Conditions: Glaucoma and Ocular Hypertension
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
This is a multiple cohort study that will evaluate the safety and efficacy of ENV515 travoprost XR in patients with open-angle glaucoma or ocular hypertension.

Detailed description:

Arms:
arm 1: ENV515-1 and ENV515-3 implants in Study Eye for 28 days arm 2: Two ENV515-3 implants in Study Eye for 12 months with optional 6 month and 3 month extensions (total of 21 months) arm 3: One or two ENV515-3-2 implants in Study Eye with optional 6 months and additional 6 month extension (total of 24 months)

Interventions: intervention 1: ENV515-3 Travoprost XR intervention 2: ENV515-1 Travoprost XR intervention 3: ENV515-3-2 Travoprost XR
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 
ENVISIA THERAPEUTICS INC. 
Clinical Study Protocol ENV515-01 Incorporating Amendment 10 
Project: 
ENV515 
Compound 
Number/Name: 
ENV515-1, ENV515-3, and ENV515-3-2 (travoprost) Intracameral 
Implants 
Protocol Number: 
ENV515-01 
Protocol Title: 
A Multi-Center, Three-Stage, Open-Label, Prospective, Active-
Comparator-Controlled Phase 2a Study of ENV515 (travoprost) 
Intracameral Implant in Patients with Bilateral Ocular Hypertension or 
Early Primary Open Angle Glaucoma 
Sponsor: 
Envisia Therapeutics Inc. 
Research Triangle Park, NC 27709 
919-219-6448 
Medical Monitor: 
M. Lynn Smiley, MD 
Tel: 844-677-3683 
Fax: 919-973-1441 
Email:  lynn.smiley@envtx.com 
Author: 
Steven Neilson, MS, Consultant, Clinical Operations 
Kristin Blackwell, RAC, Consultant, Regulatory Affairs and Quality 
Assurance 
Issue Date: 
Original Protocol: 
October 31, 2014 
Amendment 01: 
January 20, 2015 
Amendment 02: 
June 2, 2015 
Amendment 03: 
October 14, 2015 
Amendment 04: 
July 28, 2016 
Amendment 05: 
November 10, 2016 
Amendment 06:         December 29, 2016 
Amendment 07:         April 13, 2017 
Amendment 08:         August 23,, 2017 
Amendment 09:         November 30, 2017 
Amendment 10:  
February 19, 2018 
IND No: 
119347 
This study will be conducted in accordance with the protocol and in compliance with Good 
Clinical Practice (GCP), International Conference on Harmonization (ICH) guidelines, and any 
other applicable regulatory requirements.  Envisia will also continue to support the principles of 
the Declaration of Helsinki. 
CONFIDENTIAL 
This document contains confidential information that is the property of Envisia Therapeutics Inc., and must not be 
disclosed to anyone other than the recipient clinical investigator(s) and their designees, members of the Institutional 
Review Board/ Ethics Committee, regulatory Health Authority, or consultant.  This information must not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of 
Envisia Therapeutics Inc. 




 
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INVESTIGATOR PROTOCOL AGREEMENT 
 
Protocol Title:  A Multi-Center, Three-Stage, Open-Label, Prospective, Active-
Comparator-Controlled Phase 2a Study of ENV515 (travoprost) Intracameral Implant in 
Patients with Bilateral Ocular Hypertension or Early Primary Open Angle Glaucoma 
 
Protocol Number:  ENV515-01 Incorporating Amendment 10 
 
I have reviewed and understand the ENV515-01 protocol and the most current 
Investigator’s Brochure.  I will administer the protocol in accordance with ICH, FDA, and 
local regulations and guidelines.  I will keep the information provided to me within this 
protocol and by Envisia Therapeutics staff, their representatives, and designees 
confidential. 
______________________________________________________ 
______________ 
Principal Investigator’s Signature 
 
 
 
 
 
 
 
 
 
Date 
Name (print):  _________________________________________ 
Clinical Site/Institution:  _________________________________ 
Address:  ______________________________________________ 
 ______________________________________________ 
 ______________________________________________ 


 
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ENV515-01 PHASE 2A CLINICAL STUDY, COHORT 1 
Cohort 1 Protocol Synopsis 
Investigational Product:  ENV515-1 and ENV515-3 (Travoprost) Intracameral Implant 
Phase:  2a 
Study Objective: 
• 
Evaluate the safety, tolerability, efficacy, aqueous humor PK, systemic exposure, and remaining travoprost in 
ENV515 implants following a single dose of 4 dose levels of ENV515 (travoprost) intracameral implants/eye 
in patients with bilateral ocular hypertension or primary open-angle glaucoma 
Clinical Hypotheses: 
• 
A single dose of ENV515 (travoprost) Intracameral Implant is comparable to TRAVATAN Z ophthalmic 
solution dosed once daily in the control of IOP over 25 days in patients with bilateral ocular hypertension or 
primary open-angle glaucoma 
• 
ENV515 (travoprost) Intracameral Implant has an acceptable safety profile 
Study Design: 
Structure:  Cohort 1, the first-time-in-human Phase 2a clinical study conducted as a multicenter, randomized, open-
label, parallel-group, dose-ranging, fellow-eye active-comparator-controlled, 28-day Phase 2a trial of 4 dose levels 
of ENV515 (travoprost) Intracameral Implant.  Glaucoma patients scheduled for cataract removal will be dosed 
unilaterally in the study eye (pre-surgical eye) with ENV515 4 weeks prior to the cataract surgery and the implants 
will be retrieved during the cataract surgery. 
Duration of Patient Participation:  Approximately 10 to 12 weeks including up to a 42-day washout period, 
implantation/treatment administration day, 25 day primary efficacy and safety evaluation period post initial dose of 
ENV515 in the study eye, implant removal during cataract surgery on Day 28, and a safety follow-up for up to 
2 weeks. 
Study Treatment Investigational Product:  ENV515 (travoprost) Intracameral Implant administered into the study 
eye as a single, unilateral dose via intracameral injection on Day 1 
Reference Product:  TRAVATAN Z administered into the non-study eye 
Dosage/Dose Regimen/Treatment Groups: 
• 
4 dose levels of ENV515 (travoprost) Intracameral Implant achieved via the following numbers and sizes 
of implants:  28.2 µg (2 ENV515-3 implants), 42.3 µg (3 ENV515-3 implants), 42.5 µg (1 ENV515-1 
implant), and 85.0 µg (2 ENV515-1 implants). 
• 
Control Group:  TRAVATAN Z ophthalmic solution administered QD daily in the non-study, fellow eye 
 
Rescue Therapy:  Both the study and non-study eyes may be treated at any time, at the investigator’s discretion, if it 
is considered to be in the best interest of the patient. 


 
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Randomization/Stratification:  To minimize bias, patients were assigned to 1 of the 4 dose levels of ENV515 within 
each investigative site.  The non-study eye received TRAVATAN Z. 
Visit Schedule:  Visit schedule encompasses Screening Visit 1 (Day -35 to -28) followed by 4-week IOP-lowering 
medication washout period with up to 2-week additional extension to allow full washout, Baseline Visit 2 (Day -7 to 
-1), Randomization/ Treatment Visit 3 ( Day 1), Treatment Visit 4 (Day 3 ± 1 day), Treatment Visit 5 
(Day 7 ± 1 day), Treatment Visit 6 (Day 14 ± 1 day), Treatment Visit 7 (Day 21 ± 1 day), Treatment Visit 8 (Day 25 
± 1 day), Surgery Visit 9 (Day 28 ± 1 day), Follow-up Visit 10 (Day 33 to 38 ± 1 day), and Follow-up Visit 11 (Day 
42 to 49 ± 1 day) for a total of 11 visits. 
_____________________________________________________________________________________ 
Study Population Characteristics: 
Number of Patients:  Following successful screening, approximately 20 patients were enrolled into the study within 
the United States. 
Condition/Disease:  The study population consisted of patients with a diagnosis of bilateral ocular hypertension or 
primary open-angle glaucoma who were currently being treated with a topical prostaglandin analogue (PGA) in both 
eyes and who were scheduled for cataract surgery in their study eye. 
Inclusion Criteria: 
1. Provide written informed consent prior to study procedures. 
2. Are between 18 and 85 years of age. 
3. Have a willingness to comply with the investigator’s instructions, attend study visits, and stop prior eye 
medications to treat glaucoma and/or ocular hypertension. 
4. If female, patient must be non-pregnant and non-lactating, and those of childbearing potential must be 
using an acceptable method of birth control (i.e., an intrauterine contraceptive device with a failure rate of 
<1%, hormonal contraceptives, or a barrier method).  If a female patient is abstinent, she must agree to use 
one of the acceptable methods if she becomes sexually active. 
5. Have a diagnosis of bilateral ocular hypertension or mild to moderate primary open-angle glaucoma and 
have open normal appearing anterior chamber angles (Shaffer classification Grade 3 or 4, angle of 
approach 20° or larger). 
6. Are currently treated with topical PGA for ocular hypertension. 
7. At the Baseline Visit after washout (Visit 2), have IOP measurements that meet all of the following: 
• 
Have an IOP at 8:00 a.m. (±30 minutes) and at 10:00 a.m. (±30 minutes) between 22-34 mm Hg in 
both eyes with a ≤4 mm Hg difference between the eyes 
• 
Have an IOP at 4:00 p.m. (±30 minutes) between 19-34 mm Hg in both eyes with a ≤4 mm Hg 
difference between each eye 
8. Have an IOP ≤34 mm Hg in each eye at all other time points prior to the Baseline Visit (Visit 2). 


 
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9. At the Screening Visit (Visit 1), have an IOP in both eyes that is considered to be safe, so that clinical 
stability of vision and the optic nerve is likely throughout the trial. 
10. Have endothelial cell counts of at least 2000 cells/mm2 and normal endothelial cell morphology at the 
Screening Visit (Visit 1) as evaluated by central reading center. 
11. Patient is a candidate for and has been scheduled for cataract extraction in a single eye within 60 days of 
Visit 1*. 
* Following cataract removal, the patient may undergo additional procedures (e.g., iStent insertion). 
Exclusion Criteria: 
1. Are currently diagnosed with closed angle glaucoma, exfoliation syndrome or exfoliation glaucoma, and 
pigment dispersion or secondary glaucoma. 
2. Have a history of glaucoma-related surgery (trabeculectomy, cryotherapy, laser iridotomy, etc.). 
3. Have had intraocular conventional surgery, intraocular laser surgery, corneal refractive surgery or eyelids 
surgery within the past 3 months. 
4. Are currently diagnosed with active infectious/noninfectious conjunctivitis, keratitis, uveitis, or moderate to 
severe blepharitis in either eye.  (Chronic mild blepharitis or injection related to mild blepharitis, lid lag, 
mild dry eye or seasonal allergies are allowed.) 
5. Are currently taking or have taken corticosteroids (oral, ocular, injectable, IV and/or topical) or used 
dermatology formulations of steroids in the vicinity of eyes in the 1 month prior to Visit 1 with the 
exception of inhaled, intranasal, or topical (dermal) steroids if on a stable dose; or have a history of chronic 
ocular corticosteroid (topical or intraocular) use within the past year. 
6. Have a requirement for any ocular medications that are specifically disallowed in this protocol for any 
condition during the study or within the specified timeframe prior to Visit 2. 
7. Have a history of recurrent corneal erosion syndrome, multiple corneal abrasions, or an abrasion that was 
slow to heal. 
8. Have severe glaucoma with a mean defect (MD) worse than -8.0, central island of vision, or otherwise 
severe glaucoma that would not tolerate a possible short-term increase in intraocular pressure (IOP). 
9. According to the investigator’s best judgment, are at risk for progression of glaucoma, visual field (VF) or 
visual acuity (VA) worsening as a consequence of participation in the trial. 
10. Have any abnormality preventing reliable applanation tonometry in either eye. 
11. Have any corneal opacity or are uncooperative in such a way that restricts adequate examination of the 
ocular fundus or anterior chamber in either eye. 
12. Are unwilling to discontinue use of contact lenses at least 2 days prior to Visit 2 for soft lenses and at least 
7 days prior to Visit 2 for rigid gas permeable (RGP) lenses through completion of the study at Visit 11. 
13. Have progressive retinal or optic nerve disease apart from glaucoma. 
14. Have any clinically significant, serious, or severe medical or psychiatric condition. 
15. Are, in the opinion of the investigator, unable or unwilling to comply with study procedures, including 
attending the scheduled study visits. 


