocular Hypertension 
PP 
Per-Protocol Analysis set 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
 
 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TOEPH 
Toeplitz 
UN 
Unstructured 
VF 
Visual Field 


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Version History 
This Statistical Analysis Plan (SAP) for GC-009 is based on the protocol dated on 16SEP2016. 


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Statistical Analysis Plan 06JAN2022 
 
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1. 
Introduction 
This Phase 2 study evaluates the safety and efficacy of two intraocular implants that elute 
travoprost at different rates in subjects with open-angle glaucoma (OAG) or ocular hypertension 
(OHT).  The study duration is 36 months postoperative.  One database lock will occur after all 
subjects have either completed the Month 36 visit or discontinued prematurely. 
An analysis will be conducted after all subjects either completed the Month 3 visit or have 
discontinued prematurely prior to Month 3.  At that time, the randomization code will be 
unmasked to the project team after all the data queries related to the efficacy and safety outcomes 
are resolved and corresponding data revisions are completed in the database.   
This statistical analysis plan provides details of the planned analyses to be performed at the time 
of the Month 36 database lock. Shells of tables, listings and figures are presented in a separate 
document. 
This document is based on Protocol Amendment 2 (16 September 2016). The statistical 
definitions and analytical methods described in this SAP supersede that in the protocol. Any 
revisions to the primary endpoint analyses and significant revisions to the secondary endpoint 
analyses will be made prior to the database lock. Reasons for such revisions will be described in 
the final Clinical Study Report (CSR). 
 
Protocol and Amendment History 
Version 
Approval Date 
Original Protocol 
14 November 2015 
Amendment 1 
08 July 2016 
Amendment 2 
16 September 2016 
 






















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5. 
Demographic and Baseline Characteristic Analyses 
5.1. 
Subject Disposition 
Reasons for screen-failure (including baseline-failure, i.e., subjects enrolled but not randomized) 
will be tabulated. 
Exit status will be classified as completed or discontinued (including reason for discontinuation) 
for each randomized subject. The reasons for premature discontinuation are:  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Exit status will be summarized as number and percent by treatment group and overall for the ITT 
analysis set. 
The number of subjects who were randomized and the number of subjects within each analysis 
set (ITT, Safety, and PP) will be summarized by treatment group. 
Subject disposition data will be provided in a listing. A separate listing describing each subject’s 
inclusion or exclusion status for each of the analysis sets will also be provided.   
5.2. 
Protocol Deviations 
Protocol deviations will be captured in the eCRF and reviewed by medical monitor during the 
study. Classification between major or minor deviations will be decided by the study team prior to 
database lock. Subjects with major protocol deviations will be excluded from PP analysis set. 
All protocol deviations will be listed and summarized by type and treatment group for the ITT 
analysis set. 
5.3. 
Demographic and Baseline Characteristics 
Demographic and baseline subject characteristics will be summarized for the ITT analysis set. 
Demographics will include age, sex with child-bearing potential for females, race, and ethnicity.  
The baseline clinical characteristics include the following variables: 
 Type of disease (OAG or OHT) 
 Disease Duration from Time of Diagnosis (years)  
 
 
 Baseline Study Eye IOP 
 Baseline best spectacle corrected visual acuity in study eye - LogMAR 
 Iris Color for study eye 
















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6.1.7. Summary of Planned Analyses 


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7. 
Safety Analyses 
The safety analyses will be based on the safety analysis set. 
7.1.1. 
Extent of Exposure 
Duration of exposure to study treatment in days will be calculated using the study exit date – 
surgery date + 1. If the study exit date is missing for subjects with early termination, then the 
date of last visit will be used as the study exit date. Study duration will be summarized as 
continuous variable by treatment group for the Safety analysis set. A subject listing will be 
provided. 
7.1.2. 
Adverse Events 
All adverse event (AE) summaries will be restricted to Treatment Emergent Adverse Events 
(TEAE), which are defined as those AEs that occurred on/after the initial treatment at Visit 3. 
Verbatim terms reported by the study sites will be mapped to system organ classes (SOC) and 
preferred terms assigned using MedDRA (Medical Dictionary for Regulatory Activities) 
 
for summary purposes.  The adverse event listings will be displayed by treatment group.  
The number and of percentage subjects experiencing a particular event will be presented.   
 
For a given AE and subject, if more than 1 severity grade is reported, the highest severity  
grade will be used for analysis. 
 
If a subject experienced more than 1 relationship within an AE, the subject is counted once under 
maximum relationship.  AEs with a missing relationship will be considered related for this 
summary; events classified as ‘possibly’, ‘probably’ or ‘definitely’ from eCRF will be 
considered ‘related’. 
 
Adverse events will be classified into ocular AEs and non-ocular/non-study eye AEs. An ocular 
AE will be determined as indicated on the AE form of eCRF for the study eye only; a non-
ocular/non-study eye AEs will include AEs with primary SOCs of eyes for non-study eye and 
AEs with primary SOCs not for eye. 
 
All TEAEs, ocular TEAEs and non-ocular/non-study eye TEAEs will be summarized by 
treatment group separately in the following tables: 
 
• Summary of adverse events 
• TEAE by SOC and preferred term 
• TEAE by SOC, preferred term and maximum severity.   
• TEAE by SOC, preferred term and relationship (Related/Not Related) to study 
treatment.   
• Serious TEAEs by SOC and preferred term. 
• Ocular TEAEs by preferred term. 
 
The TEAE listings will be prepared, sorted chronologically within subjects for the following 
types of AEs. Each listing will be displayed by treatment group. 














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8. 
Other Analyses 
8.1.1. 
Plasma Sample 
Blood sampling will be performed to evaluate systemic drug concentrations of the travoprost 
acid in subjects’ plasma at the baseline, Day 10, Month 3, and Month 12 examinations. The 
drug concentration levels will be presented in a listing.
9. 
Interim Analysis 
No interim analysis is planned for this study. 




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Statistical Analysis Plan 06JAN2022 
 
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Statistical Analysis Plan 06JAN2022 
 
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Statistical Analysis Plan 06JAN2022 
 
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