 
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16. Have a history, or a suspected history of drug or alcohol dependence in the preceding year. 
17. Are unwilling to limit alcohol ingestion and smoking for the 8-hour period prior to and during study 
appointments after Visit 1. 
18. Have received any investigational product within the past 30 days prior to Visit 1. 
19. Have any history of allergic hypersensitivity or poor tolerance to any components of the preparations used 
in this trial such as travoprost or PLA excipients. 
20. Have a history of insufficient response to PGA topical treatment, i.e., are PGA non-responders. 
21. Are an employee of the clinical site that is directly involved in the management, administration, or support 
of this study or are an immediate family member of the same. 
22. Have a central corneal thickness greater than 600 micrometers as determined by pachymetry at the Baseline 
Visit (Visit 2). 
23. Had prior intraocular surgery or any ocular or systemic condition that may confound the study outcome per 
the investigator’s recommendation. 
Response Measures 
Primary Efficacy Measure: 
• 
Change from baseline in time-matched IOP measurements at Day 25 for study and non-study eye 
 
Secondary Efficacy Measures: 
• 
Change from baseline and percent change from baseline in time-matched IOP measurements for study eye 
and non-study at all other study time points and visits 
• 
Difference in change from baseline and percent change from baseline in time-controlled IOP measurements 
between study eye and non-study eye at all study time points and visits 
• 
Cumulative % of study and non-study eyes with at least 20, 25, and 30% reduction in IOP at all study time 
points and visits 
• 
Cumulative % of patients with IOP <18 at all time points at each study visit 
• 
Mean IOP at all visits all time points 
Safety Measures: Assessed by evaluating changes from baseline in the following: 
• 
Specular microscopy (non-contact) 
• 
Slit-lamp biomicroscopy 
• 
Corneal staining 
• 
Dilated fundus examination 
• 
Gonioscopy exam 
• 
Anterior chamber OCT exam 
• 
Pupil measurement 
• 
Pachymetry (contact) 
• 
BCVA 
• 
Visual field  


 
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• 
Physical examination 
• 
Vital signs 
• 
Non fasting clinical laboratory tests (chemistry and hematology) 
• 
Serum or urine pregnancy tests for females of childbearing potential 
• 
AEs 
 
Pharmacokinetic Measures: 
• 
Systemic exposure to travoprost via analysis of travoprost acid in plasma; 
• 
Ocular exposure to travoprost via analysis of travoprost acid in aqueous humor. 
 


 
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Table 1: 
Time and Events Schedule, Cohort 1 
Procedure 
Screening 
V1 
Day -35 
to -28 
Baseline 
V2 
-7 to -1 
Days 
Randomization/ 
Treatment 
V3 
Day 1 
Treatment 
V4 
Day 3 
+/- 1 day 
Treatment 
V5 
Day 7 
+/- 1 day 
Treatment 
V6 
Day 14 
+/- 1 day 
Treatment 
V7 
Day 21 
+/- 1 day 
Treatment 
V8 
Day 25 
+/- 1 day 
Surgery 
V9 
Day 28 
Follow-
up 
V10 
Day 33-
38 
Follow-
up 
V11 
Day 42-
49 
Informed consent 
review 
X 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
medical & ocular 
history 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication query 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events query 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA – (ETDRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pupil measurement  
X 
X 
 
 
 
X 
 
X 
 
X 
 
Slit-lamp 
biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corneal staining 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP check (8:00 a.m.) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Pachymetry (contact) 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Specular microscopy 
(non-contact) 
X1 
X 
 
 
 
X 
 
X 
 
 
X1 
Visual field  
X 
 
 
 
 
 
 
 
 
X 
 
Anterior segment OCT  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
IOP diurnal curve 
 
X2 
 
 
 
 
 
X2 
 
 
 
Dilated fundus exam 
X 
X 
 
 
 
X 
 
X 
 
X 
 


 
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Procedure 
Screening 
V1 
Day -35 
to -28 
Baseline 
V2 
-7 to -1 
Days 
Randomization/ 
Treatment 
V3 
Day 1 
Treatment 
V4 
Day 3 
+/- 1 day 
Treatment 
V5 
Day 7 
+/- 1 day 
Treatment 
V6 
Day 14 
+/- 1 day 
Treatment 
V7 
Day 21 
+/- 1 day 
Treatment 
V8 
Day 25 
+/- 1 day 
Surgery 
V9 
Day 28 
Follow-
up 
V10 
Day 33-
38 
Follow-
up 
V11 
Day 42-
49 
Physical exam 
X 
X 
 
 
 
 
 
 
 
X 
 
Vitals 
X 
X 
 
 
 
 
 
 
 
X 
 
Lab tests 
X 
X3 
 
 
 
X3 
 
 
 
X3 
 
Pregnancy test 
X 
X 
X 
 
 
 
 
 
 
X 
 
Study drug 
administration 
 
 
X 
 
 
 
 
 
 
 
 
Cataract surgery 
 
 
 
 
 
 
 
 
X 
 
 
Aqueous humor 
collection 
 
 
 
 
 
 
 
 
X 
 
 
Implant recovery 
 
 
 
 
 
 
 
 
X 
 
 
Dispense  
TRAVATAN Z 
 
 
X 
 
 
 
 
 
 
 
 
Collect  
TRAVATAN Z 
 
 
 
 
 
 
 
X 
 
 
 
Receive pre-surgical 
medications 
 
 
 
 
 
 
 
X 
 
 
 
Dismiss patient, 
complete exit form 
 
 
 
 
 
 
 
 
 
 
X 
 
1 
Non-contact specular microscopy can be performed anytime during the site visit. 
2 
IOP will be measured at 8 a.m., 10 a.m., and 4 p.m. for the diurnal curve endpoint. 
3 
Blood draws will be conducted prior to the daily administration of the TRAVATAN Z into the non-study eye.  Samples collected as Visits 6 and 10 will 
additionally be used to determine the systemic exposure to travoprost as described in Sections 15.1.7 and 1.6 .


 
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ENV515-01 PHASE 2A CLINICAL STUDY, COHORT 2 
Cohort 2 Protocol Synopsis 
Investigational Product:  ENV515-3 (Travoprost) Intracameral Implant 
Phase:  2a 
Study Objective: 
• 
Evaluate the long-term safety, tolerability, efficacy, and systemic exposure to travoprost following a unilateral, 
single dose of two ENV515-3 (travoprost) intracameral implants in the study eye in patients with bilateral 
ocular hypertension or primary open-angle glaucoma 
Clinical Hypotheses: 
• 
A single dose of ENV515-3 (travoprost) Intracameral Implant is numerically comparable to timolol maleate 
0.5% ophthalmic solution dosed twice daily in the control of IOP over 12 months in patients with bilateral 
ocular hypertension or primary open-angle glaucoma 
• 
ENV515-3 (travoprost) Intracameral Implant has an acceptable safety profile 
Study Design: 
Structure:  The Cohort 2 phase of the Phase 2a clinical study is an up to 12-month, prospective, open-label, active-
comparator-controlled, multi-center study of ENV515-3 (travoprost) Intracameral Implant.  While the Cohort 1 
enrolled glaucoma patients scheduled for cataract removal and the ENV515 implants were removed after 28 days 
during the cataract procedure, the Cohort 2 phase of the study will enroll glaucoma patients without the need for 
cataract surgery in order to study ENV515 over its entire duration of IOP-lowering efficacy, or up to 12 months after 
the first dose. 
Duration of Patient Participation:  Approximately a maximum of 14 months including up to a 49 day washout 
period, implantation/treatment administration day, 3 month primary efficacy and safety evaluation period post initial 
dose of ENV515 in the study eye, and a follow-up for 9 months after the 3 month primary efficacy and safety 
evaluation period 
Study Treatment Investigational Product:  ENV515-3 (travoprost) Intracameral Implant 
Reference Product:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 
Dosage/Dose Regimen/Treatment Groups: 
ENV515-3 Group:  Two ENV515-3 (travoprost) implants/eye administered into the study eye as a single, unilateral 
dose via intracameral injection on Day 1 
Control Group:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 
Rescue Therapy:  Rescue therapy may be allowed in the study eye for a change from baseline in IOP of <20% on 
any two visits after Day 1 separated by at least 4 weeks.  Both the study and non-study eyes may be treated at any 
time, at the investigator’s discretion, if it is considered to be in the best interest of the patient. 


 
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Randomization/Stratification:  No randomization is required as this is an open-label, single arm study. 
Visit Schedule:  Visit schedule encompasses Screening Visit 1 (Day -49 to -29) followed by 4-week IOP-lowering 
medication washout period with up to a 2-week additional extension to allow full washout, Baseline Visit 2 (Day -5 
to -1), Dosing Visit 3 (Day 1), Treatment Visit 4 (Day 2 + 3 days), Treatment Visit 5 (Day 14 ± 3 days), Treatment 
Visit 5a (Day 28 ± 3 days), Treatment Visit 6 (Day 42 ± 3 days), Treatment Visit 7 (Day 84 ± 3 days), Treatment 
Visits 8-15 (every 28 days from Month 4 to Month 11), and Exit Visit 16 (Month 12) for a total of 17 visits.  
Patients may be exited sooner than Month 12 if they have received rescue therapy, their IOP in the study eye is well-
controlled, no implant remnants are visible by gonioscopy during two consecutive visits, and no adverse events 
(AEs) are present that require continued monitoring. 
_____________________________________________________________________________________ 
Study Population Characteristics: 
Number of Patients:  Following successful screening, approximately 5-10 patients will be dosed into the open-label 
study.  
Condition/Disease:  The study population consists of patients with a diagnosis of bilateral ocular hypertension or 
primary open-angle glaucoma who are currently being treated with a topical PGA in both eyes. 
Inclusion Criteria: 
1. Male or female between 18 and 85 years of age. 
2. Have a diagnosis of bilateral ocular hypertension or primary open-angle glaucoma. 
3. Normal appearing anterior chamber angles (Shaffer classification Grade 3 or 4, with an angle of at least 20° 
determined by gonioscopy, and confirmed to have an open angle as determined by anterior chamber OCT 
evaluated by a central reading center prior to dosing. 
4. Are currently treated with topical PGA for ocular hypertension in both eyes. 
5. Patients who in the opinion of the investigator: have an IOP in both eyes that is considered to be adequately 
controlled at the Screening Visit (Visit 1); can be safely withdrawn from IOP medications in both eyes 
during the washout period, and who are not considered to be at significant risk for disease progression 
throughout the trial. 
6. At the Baseline Visit after washout (Visit 2), have IOP measurements that meet all of the following: 
a) Have an IOP at 8:00 a.m. (±30 minutes) and at 10:00 a.m. (±30 minutes) between 22 and 34 mm 
Hg in both eyes with a ≤4 mm Hg difference between the eyes 
b) Have an IOP at 4:00 p.m. (±30 minutes) between 19 and 30 mm Hg in both eyes with a ≤4 mm Hg 
difference between each eye 
7. At the Dosing Visit (Visit 3), have IOP measurement that is between 22 and 34 mm Hg in both eyes with a 
≤4 mm Hg difference between the eyes. 
8. Have endothelial cell counts of at least 2000 cells/mm2 and normal endothelial cell morphology prior to 
dosing as evaluated by central reading center. 
9. If female, patients must be incapable of pregnancy because of hysterectomy, tubal ligation or have been 
amenorrheic for at least 2 years.  Female patients much have a negative pregnancy test, and not be nursing.  


 
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If female patient is capable of pregnancy, she must use effective (e.g., double barrier) method of birth 
control for the duration of the study. 
10. Must be able to provide a written informed consent to participate in the study, in accordance with the 
international Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and local 
regulations, before initiating any study-related procedures. 
Exclusion Criteria: 
1. Are diagnosed with closed angle glaucoma, exfoliation syndrome or exfoliation glaucoma, pigment 
dispersion or secondary glaucoma. 
2. Are insufficiently responsive to PGA topical treatment, i.e., are PGA non-responders. 
3. Have a history of glaucoma-related surgery (e.g., trabeculectomy, cryotherapy, laser iridotomy and 
minimally invasive procedures including shunts/stents). 
4. Have severe glaucoma with a mean defect (MD) worse than -8.0, a central island of vision, or otherwise 
severe glaucoma that would not tolerate a short-term increase in IOP. 
5. According to the investigator’s best judgment, are at risk for progression of glaucoma, VF or VA 
worsening as a consequence of participation in the trial. 
6. Have any abnormality preventing reliable applanation tonometry in either eye. 
7. Have a central corneal thickness less than 500 micrometers or greater than 600 micrometers as determined 
by pachymetry at the Screening Visit (Visit 1). 
8. Have a history of recurrent corneal erosion syndrome, multiple corneal abrasions, or an abrasion that was 
slow to heal. 
9. Have had intraocular conventional surgery, intraocular laser surgery, corneal refractive surgery or eyelids 
surgery within the past 3 months. Complicated cataract surgery that resulted in intraocular lens placement 
outside the capsular bag or a break in the posterior capsule is not allowed. 
10. Are currently diagnosed with active infectious/noninfectious conjunctivitis, or moderate to severe 
blepharitis in either eye.  (Chronic mild blepharitis or injection related to mild blepharitis, lid lag, mild dry 
eye or seasonal allergies are allowed.) 
11. Are currently taking or have taken corticosteroids (oral, ocular, injectable, IV) or used dermatology 
formulations of steroids in the vicinity of eyes in the 1 month prior to Screening (Visit 1); have a history of 
chronic ocular corticosteroid (topical or intraocular) use within the past year. Inhaled, intranasal, or topical 
(dermal) steroids not in the vicinity of the eyes is permissible if on a stable dose for at least 1 month prior 
to Screening (Visit 1). 
12. Have any media opacity or are uncooperative in such a way that restricts adequate examination of the 
ocular fundus or anterior chamber in either eye. 
13. Are unwilling to discontinue use of contact lenses for the duration of their study participation. 
14. Have progressive retinal or optic nerve disease apart from glaucoma or history of uveitis or keratitis.  
15. Have any history of allergic hypersensitivity or poor tolerance to any components of the preparations used 
in this trial such as travoprost or poly-lactic acid or similar excipients, topical anesthetic (proparacaine 
0.5% or equivalent), iodine, timolol maleate and Vigamox® (or generic equivalent). 


 
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16. Have a requirement for any ocular medications that are specifically disallowed in this protocol for any 
condition during the study or within the specified timeframe prior to Baseline (Visit 2). 
17. Have a history, or a suspected history of drug or alcohol dependence in the preceding year. 
18. Currently using or used marijuana in the past 30 days prior to Screening (Visit 1). 
19. Have received any investigational product within the past 30 days prior to Screening (Visit 1). 
20. Are an employee of the clinical site that is directly involved in the management, administration, or support 
of this study or are an immediate family member of the same 
21. Patients who, per investigator’s judgment, are not good clinical trial candidates due to personal (e.g., 
perceived willingness or ability to comply with protocol, significant traveling distance to medical center) 
and/or medical (e.g., mental illness, other non-ocular medical conditions, or laboratory abnormalities that 
might negatively impact trial participation or outcome) conditions that would likely impede the patient’s 
successful study completion or planned analyses. 
Response Measures: 
Primary Efficacy Measure: 
• 
Change from baseline in time-matched IOP measurements at Week 2, Week 6, and Week 12 (Day 14, 42, 
and 84) for study and non-study eye  
 
Secondary Efficacy Measures: 
• 
Change from baseline and percent change from baseline in time-matched IOP measurements for study eye 
and non-study at all other study time points and visits 
• 
Difference in change from baseline and percent change from baseline in time-controlled IOP measurements 
between study eye and non-study eye at all study time points and visits 
• 
Cumulative % of study and non-study eyes with at least 20, 25, and 30% reduction in IOP at all study time 
points and visits 
• 
Cumulative % of patients with IOP <18 at all time points at each study visit 
• 
Mean IOP at all visits all time points 
 
Safety Measures: Assessed by evaluating changes from baseline in the following: 
• 
Specular microscopy (non-contact) 
• 
Slit-lamp biomicroscopy 
• 
Corneal staining 
• 
Dilated fundus examination 
• 
Gonioscopy exam 
• 
Anterior chamber OCT exam 
• 
Pupil measurement 
• 
Pachymetry (contact) 
• 
BCVA 
• 
Visual Field 


 
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• 
Body system assessment 
• 
Vital signs 
• 
Non fasting clinical laboratory tests (chemistry, hematology, and urinalysis) 
• 
Urine pregnancy tests for females of childbearing potential 
• 
AEs 
Pharmacokinetic Measures: 
• 
Systemic exposure to travoprost via analysis of travoprost acid in plasma 


 
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Table 2: 
Time and Events Schedule, Cohort 2 
Note: V16/Month 12 Time and Events Schedule should only be used if patients are not continuing into the Cohort 2 Study Extension 1 and plan to exit the study 
at V16/Month 12. If the patient is continuing into the Cohort 2 Study Extension 1, V16/Month 12 should follow the Time and Events Schedule in the Cohort 2 
Study Extension 1 Synopsis, Table 3. 
Procedure 
Screening 
V1 
Day -49 
to -29 
Baseline 
V2 
Day -7 to 
-1 
Dosing 
V3 
Day 1 
Treatment 
V4, 
5,5a,6 
Day 
2,14,28, 
42 
+/- 3 days 
Treatment 
V7 
Day 84 
+/- 7 days 
Treatment 
V8,9 
Month  
4,5 
+/- 7 days 
Treatment 
V10 
Month 6 
+/- 7 days 
Treatment 
V11 
Month 7 
+/- 7 days 
Treatment 
V12 
Month 8 
+/- 7 days 
Treatment 
V13 
Month 9 
+/- 7 days 
Treatment 
V14 
Month 10 
+/- 7 days 
Treatment 
V15 
Month 11 
+/- 7 days 
Exit/Early 
Exit8 
V16 
Month 12 
+/- 7 days 
Informed 
consent 
review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demo-
graphics/ 
medical & 
ocular 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
query 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
events query 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA – 
(ETDRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pupil 
measure-
ment  
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
Slit-lamp 
biomicro-
scopy 
X 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corneal 
staining 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy 
photographs 
(at selected 
sites) 
 
 
 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
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Procedure 
Screening 
V1 
Day -49 
to -29 
Baseline 
V2 
Day -7 to 
-1 
Dosing 
V3 
Day 1 
Treatment 
V4, 
5,5a,6 
Day 
2,14,28, 
42 
+/- 3 days 
Treatment 
V7 
Day 84 
+/- 7 days 
Treatment 
V8,9 
Month  
4,5 
+/- 7 days 
Treatment 
V10 
Month 6 
+/- 7 days 
Treatment 
V11 
Month 7 
+/- 7 days 
Treatment 
V12 
Month 8 
+/- 7 days 
Treatment 
V13 
Month 9 
+/- 7 days 
Treatment 
V14 
Month 10 
+/- 7 days 
Treatment 
V15 
Month 11 
+/- 7 days 
Exit/Early 
Exit8 
V16 
Month 12 
+/- 7 days 
Pachymetry 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Specular 
microscopy 
X2 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X2 
Visual field  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Anterior 
chamber 
OCT  
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
IOP diurnal 
curve 
X3 
X 
X3 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dilated 
fundus exam 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Body 
System 
Assessment 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
Vitals 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
Hematology, 
chemistry 
and 
urinalysis 
X 
X 
 
X5 
X 
 
X 
X 
 
X 
 
 
X 
Plasma 
collection 
for PK 
analyses 
 
X 
 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
test 
X 
X 
 
X5 
 
 
 
 
 
 
 
 
X 
Study drug 
administra-
tion 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Timolol 
maleate 
0.5% 
distribution 
and 
collection6 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
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Procedure 
Screening 
V1 
Day -49 
to -29 
Baseline 
V2 
Day -7 to 
-1 
Dosing 
V3 
Day 1 
Treatment 
V4, 
5,5a,6 
Day 
2,14,28, 
42 
+/- 3 days 
Treatment 
V7 
Day 84 
+/- 7 days 
Treatment 
V8,9 
Month  
4,5 
+/- 7 days 
Treatment 
V10 
Month 6 
+/- 7 days 
Treatment 
V11 
Month 7 
+/- 7 days 
Treatment 
V12 
Month 8 
+/- 7 days 
Treatment 
V13 
Month 9 
+/- 7 days 
Treatment 
V14 
Month 10 
+/- 7 days 
Treatment 
V15 
Month 11 
+/- 7 days 
Exit/Early 
Exit8 
V16 
Month 12 
+/- 7 days 
Exit patient, 
complete 
exit form 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 
Slit lamp exam is performed twice during Dosing (Visit 3), before and after ENV515 administration. 
2 
Specular microscopy is needed for all study eyes on all indicated visits; for non-study eyes, it is collected only during Screening (Visit 1) and Exit/Early Exit 
(Visit 16). Additional measurements may be taken at the investigator’s discretion. 
3 
During Screening (Visit 1) and Dosing (Visit 3), only one IOP timepoint in the morning is needed (see Section 12 for specific time window). 
4 
During Day 2 (Visit 4) and Day 28 (Visit 5a), only the 8 a.m. IOP timepoint is needed. Day 14 (Visits 5) and Day 42 (Visit 6) require full diurnal evaluation. 
5 
Lab and PK samples were not collected at Day 2 (Visit 4) and Day 28 (Visit 5a). Pregnancy test is only required at Day 14 (Visit 5).  
6  
Timolol maleate 0.5% ophthalmic solution is given to the patient to take their first dose in the non-study eye the evening of the their Day 1 Dosing (Visit 3) 
then dose BID for the remaining portion of the study.  Patients will be instructed to return their used bottle(s) at each visit for accountability purposes.  A 
new supply of timolol maleate 0.5% ophthalmic solution will be provided on a monthly basis starting at Day 42 (Visit 6) through Month 11 (Visit 15). 
During post dose study visits, ensure Timolol maleate 0.5% ophthalmic solution is administered after the 8 AM IOP measurement. 
7  
Gonioscopy photographs are not collected at Day 2 (Visit 4).  
8   
V16/Month 12 Time and Events Schedule should only be used if patients are not continuing into the Cohort 2 Study Extension 1 and plan to exit the study at 
V16/Month 12. If the patient is continuing into the Cohort 2 Study Extension 1, V16/Month 12 should follow the Time and Events Schedule in the Cohort 2 
Study Extension 1 Synopsis, Table 3. 


 
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ENV515-01 PHASE 2A CLINICAL STUDY, COHORT 2 EXTENSION 1 
Cohort 2 Extension 1 Protocol Synopsis 
Investigational Product:  ENV515-3 (Travoprost) Intracameral Implant 
Phase:  2a Cohort 2 Extension 1 
Cohort 2 Study Extension 1 Objective: 
• 
Extend the ENV515-01 Ph2a Cohort 2 study duration beyond 12 months by an additional 6 months to continue 
evaluation of the ENV515-3 long term safety, efficacy, and biodissolution in patients with bilateral ocular 
hypertension or primary open-angle glaucoma 
Clinical Hypotheses: 
• 
A single dose of two ENV515-3 (travoprost) Intracameral Implants will demonstrate end of duration of IOP 
treatment effect and full biodissolution in the time period between 13 and 18 months 
Cohort 2 Study Extension 1 Design: 
Structure:  The Cohort 2 study Extension 1 will extend the ongoing 12 month Cohort 2 by 6 months for a total of 18 
months duration for up to 5 patients dosed with a single low dose of ENV515-3 in Cohort 2. The original Cohort 2 
of the Phase 2a clinical study was up to 12-month, prospective, open-label, active-comparator-controlled, multi-
center study of ENV515-3 (travoprost) Intracameral Implants. The Cohort 2 phase of the study enrolled glaucoma 
patients to study ENV515 over its entire duration of IOP-lowering efficacy, or up to 12 months after the first dose. 
Duration of Patient Participation including study Extension 1:  Approximately a maximum of 20 months including 
up to a 49 day washout period, implantation/treatment administration day, 3 month primary efficacy and safety 
evaluation period post initial dose of ENV515 in the study eye, a follow-up for 9 months, and 6 month study 
Extension 1 
Study Treatment Investigational Product:  ENV515-3 (travoprost) Intracameral Implant 
Reference Product:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 
Dosage/Dose Regimen/Treatment Groups: 
ENV515-3 Group:  Two ENV515-3 (travoprost) implants/eye administered into the study eye as a single, unilateral 
dose via intracameral injection on Day 1 
Control Group:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 
Rescue Therapy:  Rescue therapy may be allowed in the study eye for a change from baseline in IOP of <20% on 
any two visits after Day 1 separated by at least 4 weeks.  Both the study and non-study eyes may be treated at any 
time, at the investigator’s discretion, if it is considered to be in the best interest of the patient. 
Randomization/Stratification:  No randomization is required as this is an open-label, single arm study extension for 
up to 5 patients who had been dosed in ENV515-01 Cohort 2 study. 


 
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Cohort 2 Study Extension 1 Visit Schedule: Visit schedule encompasses Treatment Visits 17 to 21 (Month 13 and 
every month thereafter to Month 17) and Exit Visit 22 (Month 18). Patients may be exited sooner than Month 18 if 
they have received rescue therapy, their IOP in the study eye is well-controlled, no implant remnants are visible by 
gonioscopy during two consecutive visits, and no treatment related adverse events (AEs) are present that require 
continued monitoring. 
Response Measures in Cohort 2 Study Extension 1 (Month 12 to 18): 
Exploratory Efficacy Measure: 
• 
Change from baseline in time-matched 8 AM IOP measurements at Months 13, 14, 15, 16, 17 and 18 for 
study and non-study eye  
• 
Percent change from baseline in time-matched 8 AM IOP measurements for study eye and non-study at 
Months 13, 14, 15, 16, 17 and 18 
• 
Difference in change from baseline and percent change from baseline in time-matched 8 AM IOP 
measurements between study eye and non-study eye at all study time points and visits 
• 
Cumulative % of study and non-study eyes with at least 20, 25, and 30% reduction in 8 AM IOP at all 
study time points and visits 
• 
Cumulative % of patients with 8 AM IOP <18 at all time points at each study visit 
• 
Mean 8 AM IOP at all visits all time points 
 
Safety Measures: Assessed by evaluating changes from baseline in the following: 
• 
Specular microscopy (non-contact) 
• 
Slit-lamp biomicroscopy 
• 
Corneal staining 
• 
Dilated fundus examination 
• 
Gonioscopy exam 
• 
Anterior chamber OCT exam 
• 
Pupil measurement 
• 
Pachymetry (contact) 
• 
BCVA (ETDRS) 
• 
Visual Field 
• 
Body system assessment 
• 
Vital signs 
• 
Non fasting clinical laboratory tests (chemistry, hematology, urinalysis) 
• 
Urine pregnancy tests for females of childbearing potential 
• 
AEs 


 
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Table 3: 
Time and Events Schedule, Cohort 2 Extension 1, Months 12 to 18, Including 
New Schedule for Month 12 Visit for Patients Enrolled in the Cohort 2 
Extension 1 
Note: If the patient is continuing into the Cohort 2 Study Extension 2, V22/Month 18 should follow the Time and 
Events Schedule in the Cohort 2 Study Extension 2 Synopsis, Table 4. 
Procedure 
Treatment 
V16 
Month  
12 
+/- 7 days 
 
Treatment 
V17 
Month 
13 
+/- 7 
days 
Treatment 
V18 
Month 
14 
+/- 7 
days 
Treatment 
V19 
Month 
15 
+/- 7 
days 
Treatment 
V20 
Month 
16 
+/- 7 days 
 
Treatment 
V21 
Month 
17 
+/- 7 days 
 
Exit/Early 
Exit4 
V22 
Month 
18 
+/- 7 days 
Informed consent review 
X 
 
 
 
 
 
 
Concomitant medication query 
X 
X 
X 
X 
X 
X 
X 
Adverse events query 
X 
X 
X 
X 
X 
X 
X 
BCVA – (ETDRS) 
X 
X 
X 
X 
X 
X 
X 
Pupil measurement  
X 
 
X 
 
X 
 
X 
Slit-lamp biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
Corneal staining 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy photographs (at selected 
sites) 
X 
X 
X 
X 
X 
X 
X 
Pachymetry 
X 
 
X 
 
X 
 
X 
Specular microscopy 
X1 
 
X1 
 
X1 
X1 
X1 
Visual field  
 
 
 
 
 
 
X 
Anterior chamber OCT3 
X 
 
 
 
 
X 
X 
8 AM IOP 
X 
X 
X 
X 
X 
X 
 
IOP diurnal curve 
 
 
 
 
 
 
X 
Dilated fundus exam 
X 
 
 
 
 
 
X 
Body System Assessment 
X 
 
 
 
 
 
X 
Vitals 
X 
 
 
X 
 
 
X 
Hematology, chemistry and urinalysis 
X 
 
 
 
 
 
X 
Plasma collection for PK analyses 
 
 
 
 
 
 
X 
Urine Pregnancy test 
 
 
 
 
 
 
X 
Timolol maleate 0.5% distribution and 
collection2 
X 
X 
X 
X 
X 
X 
X 
Exit patient, complete exit form 
 
 
 
 
 
 
X 


 
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1  
Specular microscopy is needed for all study eyes on all indicated visits; for non-study eyes, it is collected only 
during Exit/Early Exit (Visit 22). Additional measurements may be taken at the investigator’s discretion. 
2   
Timolol maleate 0.5% ophthalmic solution is given to the patient to continue dosing BID for the remainder of 
the study.  Patients will be instructed to return their used bottle(s) at each visit for accountability purposes.  A 
new supply of timolol maleate 0.5% ophthalmic solution will be provided on a monthly basis through Month 17 
(Visit 21). During post dose study visits, ensure timolol maleate 0.5% ophthalmic solution is administered after 
the 8 AM IOP measurement. 
3   
Always capture the ENV515 implant(s) in the field of view of at least one OCT image. 
4         V16/Month 12 Time and Events Schedule should only be used if patients are continuing into the Cohort 2 Study 
Extension 1. If the patients are continuing into the Cohort 2 Study Extension 2, V22/Month 18 should follow 
the Time and Events Schedule in the Cohort 2 Study Extension 2 Synopsis, Table 4. 
 
 


 
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ENV515-01 PHASE 2A CLINICAL STUDY, COHORT 2 EXTENSION 2 
Cohort 2 Extension 2 Protocol Synopsis 
Investigational Product:  ENV515-3 (Travoprost) Intracameral Implant 
Phase:  2a Cohort 2 Extension 2 
Cohort 2 Study Extension 2 Objective: 
• 
Extend the ENV515-01 Ph2a Cohort 2 study duration beyond 18 months (12 month Cohort 2 + 6 month 
Extension 1) by an additional 3 months in Extension 2 to continue evaluation of the ENV515-3 long term 
safety, efficacy, and biodissolution in patients with bilateral ocular hypertension or primary open-angle 
glaucoma 
Clinical Hypotheses: 
• 
A single dose of two ENV515-3 (travoprost) Intracameral Implants will demonstrate end of duration of IOP 
treatment effect and full biodissolution in the time period between 13 and 21 months 
Cohort 2 Study Extension 2 Design: 
Structure:  The Cohort 2 study Extension 2 will extend the ongoing 18 month Cohort 2, including 12 month initial 
study and its 6 month Extension 1, by an additional 3 months for a total of 21 months duration for up to 5 patients 
dosed with a single low dose of ENV515-3 in Cohort 2. The initial Cohort 2 of the Phase 2a clinical study was up to 
12-month, prospective, open-label, active-comparator-controlled, multi-center study of ENV515-3 (travoprost) 
Intracameral Implants. This 12 month period of Cohort 2 was extended via Extension 1 by up to additional 6 
months. The Cohort 2 phase of the study enrolled glaucoma patients to study ENV515 over its entire duration of 
IOP-lowering efficacy, or up to 12 months after the first dose, all of whom have the option of enrolling sequentially 
in Extension 1 and 2 for a total of 21 months (12 months of the original Cohort 2 duration, 6 months of the 
Extension 1, and 3 months of the Extension 2).  
Duration of Patient Participation including Cohort 2 Extension 1 and Extension 2:  Approximately a maximum of 
23 months including up to a 49 day washout period, implantation/treatment administration day, 3 month primary 
efficacy and safety evaluation period post initial dose of ENV515 in the study eye, follow-up for 9 months, 6 month 
study Extension 1, and 3 month study Extension 2. 
Study Treatment Investigational Product:  ENV515-3 (travoprost) Intracameral Implant 
Reference Product:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 
Dosage/Dose Regimen/Treatment Groups: 
ENV515-3 Group:  Two ENV515-3 (travoprost) implants/eye administered into the study eye as a single, unilateral 
dose via intracameral injection on Day 1 
Control Group:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 


 
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Rescue Therapy:  Rescue therapy may be allowed in the study eye for a change from baseline in IOP of <20% on 
any two visits after Day 1 separated by at least 4 weeks.  Both the study and non-study eyes may be treated at any 
time, at the investigator’s discretion, if it is considered to be in the best interest of the patient. 
Randomization/Stratification:  No randomization is required as this is an open-label, single arm study extension for 
up to 5 patients who had been dosed in ENV515-01 Cohort 2 study Extension 1. 
Cohort 2 Study Extension 2 Visit Schedule: Visit schedule encompasses Treatment Visits 23 and 24 (Months 19 and 
20) and Exit Visit 25 (Month 21). Patients may be exited sooner than Month 21 if they have received rescue therapy, 
their IOP in the study eye is well-controlled, no implant remnants are visible by gonioscopy during two consecutive 
visits, and no treatment related adverse events (AEs) are present that require continued monitoring. 
Response Measures in Cohort 2 Study Extension 2 (Month 18 to 21): 
Exploratory Efficacy Measure: 
• 
Change from baseline in time-matched 8 AM IOP measurements at Months 19, 20 and 21 for study and 
non-study eye  
• 
Percent change from baseline in time-matched 8 AM IOP measurements for study eye and non-study at 
Months 19, 20, and 21  
• 
Difference in change from baseline and percent change from baseline in time-matched 8 AM IOP 
measurements between study eye and non-study eye at all study time points and visits 
• 
Cumulative % of study and non-study eyes with at least 20, 25, and 30% reduction in 8 AM IOP at all 
study time points and visits 
• 
Cumulative % of patients with 8 AM IOP <18 at all time points at each study visit 
• 
Mean 8 AM IOP at all visits all time points 
Safety Measures: Assessed by evaluating changes from baseline in the following: 
• 
Specular microscopy (non-contact) 
• 
Slit-lamp biomicroscopy 
• 
Corneal staining 
• 
Dilated fundus examination 
• 
Gonioscopy exam 
• 
Anterior chamber OCT exam 
• 
Pupil measurement 
• 
Pachymetry (contact) 
• 
BCVA (ETDRS) 
• 
Visual Field 
• 
Body system assessment 
• 
Vital signs 
• 
Non fasting clinical laboratory tests (chemistry, hematology, urinalysis) 
• 
Urine pregnancy tests for females of childbearing potential 
• 
AEs 


 
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Table 4: 
Time and Events Schedule, Cohort 2 Study Extension 2, Months 18 to 21, 
Including New Schedule for Month 18 Visit for Patients Enrolled in the 
Extension 2 
Procedure 
Treatment 
V22 
Month 18 
+/- 7 days 
Treatment 
V23 
Month 19 
+/- 7 days 
Treatment 
V24 
Month 20 
+/- 7 days 
Exit/Early Exit 
V25 
Month 21 
+/- 7 days 
Informed consent review 
X 
 
 
 
Concomitant medication query 
X 
X 
X 
X 
Adverse events query 
X 
X 
X 
X 
BCVA – (ETDRS) 
X 
X 
X 
X 
Pupil measurement  
X 
X 
X 
X 
Slit-lamp biomicroscopy 
X 
X 
X 
X 
Corneal staining 
X 
X 
X 
X 
Gonioscopy 
X 
X 
X 
X 
Gonioscopy photographs (at selected 
sites) 
X 
X 
X 
X 
Pachymetry 
X 
X 
X 
X 
Specular microscopy 
X1 
X1 
X1 
X1 
Visual field  
 
 
 
X 
Anterior chamber OCT3 
X 
X 
X 
X 
8 AM IOP 
X 
X 
X 
 
IOP diurnal curve 
 
 
 
X 
Dilated fundus exam 
 
 
 
X 
Body System Assessment 
 
 
 
X 
Vitals 
 
 
 
X 
Hematology, chemistry and urinalysis 
 
 
 
X 
Plasma collection for PK analyses 
 
 
 
X 
Urine Pregnancy test 
 
 
 
X 
Timolol maleate 0.5% distribution and 
collection2 
X 
X 
X 
X 
Exit patient, complete exit form 
 
 
 
X 
1  
Specular microscopy is needed for all study eyes on all indicated visits including unscheduled visits; for non-
study eyes, it is collected only during Exit/Early Exit (Visit 25).  
2   
Timolol maleate 0.5% ophthalmic solution is given to the patient to continue dosing BID for the remainder of 
the study.  Patients will be instructed to return their used bottle(s) at each visit for accountability purposes.  A 
new supply of timolol maleate 0.5% ophthalmic solution will be provided on a monthly basis through Month 20 


 
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(Visit 24). During post dose study visits, ensure timolol maleate 0.5% ophthalmic solution is administered after 
the 8 AM IOP measurement.  
3   
 Always capture the ENV515 implant(s) in the field of view of at least one OCT image. 
 
 


 
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ENV515-01 PHASE 2A CLINICAL STUDY, COHORT 3 
Cohort 3 Protocol Synopsis 
Investigational Product:  ENV515-3-2 (Travoprost) Intracameral Implant 
Phase:  2a 
Study Objective: 
• 
Evaluate the long-term safety, tolerability, and systemic exposure to travoprost following a unilateral, single 
dose of one or two ENV515-3-2 (travoprost) intracameral implant(s) in the study eye in patients with 
bilateral ocular hypertension or primary open-angle glaucoma 
Clinical Hypotheses: 
• 
ENV515-3-2 (travoprost) Intracameral Implants haves an acceptable safety profile 
Study Design: 
Structure:  Cohort 3 of the Phase 2a clinical study is an up to 12-month, prospective, open-label, active-comparator-
controlled, multi-center study of ENV515-3-2 (travoprost) Intracameral Implants.  While all cohorts enrolled 
glaucoma patients, Cohort 1 included patients scheduled for cataract removal and the ENV515 implants were 
removed after 28 days during cataract surgery. The Cohort 2 phase enrolled patients without the need for cataract 
surgery in order to study ENV515-3 over its entire duration of IOP-lowering efficacy.  Cohort 3 will enroll similar 
patients as Cohort 2 with similar study design studying ENV515-3-2 over its entire duration of IOP-lowering 
efficacy.  ENV515-3-2 has been reformulated to achieve the same efficacy of two ENV515-3 implants with just one 
implant and the efficacy of three ENV515-3 implants with just two implants. 
Duration of Patient Participation:  Approximately 14 months including washout of current PGA therapy, 
implantation/treatment of investigational product, 3-month primary efficacy and safety evaluation period post  dose 
of ENV515 in the study eye, and followed for an additional 9 months of safety follow-up. 
Study Treatment Investigational Product:  one or two implant(s) per eye of ENV515-3-2 (travoprost) Intracameral 
Implant 
Reference Product:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 
Dosage/Dose Regimen/Treatment Groups: 
• 
ENV515-3-2 Low Dose Group: One ENV515-3-2 (travoprost) implant administered into the study eye as a 
single, unilateral dose via intracameral injection on Day 1 
• 
ENV515-3-2 High Dose Group: Two ENV515-3-2 (travoprost) implants administered into the study eye as 
a single, unilateral dose via intracameral injection on Day 1 
• 
Control Group:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 
Rescue Therapy: Rescue therapy may be allowed in the study eye if, in the opinion of the investigator, the IOP is not 
well controlled on any two visits after Month 3 (Day 84) that are separated by at least 4 weeks (+/- 7 days).  Timolol 


 
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maleate 0.5% ophthalmic solution administered BID daily will be used for rescue therapy. The patient should be 
permanently rescued with Timolol maleate 0.5% ophthalmic solution twice a day until the completion of the study. 
Notwithstanding the above, both the study and non-study eyes may be rescued at any time, at the investigator’s 
discretion, if it is considered to be in the best interest of the patient. 
Randomization/Stratification:  No randomization is conducted as this is an open-label study. 
Visit Schedule:  Visit schedule encompasses Screening Visit 1 (Day -56 to -42 followed by a 6 week PGA washout 
period, Baseline Visit 2 (Day -7 to -1), Dosing Visit 3 (Day 1), Treatment Visit 4 (Day 2 + 3 days), Treatment Visit 
5(Day 14 ± 3 days), Treatment Visit 5a (Day 28 ± 3 days), Treatment Visit 6 (Day 42 ± 3 days), Treatment Visit 7 
(Day 84 ± 7 days), Treatment Visits 8-15 (every 28 days from Month 4 to Month 11), and Exit Visit 16 (Month 12) 
for a total of 17 visits.  Patients may be exited sooner than Month 12 if they have received rescue therapy, their IOP 
in the study eye is well-controlled, no implant remnants are visible by gonioscopy during two consecutive visits, and 
no treatment related adverse events (AEs) are present that require continued monitoring. 
_____________________________________________________________________________________ 
Study Population Characteristics: 
Number of Patients:  Following successful screening and washout, 15 patients in Cohort 3 were dosed with 
investigational product.  
Condition/Disease:  The study population consists of patients with a diagnosis of bilateral ocular hypertension or 
primary open-angle glaucoma who are currently being treated with a topical PGA in both eyes. 
Inclusion Criteria: 
1. Male or female between 18 and 85 years of age. 
2. Have a diagnosis of bilateral ocular hypertension or primary open-angle glaucoma. 
3. Normal appearing anterior chamber angles (Shaffer classification Grade 3 or 4, with an angle of at least 20° 
determined by gonioscopy, and confirmed to have an open angle as determined by anterior chamber OCT 
evaluated by a central reading center prior to dosing). 
4. Are currently treated with topical PGA for ocular hypertension in both eyes. (Dual therapy with PGA (i.e. 
PGA and another IOP lowering agent) is acceptable) 
5. In the opinion of the investigator, the non-study eye can be adequately controlled with timolol maleate 
0.5% ophthalmic solution BID. 
6. Patients who in the opinion of the investigator, have an IOP in both eyes that is considered to be adequately 
controlled at  Screening (Visit 1), can be safely withdrawn from IOP medications in both eyes during the 
washout period, and who are not considered to be at significant risk for disease progression throughout the 
trial. 


 
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7. At the Baseline Visit after washout (Visit 2), have IOP measurements that meet all of the following: 
a. 
Have an IOP at 8:00 a.m. (±30 minutes) and at 10:00 a.m. (±30 minutes) between 22 and 34 mm 
Hg in both eyes with a ≤4 mm Hg difference between the eyes 
b. Have an IOP at 4:00 p.m. (±30 minutes) between 19 and 30  mm Hg in both eyes with a 
≤4 mm Hg difference between each eye 
c. 
Demonstrate IOP increase of at least 4 mmHg in each eye at Baseline (Visit 2) compared to the 
Screening (Visit 1) IOP measurements.  
8. At the Dosing Visit (Visit 3), have IOP measurement that is between 22 and 34 mm Hg in both eyes with a 
≤4 mm Hg difference between the eyes. 
9. Have endothelial cell counts of at least 2000 cells/mm2 and normal endothelial cell morphology at 
Screening (Visit 1) as evaluated by central reading center. 
10. If female, patients must either be incapable of pregnancy because of hysterectomy, tubal ligation or have 
been amenorrheic for at least 2 years or must use effective (e.g., double barrier) method of birth control for 
the duration of the study.  Female patients must have a negative pregnancy test and not be nursing.  
11. Must be able to provide a written informed consent to participate in the study, in accordance with the 
international Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and local 
regulations, before initiating any study-related procedures. 
Exclusion Criteria: 
1. Are diagnosed with closed angle glaucoma, exfoliation syndrome or exfoliation glaucoma, pigment 
dispersion or secondary glaucoma. 
2. Are insufficiently responsive to PGA topical treatment, i.e., are PGA non-responders. 
3. Have a history of glaucoma-related surgery (e.g., Selective Laser Trabeculoplasty (SLT), Argon Laser 
Trabeculoplasty (ALT), trabeculectomy, cryotherapy, laser iridotomy and minimally invasive procedures 
including shunts/stents) in the study eye. 
4. Have severe glaucoma with a mean defect (MD) worse than -8.0, a central island of vision, or otherwise 
severe glaucoma that would not tolerate a short-term increase in IOP including advanced cupping. 
5. Have manifest refraction BCVA worse than 20/80 Snellen in either eye as measured using ETDRS chart. 
6. Have hyperemia score of 1 or greater at Baseline (Visit 2) 
7. According to the investigator’s best judgment, are at risk for progression of glaucoma, VF or VA 
worsening as a consequence of participation in the trial in either eye. 
8. Have any abnormality preventing reliable applanation tonometry in either eye. 
9. Have a central corneal thickness less than 500 micrometers or greater than 600 micrometers as determined 
by pachymetry at Screening (Visit 1) in either eye. 
10. Have a history of recurrent corneal erosion syndrome, multiple corneal abrasions, or an abrasion that was 
slow to heal in either eye. 
11. Have had intraocular conventional surgery, intraocular laser surgery, corneal refractive surgery or eyelids 
surgery within the past 3 months in the study eye. Complicated cataract surgery that resulted in intraocular 
lens placement outside the capsular bag or a break in the posterior capsule is not allowed. 


 
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12. Are currently diagnosed with active infectious/noninfectious conjunctivitis, or moderate to severe 
blepharitis in either eye.  (Chronic mild blepharitis or injection related to mild blepharitis, lid lag, mild dry 
eye or seasonal allergies are allowed.) 
13. Are currently taking or have taken corticosteroids (oral, ocular, injectable, IV) or used dermatology 
formulations of steroids in the vicinity of eyes in the 1 month prior to Screening (Visit 1); have a history of 
chronic ocular corticosteroid (topical or intraocular) use within the past year. Inhaled, intranasal, or topical 
(dermal) steroids not in the vicinity of the eyes is permissible if on a stable dose for at least 1 month prior 
to Screening (Visit 1). 
14. Have any media opacity or are uncooperative in such a way that restricts adequate examination of the 
ocular fundus or anterior chamber in either eye. 
15. Are unwilling to discontinue use of contact lenses for the duration of their study participation. 
16. Have progressive retinal or optic nerve disease apart from glaucoma or history of uveitis or keratitis.  
17. Have any history of allergic hypersensitivity or poor tolerance to any components of the preparations used 
in this trial such as travoprost or poly-lactic acid or similar excipients, topical anesthetic (proparacaine 
0.5% or equivalent), iodine, timolol maleate, and VIGAMOX® (or generic equivalent). 
18. Have a requirement for any ocular medications that are specifically disallowed in this protocol for any 
condition during the study or within the specified timeframe prior to Baseline (Visit 2). 
19. Have a history, or a suspected history of illicit drug or alcohol dependence in the preceding year. 
20. Currently using or used marijuana in the past 30 days prior to Screening (Visit 1). 
21. Have received any investigational product within the past 30 days prior to Screening (Visit 1) or have ever 
been previously implanted in the anterior segment with experimental therapies. 
22. Are an employee of the clinical site that is directly involved in the management, administration, or support 
of this study or are an immediate family member of the same 
23. Patients who, per investigator’s judgment, are not good clinical trial candidates due to personal (e.g., 
perceived willingness or ability to comply with protocol, significant traveling distance to medical center) 
and/or medical (e.g., mental illness, other non-ocular medical conditions, or laboratory abnormalities that 
might negatively impact trial participation or outcome) conditions that would likely impede the patient’s 
successful study completion or planned analyses. 
Response Measures: 
Safety Measures: Assessed by evaluating changes from baseline in the following: 
• 
Specular microscopy (non-contact) 
• 
Slit-lamp biomicroscopy 
• 
Corneal staining 
• 
Dilated fundus examination 
• 
Gonioscopy exam 
• 
Anterior chamber OCT exam 
• 
Pupil measurement 
• 
Pachymetry (contact) 


 
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• 
BCVA 
• 
Visual Field 
• 
Body system assessment 
• 
Vital signs 
• 
Non fasting clinical laboratory tests (chemistry and hematology) 
• 
Urine pregnancy tests for females of childbearing potential 
• 
AEs 
Pharmacokinetic Measures: 
• 
Systemic exposure to travoprost via analysis of travoprost acid in plasma 
 


 
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Table 5: 
Time and Events Schedule, Cohort 311 
Note: V16/Month 12 Time and Events Schedule should only be used if patients are not continuing into the Cohort 3 Study Extension 1 and plan to exit the study 
at V16/Month 12. If the patient is continuing into the Cohort 3 Study Extension 1, V16/Month 12 should follow the Time and Events Schedule in the Cohort 3 
Study Extension 1 Synopsis, Table 6. 
Procedure 
Screening 
V1 
Day -56 
to -42 
 
 
 
Baseline 
V2 
Day -7 to 
-1 
 
 
 
Dosing 
V3 
Day 1 
 
 
 
 
Treatment 
V4, 
5,5a,6 
Day 
2,14,28, 
42 
+/- 3 days 
Treatment 
V7 
Day 84 
+/- 7 days 
 
 
 
Treatment 
V8,9 
Month  
4,5 
+/- 7 days 
 
 
Treatment 
V10 
Month 6 
+/- 7 days 
 
 
 
Treatment 
V11 
Month 7 
+/- 7 days 
 
 
 
Treatment 
V12 
Month 8 
+/- 7 days 
 
 
 
Treatment 
V13 
Month 9 
+/- 7 days 
 
 
 
Treatment 
V14 
Month 10 
+/- 7 days 
 
 
 
Treatment 
V15 
Month 11 
+/- 7 days 
 
 
 
Exit/Early 
Exit 
V16 
Month 12 
+/- 7 days 
 
 
Informed 
consent review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demo-graphics/ 
medical & ocular 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Criteria  
Confirmation 
Prior to Dosing 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
query 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
query 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA – 
(ETDRS) 
With manifest 
refraction 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pupil 
measurement  
X 
X 
 
X1 
X 
X 
X 
X 
X 
 
 
 
 
Slit lamp 
biomicroscopy 
X 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corneal staining 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
8 AM IOP 
X3 
 
X3 
 
 
 
 
 
 
X 
X 
X 
X3 


 
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Procedure 
Screening 
V1 
Day -56 
to -42 
 
 
 
Baseline 
V2 
Day -7 to 
-1 
 
 
 
Dosing 
V3 
Day 1 
 
 
 
 
Treatment 
V4, 
5,5a,6 
Day 
2,14,28, 
42 
+/- 3 days 
Treatment 
V7 
Day 84 
+/- 7 days 
 
 
 
Treatment 
V8,9 
Month  
4,5 
+/- 7 days 
 
 
Treatment 
V10 
Month 6 
+/- 7 days 
 
 
 
Treatment 
V11 
Month 7 
+/- 7 days 
 
 
 
Treatment 
V12 
Month 8 
+/- 7 days 
 
 
 
Treatment 
V13 
Month 9 
+/- 7 days 
 
 
 
Treatment 
V14 
Month 10 
+/- 7 days 
 
 
 
Treatment 
V15 
Month 11 
+/- 7 days 
 
 
 
Exit/Early 
Exit 
V16 
Month 12 
+/- 7 days 
 
 
IOP diurnal 
curve  
 
X 
 
X4 
X 
X 
X 
X 
X 
 
 
 
 
Gonioscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy 
photographs (at 
selected sites) 
 
 
 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pachymetry 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corneal 
photography 
(at selected 
sites) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Specular 
microscopy6 
X6 
X6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual field 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Anterior 
chamber 
OCT10 
X 
 
 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dilated fundus 
exam 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Body System 
Assessment 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
Vitals 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Hematology, 
chemistry and 
urinalysis 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
PK sampling 
 
X 
 
X7 
X 
X 
X 
X 
X 
 
 
 
 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 


 
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Procedure 
Screening 
V1 
Day -56 
to -42 
 
 
 
Baseline 
V2 
Day -7 to 
-1 
 
 
 
Dosing 
V3 
Day 1 
 
 
 
 
Treatment 
V4, 
5,5a,6 
Day 
2,14,28, 
42 
+/- 3 days 
Treatment 
V7 
Day 84 
+/- 7 days 
 
 
 
Treatment 
V8,9 
Month  
4,5 
+/- 7 days 
 
 
Treatment 
V10 
Month 6 
+/- 7 days 
 
 
 
Treatment 
V11 
Month 7 
+/- 7 days 
 
 
 
Treatment 
V12 
Month 8 
+/- 7 days 
 
 
 
Treatment 
V13 
Month 9 
+/- 7 days 
 
 
 
Treatment 
V14 
Month 10 
+/- 7 days 
 
 
 
Treatment 
V15 
Month 11 
+/- 7 days 
 
 
 
Exit/Early 
Exit 
V16 
Month 12 
+/- 7 days 
 
 
Study drug 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Timolol 
maleate 0.5% 
distribution 
and collection8 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rescue therapy 
with timolol (if 
eligible) 
 
 
 
 
X9 
X9 
X9 
X9 
X9 
X 
X 
X 
 
Exit patient, 
complete exit 
form 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1   
Pupil measurement required only at Visit 5 (Day 14). 
2  
Slit lamp exam is performed twice during Day 1 Dosing (Visit 3), before and after ENV515 administration. 
3  
During Screening (Visit 1), Day 1 Dosing (Visit 3) and Month 12 Exit/Early Exit (Visit 16), only one IOP timepoint in the morning is needed (see 
Section 13 for specific time windows). 
4  
During Day 2 (Visit 4) only the 8 a.m. IOP timepoint is needed.  Day 14 (Visit 5), Day 28 (Visit 5a) and Day 42 (Visit 6) require full diurnal evaluation. 
5   
Gonioscopy photographs are not collected at Day 2 (Visit 4).  
6  
Specular microscopy is needed for all study eyes on indicated visits; for non-study eyes, it is collected only during Screening (Visit 1) and Baseline (Visit 2). 
Additional measurements may be taken at the investigator’s discretion. 
7  
PK sampling not required at Day 2 (Visit 4).  
8  
Timolol maleate 0.5% ophthalmic solution is given to the patient to take their first dose in the non-study eye the evening of their Day 1 Dosing (Visit 3) then 
dose BID for the duration of the study.  Patients will be instructed to return their used bottle(s) at each visit for accountability purposes.  A new supply of 
timolol maleate 0.5% ophthalmic solution will be provided on a monthly basis starting at Day 28 (Visit 5a) through Month 11 (Visit 15). During post dose 
study visits, ensure that timolol maleate 0.5% ophthalmic solution is administered after the 8 a.m. IOP measurement. 
9   
Patient can only be rescued after all diurnal IOP measurements have been collected for the visit. 
10     Capture the ENV515 implant(s) in the field of view of at least one OCT image. 
11  
Due to Amendment 7, some patients may not have all assessments performed as they have already completed the visits where assessments were added. 
12          Collect OCT images during visits 5, 5a and 6. No OCT images should be collected during Visit 4. 


 
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ENV515-01 PHASE 2A CLINICAL STUDY, COHORT 3 EXTENSION 1 
 
  
Cohort 3 Extension 1 Protocol Synopsis 
Investigational Product:  ENV515-3-2 (Travoprost) Intracameral Implant 
Phase:  2a Cohort 3 Extension 1 
Cohort 3 Study Extension 1 Objective: 
• 
Extend the 12-month ENV515-01 Ph2a Cohort 3 study duration by an additional 6 months in Cohort 3 
Extension 1 to continue evaluation of the ENV515-3-2 long term safety and biodissolution in patients with 
bilateral ocular hypertension or primary open-angle glaucoma 
Clinical Hypotheses: 
• 
ENV515-3-2 (travoprost) Intracameral Implants haves an acceptable safety profile 
Cohort 3 Study Extension 1 Design: 
Structure:  The Cohort 3 Extension 1 extended the ongoing 12 month Cohort 3, including both dose arms of the low 
and high doses of ENV515-3-2, by an additional 6 months for a total of 18 months duration for 15 patients. The 
initial Cohort 3 of the Phase 2a clinical study was up to 12-month, prospective, open-label, active-comparator-
controlled, multi-center study of ENV515-3-2 (travoprost) Intracameral Implants. The Cohort 3 phase of the study 
enrolled glaucoma patients to study ENV515 over its entire duration of IOP-lowering efficacy, or up to 12 months 
after the first dose, all of whom have the option of enrolling in Cohort 3 Extension 1 for a total of 18 months (12 
months of the original Cohort 3 duration and 6 months of the Cohort 3 Extension 1). The Cohort 3 investigational 
product, ENV515-3-2 implant, has been reformulated to achieve the same efficacy of two ENV515-3 implants 
studied in Cohort 2 with just one implant and the efficacy of three ENV515-3 implants with just two implants. 
Duration of Patient Participation including Cohort 3 Extension 1:  Approximately a maximum of 20 months 
including up to a 56 day screening and washout periods, implantation/treatment administration day, a 3 month 
primary efficacy and safety evaluation period post initial dose of ENV515 in the study eye, follow-up for 9 months, 
and an additional 6 month Cohort 3 Extension 1. 
Study Treatment Investigational Product:  one or two implant(s) per eye of ENV515-3-2 (travoprost) Intracameral 
Implant 
Reference Product:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 
Dosage/Dose Regimen/Treatment Groups: 
• 
 ENV515-3-2 Low Dose Group: One ENV515-3-2 (travoprost) implant administered into the study eye as a 
single, unilateral dose via intracameral injection on Day 1 
• 
ENV515-3-2 High Dose Group: Two ENV515-3-2 (travoprost) implants administered into the study eye as 
a single, unilateral dose via intracameral injection on Day 1 
• 
Control Group:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 


 
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Rescue Therapy:  Rescue therapy may be allowed in the study eye if, in the opinion of the investigator, the IOP is 
not well controlled on any two visits after Month 3 (Day 84) that are separated by at least 4 weeks (+/- 7 days).  
Timolol maleate 0.5% ophthalmic solution administered BID daily will be used for rescue therapy. The patient 
should be permanently rescued with Timolol maleate 0.5% ophthalmic solution twice a day until the completion of 
the study. Notwithstanding the above, both the study and non-study eyes may be rescued at any time, at the 
investigator’s discretion, if it is considered to be in the best interest of the patient. 
Randomization/Stratification: No randomization is required as this is an open-label, two arm study Extension 1 for 
15 patients who had been dosed in ENV515-01 Ph2a Cohort 3 study. 
Cohort 3 Extension 1 Visit Schedule: Visit schedule encompasses Treatment Visits 17 to 21 (Month 13 and every 
month thereafter to Month 17) and Exit Visit 22 (Month 18). Patients may be exited sooner than Month 18 if they 
have received rescue therapy, their IOP in the study eye is well-controlled, no implant remnants are visible by 
gonioscopy during two consecutive visits, and no treatment related adverse events (AEs) are present that require 
continued monitoring. 
Response Measures in Cohort 3 Study Extension 1 (Month 13 to 18): 
Safety Measures: Assessed by evaluating changes from baseline in the following: 
• 
Specular microscopy (non-contact) 
• 
Slit-lamp biomicroscopy 
• 
Corneal staining 
• 
Dilated fundus examination 
• 
Gonioscopy exam 
• 
Anterior chamber OCT exam 
• 
Pupil measurement 
• 
Pachymetry (contact) 
• 
BCVA (ETDRS) 
• 
Visual Field 
• 
Body system assessment 
• 
Vital signs 
• 
Non fasting clinical laboratory tests (chemistry, hematology, urinalysis) 
• 
Urine pregnancy tests for females of childbearing potential 
• 
AEs 


 
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Table 6: 
Time and Events Schedule, Cohort 3 Extension 1, Months 12 to 18, Including New Schedule for Month 12 Visit 
for Cohort 3 Patients Enrolled in the Cohort 3 Extension 1 
Note: If the patient is continuing into the Cohort 3 Extension 2, V22/Month 18 should follow the Time and Events Schedule in the Cohort 3 Extension 2 
Synopsis, Table 7. 
Procedure 
Treatment 
V16 
Month 12 
+/- 7 days4 
Treatment 
V17 
Month 13 
+/- 7 days 
Treatment 
V18 
Month 14 
+/- 7 days 
Treatment 
V19 
Month 15 
+/- 7 days 
Treatment 
V20 
Month 16 
+/- 7 days 
Treatment 
V21 
Month 17 
+/- 7 days 
Exit/Early Exit 
V22 
Month 18 
+/- 7 days 
Informed consent review 
X 
 
 
 
 
 
 
Concomitant medication query 
X 
X 
X 
X 
X 
X 
X 
Adverse events query 
X 
X 
X 
X 
X 
X 
X 
BCVA – (ETDRS) 
X 
X 
X 
X 
X 
X 
X 
Slit-lamp biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
8 AM IOP 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy photographs (at selected sites) 
X 
X 
X 
X 
X 
X 
X 
Pachymetry 
X 
X 
X 
X 
X 
X 
X 
Specular microscopy 
X1 
X1 
X1 
X1 
X1 
X1 
X 
Visual field  
 
 
 
 
 
 
X 
Anterior chamber OCT3 
X 
X 
X 
X 
X 
X 
X 


 
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Procedure 
Treatment 
V16 
Month 12 
+/- 7 days4 
Treatment 
V17 
Month 13 
+/- 7 days 
Treatment 
V18 
Month 14 
+/- 7 days 
Treatment 
V19 
Month 15 
+/- 7 days 
Treatment 
V20 
Month 16 
+/- 7 days 
Treatment 
V21 
Month 17 
+/- 7 days 
Exit/Early Exit 
V22 
Month 18 
+/- 7 days 
Dilated fundus exam 
 
 
 
 
 
 
X 
Body System Assessment 
 
 
 
 
 
 
X 
Vitals 
 
 
 
 
 
 
X 
Hematology, chemistry and urinalysis 
 
 
 
 
 
 
X 
Urine Pregnancy test 
 
 
 
 
 
 
X 
Timolol maleate 0.5% distribution and 
collection2 
X 
X 
X 
X 
X 
X 
X 
Exit patient, complete exit form 
 
 
 
 
 
 
X 
1  
Specular microscopy is needed for all study eyes on all indicated visits. Additional measurements may be taken at the investigator’s discretion. 
2   
Timolol maleate 0.5% ophthalmic solution is given to the patient to continue dosing BID for the remainder of the study.  Patients will be instructed to return 
their used bottle(s) at each visit for accountability purposes.  A new supply of timolol maleate 0.5% ophthalmic solution will be provided on a monthly basis 
through Month 17 (Visit 21). During post dose study visits, ensure timolol maleate 0.5% ophthalmic solution is administered after the 8 AM IOP 
measurement. 
3   
Capture the ENV515 implant(s) in the field of view of at least one OCT image. 
4         V16/Month 12 Time and Events Schedule should only be used if patients are continuing into the Cohort 3 Study Extension 1. If the patients are continuing 
 
into the Cohort 3 Extension 2, V22/Month 18 should follow the Time and Events Schedule in the Cohort 3 Extension 2 Synopsis, Table 7.


 
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ENV515-01 PHASE 2A CLINICAL STUDY, COHORT 3 EXTENSION 2 
 
  
Cohort 3 Extension 2 Protocol Synopsis 
Investigational Product:  ENV515-3-2 (Travoprost) Intracameral Implant 
Phase:  2a Cohort 3 Extension 2 
Cohort 3 Study Extension 2 Objective: 
• 
Extend the 18-month ENV515-01 Ph2a Cohort 3 study duration by an additional 6 months in Cohort 3 
Extension 2 to continue evaluation of the ENV515-3-2 long term safety and biodissolution in patients with 
bilateral ocular hypertension or primary open-angle glaucoma 
Clinical Hypotheses: 
• 
ENV515-3-2 (travoprost) Intracameral Implants haves an acceptable safety profile 
Cohort 3 Study Extension 2 Design: 
Structure:  The Cohort 3 Extension 2 is extending the ongoing 18 month Cohort 3, including both dose arms of the 
low and high doses of ENV515-3-2, by an additional 6 months for a total of 24 months duration for up to 15 
patients. The initial Cohort 3 of the Phase 2a clinical study was up to 12-month, prospective, open-label, active-
comparator-controlled, multi-center study of ENV515-3-2 (travoprost) Intracameral Implants. The Cohort 3 phase of 
the study enrolled glaucoma patients to study ENV515 over its entire duration of IOP-lowering efficacy, or up to 12 
months after the first dose, all of whom had the option of enrolling in Cohort 3 Extension 1 for a total of 18 months 
(12 months of the original Cohort 3 duration and 6 months of the Cohort 3 Extension 1). The Cohort 3 
investigational product, ENV515-3-2 implant, has been reformulated to achieve the same efficacy of two ENV515-3 
implants studied in Cohort 2 with just one implant and the efficacy of three ENV515-3 implants with just two 
implants. 
Duration of Patient Participation including Cohort 3 Extension 2:  Approximately a maximum of 26 months 
including up to a 56 day screening and washout periods, implantation/treatment administration day, a 3 month 
primary efficacy and safety evaluation period post initial dose of ENV515 in the study eye, follow-up for 9 months, 
additional 6 month Cohort 3 Extension 1, and an additional 6 month Cohort 3 Extension 2. 
Study Treatment Investigational Product:  one or two implant(s) per eye of ENV515-3-2 (travoprost) Intracameral 
Implant 
Reference Product:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 
Dosage/Dose Regimen/Treatment Groups: 
• 
 ENV515-3-2 Low Dose Group: One ENV515-3-2 (travoprost) implant administered into the study eye as a 
single, unilateral dose via intracameral injection on Day 1 
• 
ENV515-3-2 High Dose Group: Two ENV515-3-2 (travoprost) implants administered into the study eye as 
a single, unilateral dose via intracameral injection on Day 1 
• 
Control Group:  Timolol maleate 0.5% ophthalmic solution administered BID daily in the non-study eye 


 
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Rescue Therapy:  Rescue therapy may be allowed in the study eye if, in the opinion of the investigator, the IOP is 
not well controlled on any two visits after Month 3 (Day 84) that are separated by at least 4 weeks (+/- 7 days).  
Timolol maleate 0.5% ophthalmic solution administered BID daily will be used for rescue therapy. The patient 
should be permanently rescued with Timolol maleate 0.5% ophthalmic solution twice a day until the completion of 
the study. Notwithstanding the above, both the study and non-study eyes may be rescued at any time, at the 
investigator’s discretion, if it is considered to be in the best interest of the patient. 
Randomization/Stratification: No randomization is required as this is an open-label, two arm study Extension 2 for 
15 patients who had been dosed in ENV515-01 Ph2a Cohort 3 study. 
Cohort 3 Extension 2 Visit Schedule: Visit schedule encompasses Treatment Visits 22 to 27 (Month 18 and every 
month thereafter to Month 23) and Exit Visit 28 (Month 24). Patients may be exited sooner than Month 24 if they 
have received rescue therapy, their IOP in the study eye is well-controlled, no implant remnants are visible by 
gonioscopy during two consecutive visits, and no treatment related adverse events (AEs) are present that require 
continued monitoring. 
Response Measures in Cohort 3 Study Extension 2 (Months 18 to 24): 
Safety Measures: Assessed by evaluating changes from baseline in the following: 
• 
Specular microscopy (non-contact) 
• 
Slit-lamp biomicroscopy 
• 
Corneal staining 
• 
Dilated fundus examination 
• 
Gonioscopy exam 
• 
Anterior chamber OCT exam 
• 
Pupil measurement 
• 
Pachymetry (contact) 
• 
BCVA (ETDRS) 
• 
Visual Field 
• 
Body system assessment 
• 
Vital signs 
• 
Non fasting clinical laboratory tests (chemistry, hematology, urinalysis) 
• 
Urine pregnancy tests for females of childbearing potential 
• 
AEs 


 
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Table 7: 
Time and Events Schedule, Cohort 3 Extension 2, Months 18 to 24, Including New Schedule for Month 18 Visit 
for Cohort 3 Patients Enrolled in the Cohort 3 Extension 2 
Procedure 
Treatment 
V22 
Month 18 
+/- 7 days1 
Treatment 
V23 
Month 19 
+/- 7 days 
Treatment 
V24 
Month 20 
+/- 7 days 
Treatment 
V25 
Month 21 
+/- 7 days 
Treatment 
V26 
Month 22 
+/- 7 days 
Treatment 
V27 
Month 23 
+/- 7 days 
Exit/Early Exit 
V28 
Month 24 
+/- 7 days 
Informed consent review 
X 
 
 
 
 
 
 
Concomitant medication query 
X 
X 
X 
X 
X 
X 
X 
Adverse events query 
X 
X 
X 
X 
X 
X 
X 
BCVA – (ETDRS) 
X 
X 
X 
X 
X 
X 
X 
Slit-lamp biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
8 AM IOP 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy photographs (at selected sites) 
X 
X 
X 
X 
X 
X 
X 
Pachymetry 
X 
X 
X 
X 
X 
X 
X 
Specular microscopy 
X2 
X2 
X2 
X2 
X2 
X2 
X 
Visual field  
 
 
 
 
 
 
X 
Anterior chamber OCT3 
X 
X 
X 
X 
X 
X 
X 
Dilated fundus exam 
 
 
 
 
 
 
X 
Body System Assessment 
 
 
 
 
 
 
X 


 
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Procedure 
Treatment 
V22 
Month 18 
+/- 7 days1 
Treatment 
V23 
Month 19 
+/- 7 days 
Treatment 
V24 
Month 20 
+/- 7 days 
Treatment 
V25 
Month 21 
+/- 7 days 
Treatment 
V26 
Month 22 
+/- 7 days 
Treatment 
V27 
Month 23 
+/- 7 days 
Exit/Early Exit 
V28 
Month 24 
+/- 7 days 
Vitals 
 
 
 
 
 
 
X 
Hematology, chemistry and urinalysis 
 
 
 
 
 
 
X 
Urine Pregnancy test 
 
 
 
 
 
 
X 
Timolol maleate 0.5% distribution and 
collection4 
X 
X 
X 
X 
X 
X 
X 
Exit patient, complete exit form 
 
 
 
 
 
 
X 
1  
V22/Month 18 Time and Events Schedule should only be used if patients are continuing into the Cohort 3 Study Extension 2. 
2  
Specular microscopy is needed for all study eyes on all indicated visits. Additional measurements may be taken at the investigator’s discretion. 
3  
Timolol maleate 0.5% ophthalmic solution is given to the patient to continue dosing BID for the remainder of the study.  Patients will be instructed to return 
their used bottle(s) at each visit for accountability purposes.  A new supply of timolol maleate 0.5% ophthalmic solution will be provided on a monthly basis 
through Month 23 (Visit 27). During post dose study visits, ensure timolol maleate 0.5% ophthalmic solution is administered after the 8 AM IOP 
measurement. 
4   
Capture the ENV515 implant(s) in the field of view of at least one OCT image. 
    


 
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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 
TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE ...........................................................................2 
INVESTIGATOR PROTOCOL AGREEMENT ............................................................................3 
COHORT 1 PROTOCOL SYNOPSIS ............................................................................................4 
COHORT 2 PROTOCOL SYNOPSIS ..........................................................................................11 
COHORT 2 EXTENSION 1 PROTOCOL SYNOPSIS ................................................................19 
COHORT 2 EXTENSION 2 PROTOCOL SYNOPSIS ................................................................23 
COHORT 3 PROTOCOL SYNOPSIS ..........................................................................................27 
COHORT 3 EXTENSION 1 PROTOCOL SYNOPSIS ................................................................35 
COHORT 3 EXTENSION 2 PROTOCOL SYNOPSIS ................................................................39 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ..................................43 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................52 
1. 
INTRODUCTION ......................................................................................................54 
1.1. 
Description of Investigational Product .......................................................................54 
1.2. 
Overall Trial Design ...................................................................................................56 
1.3. 
Justification for Route of Administration and Dose Selection ...................................57 
1.4. 
Summary of Results from Cohort 1 of ENV515-01 Phase 2a Study .........................60 
1.4.1. 
Summary of Disposition of Cohort 1 Patients in ENV515-01 Phase 2a Study ..........60 
1.4.2. 
Summary of Efficacy Results from Cohort 1 of ENV515-01 Phase 2a Study ...........61 
1.4.3. 
Summary of Safety Results from Cohort 1 of ENV515-01 Phase 2a Study ..............62 
1.5. 
Interim Summary of Results from Cohort 2 of ENV515-01 Phase 2a Study .............64 
1.5.1. 
Summary of Disposition of Cohort 2 Patients in ENV515-01 Phase 2a Study ..........64 
1.5.2. 
Interim Summary of Safety Results from Cohort 2 of ENV515-01 Phase 2a 
Study ...........................................................................................................................65 
1.6. 
Summary of the Known and Potential Risks and Benefits to Human Patients ..........66 
1.7. 
GCP Compliance ........................................................................................................70 
1.8. 
Population to Be Studied ...........................................................................................70 
2. 
TRIAL OBJECTIVES AND PURPOSE, COHORT 1 ................................................71 


 
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3. 
TRIAL DESIGN, COHORT 1 ...................................................................................72 
3.1. 
Safety Evaluations, Cohort 1 ......................................................................................74 
3.1.1. 
Review of Safety Data by Medical Monitor, Cohort 1 .............................................74 
3.2. 
Endpoints, Cohort 1 ....................................................................................................74 
3.2.1. 
Trial Treatments, Cohort 1 .........................................................................................75 
3.3. 
Methods to Minimize Bias in Cohort 1 ......................................................................75 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS, COHORT 1.......................76 
4.1. 
Patient Inclusion Criteria, Cohort 1 ............................................................................76 
4.2. 
Patient Exclusion Criteria, Cohort 1 ...........................................................................77 
4.3. 
Randomization Criteria, Cohort 1 ..............................................................................78 
4.4. 
Patient Withdrawal Criteria, Cohort 1 ........................................................................78 
4.4.1. 
Specific Withdrawal Criteria, Cohort 1 .......................................................................79 
5. 
PROCEDURE SCHEDULE BY VISIT, COHORT 1 ...............................................80 
5.1. 
Visit 1/-35 to -28 days/Screening Evaluation, Cohort 1 .............................................80 
5.1.1. 
Screening Assessments, Cohort 1 ...............................................................................80 
5.1.2. 
Patient Instructions, Cohort 1 .....................................................................................81 
5.2. 
Visit 2/Day -7 to -1/Baseline, Cohort 1 ......................................................................81 
5.2.1. 
Baseline Assessments, Cohort 1 .................................................................................82 
5.2.2. 
Patient Instructions, Cohort 1 .....................................................................................83 
5.3. 
Visit 3/Day 1/Randomization/Treatment, Cohort 1 ....................................................83 
5.3.1. 
Pre-dose Assessments, Cohort 1 .................................................................................83 
5.3.2. 
Randomization and Study Drug Administration, Cohort 1 ........................................83 
5.3.3. 
Post-dose Assessments, Cohort 1 ...............................................................................84 
5.3.4. 
Patient Instructions, Cohort 1 .....................................................................................84 
5.4. 
Visit 4/Day 3 ± 1 Day/Treatment Period, Cohort 1 ....................................................84 
5.5. 
Visit 5/Day 7 ± 1 Day/Treatment Period, Cohort 1 ....................................................85 
5.6. 
Visit 6/Day 14 ± 1 Day/Treatment Period, Cohort 1 ..................................................85 
5.7. 
Visit 7/Day 21 ± 1 Day/Treatment Period, Cohort 1 ..................................................86 
5.8. 
Visit 8/Day 25 ± 1 Day/Treatment Period, Cohort 1 ..................................................87 
5.8.1. 
Disbursement and First Administration of Pre-Surgical Medications ........................87 


 
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5.9. 
Visit 9/Day 28/Cataract Surgery, Cohort 1 .................................................................88 
5.9.1. 
Pre-surgery Assessment, Cohort 1 ..............................................................................88 
5.9.2. 
Cataract Removal Procedure Combined with Aqueous Humor Sampling and 
Implant Recovery, Cohort 1 .......................................................................................88 
5.9.3. 
Post-Surgical Assessments, Cohort 1 .........................................................................89 
5.10. 
Visit 10/Day 33 to 38/Follow-up, Cohort 1 ................................................................89 
5.11. 
Visit 11/Day 42 to 49/Study Exit, Cohort 1 ...............................................................90 
5.12. 
Unscheduled Visits, Cohort 1 .....................................................................................91 
6. 
TREATMENT OF PATIENTS, COHORT 1 .............................................................92 
6.1. 
Treatments to be Administered, Cohort 1...................................................................92 
6.1.1. 
Implantation of ENV515, Cohort 1 ............................................................................92 
6.1.2. 
TRAVATAN Z for Non-Study Eye, Cohort 1 ...........................................................93 
7. 
ASSESSMENT OF EFFICACY, COHORT 1 ...........................................................94 
8. 
ASSESSMENT OF SAFETY, COHORT 1 ...............................................................94 
8.1. 
Safety Parameters, Cohort 1 .......................................................................................94 
9. 
TRIAL OBJECTIVES AND PURPOSE, COHORTS 2 AND 3 .................................95 
10. 
TRIAL DESIGN, COHORTS 2 AND 3 .....................................................................96 
10.1. 
Safety Evaluations, Cohorts 2 and 3 ..........................................................................98 
10.1.1. 
Review of Safety Data by Medical Monitor, Cohorts 2 and 3 .................................98 
10.2. 
Safety Endpoints, Cohorts 2 and 3 .............................................................................98 
10.3. 
Endpoints, Cohorts 2 and 3 .........................................................................................99 
10.3.1. 
Trial Treatments, Cohorts 2 and 3 ..............................................................................99 
10.3.2. 
Study Eye Selection ....................................................................................................99 
10.4. 
Methods to Minimize Bias in Cohorts 2 and 3 ...........................................................99 
11. 
SELECTION AND WITHDRAWAL OF PATIENTS, COHORTS  2 AND 
3 ................................................................................................................................100 
11.1. 
Patient Inclusion Criteria, Cohort 2 ..........................................................................100 
11.2. 
Patient Exclusion Criteria, Cohort 2 .........................................................................101 
11.3. 
Patient Inclusion Criteria, Cohort 3 ..........................................................................102 
11.4. 
Patient Exclusion Criteria, Cohort 3 .........................................................................103 
11.5. 
Dosing Criteria, Cohorts 2 and 3 .............................................................................105 


 
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11.6. 
Patient Rescue Criteria, Cohorts 2 and 3 ..................................................................105 
11.7. 
Patient Withdrawal Criteria, Cohorts 2 and 3 ...........................................................106 
11.8. 
Early Exit Criteria, Cohorts 2 and 3 .........................................................................107 
12. 
PROCEDURE SCHEDULE BY STUDY VISIT, COHORT 2 ...............................108 
12.1. 
Visit 1/-49 to -29 days/Screening Evaluation, Cohort 2 ...........................................108 
12.1.1. 
Screening Assessments .............................................................................................108 
12.2. 
Visit 2/Day -7 to -1/Baseline, Cohort 2 ....................................................................109 
12.2.1. 
Baseline Assessments ...............................................................................................109 
12.3. 
Visit 3/Day 1/Dosing/Treatment, Cohort 2 ..............................................................110 
12.3.1. 
Pre-dose Assessments ...............................................................................................110 
12.3.2. 
Study Eye Assignment and Study Drug Administration ..........................................111 
12.3.3. 
Post-dose Assessments .............................................................................................111 
12.3.4. 
Patient Instructions ...................................................................................................111 
12.4. 
Visit 4/Day 2 + up to 3 Days/Treatment Period, Cohort 2 .......................................111 
12.5. 
Visit 5/Day 14 ± 3 Days/Treatment Period, Cohort 2 ..............................................112 
12.6. 
Visit 5a/Day 28 ± 3 Days/Treatment Period, Cohort 2 ............................................113 
12.7. 
Visit 6/Day 42 ± 3 Days/Treatment Period, Cohort 2 ..............................................113 
12.8. 
Visit 7/Day 84 ± 7 Days/Treatment Period, Cohort 2 ..............................................114 
12.9. 
Visit 8/Month 4 – Visit 15/Month 11 ± 7 Days/Treatment Period, Cohort 2 ...........115 
12.10. 
Visit 16/Month 12 ± 7 Days/Treatment Period Study Exit, Cohort 2 (if 
patient chooses not to enroll in Extension 1) ............................................................116 
12.11. 
Visit 16/Month 12 – Visit 21/Month 17 ± 7 Days/Treatment Period, Cohort 
2 Study Extension 1 (if patient chooses to enroll in Extension 1) ............................117 
12.12. 
Visit 22/Month 18 ± 7 Days/Treatment Period Study Exit, Cohort 2 
Extension 1 (if patient chooses not to enroll in Extension 2) ...................................119 
12.13. 
Visit 22/Month 18 – Visit 24/Month 20 ± 7 Days/Treatment Period, Cohort 
2 Study Extension 2 (if patient chooses to enroll in Extension 2) ............................120 
12.14. 
Visit 25/Month 21 ± 7 Days/Treatment Period Study Exit, Cohort 2 Study 
Extension 2 ...............................................................................................................121 
13. 
PROCEDURE SCHEDULE BY STUDY VISIT, COHORT 3 ...............................122 
13.1. 
Visit 1/Day -56 to -42/Screening Evaluation, Cohort 3 ...........................................122 
13.1.1. 
Screening Assessments .............................................................................................122 


 
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13.1.2. 
Patient Instructions ...................................................................................................123 
13.2. 
Visit 2/-7 to -1 days/Baseline Assessments, Cohort 3 ..............................................123 
13.2.1. 
Patient Instructions ...................................................................................................124 
13.3. 
Visit 3/Day 1/Dosing/Treatment, Cohort 3 ..............................................................124 
13.3.1. 
Pre-dose Assessments ...............................................................................................124 
13.3.2. 
Study Eye Assignment and Study Drug Administration ..........................................125 
13.3.3. 
Post-dose Assessments .............................................................................................125 
13.3.4. 
Patient Instructions ...................................................................................................125 
13.4. 
Visit 4/Day 2 + up to 3 Days/Treatment Period, Cohort 3 .......................................126 
13.5. 
Visit 5/Day 14 ± 3 Days/Treatment Period, Cohort 3 ..............................................126 
13.6. 
Visit 5a/Day 28 ± 3 Days/Treatment Period, Cohort 3 ............................................127 
13.7. 
Visit 6/Day 42 ± 3 Days/Treatment Period, Cohort 3 ..............................................128 
13.8. 
Visit 7/Day 84 ± 7 Days/Treatment Period, Cohort 3 ..............................................129 
13.9. 
Visit 8/Month 4 – Visit 12/Month 8 ± 7 Days/Treatment Period, Cohort 3 .............130 
13.10. 
Visit 13/Month 9 – Visit 15/Month 11 ± 7 Days/Treatment Period, Cohort 3 .........131 
13.11. 
Visit 16/Month 12 ± 7 Days/Treatment Period Study Exit, Cohort 3 (if 
patient chooses not to enroll in Cohort 3 Extension 1) .............................................132 
13.12. 
Visit 16/Month 12 – Visit 21/Month 17 ± 7 Days/Treatment Period, Cohort 
3 Study Extension 1 (if patient chooses to enroll in Cohort 3 Extension 1) .............133 
13.13. 
Visit 22/Month 18 ± 7 Days/Treatment Period Study Exit, Cohort 3 Study 
Extension 1 (if patient chooses not to enroll in Cohort 3 Extension 2) ....................134 
13.14. 
Visit 23/Month 19 – Visit 27/Month 23 ± 7 Days/Treatment Period, Cohort 
3 Study Extension 1 (if patient chooses to enroll in Cohort 3 Extension 2) .............135 
13.15. 
Visit 28/Month 24 ± 7 Days/Treatment Period Study Exit, Cohort 3 Study 
Extension 2 ...............................................................................................................135 
13.16. 
Unscheduled Visits, Cohorts 2 and 3 ........................................................................136 
14. 
TREATMENT OF PATIENTS, COHORTS 2 AND 3 ............................................138 
14.1. 
Treatments to be Administered, Cohorts 2 and 3 .....................................................138 
14.1.1. 
Implantation of ENV515, Cohorts 2 and 3 ...............................................................138 
14.1.2. 
Timolol maleate 0.5% Ophthalmic Solution for Non-Study Eye, Cohorts 2 
and 3 ..........................................................................................................................139 
15. 
PROCEDURE DESCRIPTION ................................................................................140 


 
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15.1. 
Measurements and Evaluations, Cohorts 1, 2 and 3 .................................................140 
15.1.1. 
Best-Corrected Distance VA With Manifest Refraction Guidelines ........................140 
15.1.2. 
Slit Lamp Biomicroscopy Exam Guidelines ............................................................140 
15.1.3. 
Corneal Staining .......................................................................................................141 
15.1.4. 
Binocular Indirect Ophthalmoscopy (Dilated Fundus Exam) Guidelines ................142 
15.1.5. 
Body System Review ................................................................................................142 
15.1.6. 
Vital Signs ................................................................................................................143 
15.1.7. 
Laboratory Safety Assessments and Systemic Exposure to Travoprost ...................143 
15.1.8. 
Anterior Chamber Optical Coherence Tomography (OCT) .....................................143 
15.1.9. 
Gonioscopy ...............................................................................................................143 
15.1.10. 
Visual Field (Humphrey Program 24-2 SITA-Standard Strategy) ...........................143 
15.1.11. 
Intraocular Pressure ..................................................................................................144 
15.1.12. 
Pachymetry (Contact) ...............................................................................................144 
15.1.13. 
Specular Microscopy (Non-contact) .........................................................................144 
15.1.14. 
Pupil Measurement ...................................................................................................145 
15.1.15. 
Implant Recovery and Aqueous Humor Sampling ...................................................145 
15.2. 
Stopping Rules ..........................................................................................................146 
15.2.1. 
Stopping Rules for the Study ....................................................................................146 
16. 
WASHOUT MEDICATIONS, CONCOMITANT MEDICATIONS, DRUG 
ACCOUNTABILITY, AND MAINTENANCE OF RANDOMIZATION .............147 
16.1. 
Washout Medications ...............................................................................................147 
16.2. 
Concomitant Medications .........................................................................................147 
16.2.1. 
Permitted Medications ..............................................................................................147 
16.2.2. 
Medications Not Permitted .......................................................................................147 
16.3. 
Investigational Product Accountability ....................................................................148 
16.4. 
Maintenance of Randomization ................................................................................148 
17. 
SAFETY REPORTING ............................................................................................150 
17.1. 
Adverse Events Reporting ........................................................................................150 
17.2. 
AEs of Special Interest and Their Reporting ............................................................152 
17.3. 
Prospective Definitions of Select AEs ......................................................................152 
17.4. 
Serious Adverse Event Reporting .............................................................................153 


 
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17.5. 
Additional Medically Relevant Considerations for Defining Corneal 
Endothelial Cell Loss as an SAE ..............................................................................154 
18. 
STATISTICS ............................................................................................................156 
18.1. 
Statistical Methods ....................................................................................................156 
18.1.1. 
Patient Disposition, Demographic and Background Characteristics ........................157 
18.1.2. 
Analysis of Safety .....................................................................................................157 
18.2. 
Sample Size Estimation ............................................................................................158 
18.3. 
Level of Significance ................................................................................................159 
18.4. 
Procedure for Accounting for Missing, Unused, or Spurious Data ..........................159 
18.5. 
Procedure for Reporting Deviations from the Statistical Plan ..................................159 
18.6. 
Patients to be Included in the Analysis .....................................................................159 
19. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................160 
20. 
QUALITY CONTROL .............................................................................................161 
21. 
ETHICS ....................................................................................................................162 
21.1. 
Institutional Review Board (IRB) .............................................................................162 
21.2. 
Informed Consent Requirements ..............................................................................162 
21.3. 
Maintaining Privacy and Confidentiality..................................................................163 
22. 
DATA HANDLING AND RECORDKEEPING ...................................................164 
22.1. 
Data Quality Control and Reporting .........................................................................164 
22.2. 
Records Retention .....................................................................................................164 
23. 
PUBLICATION POLICY ........................................................................................166 
24. 
REFERENCES .........................................................................................................167 
APPENDIX 1 ...............................................................................................................................168 
Blood/Plasma Sample Collection and Processing, Cohorts 1, 2 and 3 ........................................168 
Aqueous Humor Sample Collection and Processing, Cohort 1 ...................................................168 
Implant Removal and handling, Cohort 1 ....................................................................................168 
 
LIST OF TABLES 
Table 1: 
Time and Events Schedule, Cohort 1 .......................................................................9 
Table 2: 
Time and Events Schedule, Cohort 2 .......................................................................16 


 
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Table 3: 
Time and Events Schedule, Cohort 2 Extension 1, Months 12 to 18, 
Including New Schedule for Month 12 Visit for Patients Enrolled in the 
Cohort 2 Extension 1 ..................................................................................................21 
Table 4: 
Time and Events Schedule, Cohort 2 Study Extension 2, Months 18 to 21, 
Including New Schedule for Month 18 Visit for Patients Enrolled in the 
Extension 2 .................................................................................................................25 
Table 5: 
Time and Events Schedule, Cohort 311 ....................................................................32 
Table 6: 
Time and Events Schedule, Cohort 3 Extension 1, Months 12 to 18, 
Including New Schedule for Month 12 Visit for Cohort 3 Patients Enrolled 
in the Cohort 3 Extension 1 ........................................................................................37 
Table 7: 
Time and Events Schedule, Cohort 3 Extension 2, Months 18 to 24, 
Including New Schedule for Month 18 Visit for Cohort 3 Patients Enrolled 
in the Cohort 3 Extension 2 ........................................................................................41 
Table 8: 
Abbreviations and Specialist Terms ...........................................................................52 
Table 9: 
Patient Disposition Table for Cohort 1 of ENV515-01 Phase 2a Study .....................61 
Table 10: Overall Summary of Adverse Events by Patient Classification .................................63 
Table 11: Classification of Adverse Events Occurring in > 1 Patient ........................................63 
Table 12: Patient Disposition Table for Cohort 2 of ENV515-01 Phase 2a Study .....................64 
Table 13: Overall Summary of Ocular Adverse Events for ENV515-3 Excluding 
Hyperemia ...................................................................................................................65 
Table 14: Summary of Hyperemia Adverse Events for ENV515-3 Dose Arm ..........................66 
Table 15: Patient-level Analyses, Cohort 1 ..............................................................................156 
Table 16: Eye-level Analyses, Cohort 1 ...................................................................................157 
Table 17: Patient-level Analyses, Cohorts 2 and 3 ...................................................................157 
Table 18: Eye-level Analyses, Cohort 2 and 3 .........................................................................157 
Table 19: Toxicity Probabilities (n = 5), Cohorts 1, 2, and 3 ................................................158 
Table 20: Toxicity Probabilities (n = 10), Cohort 3 ...............................................................158 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................57 
Figure 2: 
ENV515 Treatment Arms, Cohort 1 ...........................................................................72 


 
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Figure 3: 
Study Design for ENV515-01 (Cohort 1): 4-Week Phase 2a Safety, 
Tolerability, and IOP Lowering Effects of ENV515 in Glaucoma Patients in 
Need of Cataract Surgery ............................................................................................73 
Figure 4: 
ENV515 Treatment, Cohort 2 .....................................................................................96 
Figure 5: 
ENV515 Treatment, Cohort 3 .....................................................................................97 
Figure 6: 
Study Design for ENV515-01 (Cohorts 2 and 3) .......................................................97 
 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 8: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Argon Laser Trabeculoplasty 
BCVA 
Best Corrected Visual Acuity 
CME 
Cystoid Macular Edema 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
ENV515-1 
Envisia Therapeutics designation for Intracameral Implant containing 
42.5 μg travoprost 
ENV515-3 
Envisia Therapeutics designation for Intracameral Implant containing 
14.1 μg travoprost 
ENV515-3-2 
Envisia Therapeutics designation for Intracameral Implant containing 
26.1 μg travoprost 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IOL 
Intraocular Lens 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MD 
Mean Defect (as in visual field test) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIG 
Minimally Invasive Glaucoma implants  
NOAEL 
No-Observed Adverse Effect Level 


 
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Abbreviation or Specialist Term 
Explanation 
NSE 
Non-Study Eye 
OCT 
Optical Coherence Tomography 
PGA 
Prostaglandin Analogue 
PK 
Pharmacokinetic(s) 
PLA 
poly(D,L-lactide) 
PLGA 
poly(lactic-co-glycolic acid) 
RGP 
Rigid Gas Permeable (lenses) 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SE 
Study Eye 
SITA 
Swedish Interactive Threshold Algorithms 
SOP 
Standard Operating Procedures 
SLT 
Selective Laser Trabeculoplasty 
TBD 
To Be Determined 
TM 
Trabecular Meshwork 
VA 
Visual Acuity 
VF 
Visual Field 
 


 
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1. 
INTRODUCTION 
Glaucoma is a progressive optic neuropathy affecting more than 3 million Americans over the 
age of 39 and is a leading cause of blindness in adults over age 60.  According to the National 
Eye Institute, more than 120,000 Americans are blind due to glaucoma (3, 4).  Elevated 
intraocular pressure (IOP) is the most important risk factor for the development of glaucoma and 
is a result of abnormally high resistance to aqueous humor drainage through the trabecular 
meshwork (TM), a multi-laminar array of collagen beams covered by endothelial-like cells. 
Due to limited understanding of the pathophysiology of the optic neuropathy characteristic of 
glaucoma, current glaucoma therapies are focused on reducing IOP.  The prostaglandin 
analogues (PGAs) are currently the most prescribed class of topical therapies for ocular 
hypertension or glaucoma in the United States, with latanoprost, travoprost, and bimatoprost 
being used most frequently.  However, their use has been limited by several shortcomings. 
First, the compliance with existing glaucoma topical therapies is generally low, with 30% to 60% 
of patients discontinuing the therapy within the first year of treatment.  Second, topical 
ophthalmic agents currently in use have local and systemic side effects (e.g., a relatively high 
incidence of hyperemia for topical PGAs, including travoprost).  Third, the once a day 
administration of PGAs, accompanied by drug level peaks and troughs in the aqueous humor and 
the surrounding tissues, potentially leads to 24-hour IOP fluctuations that may contribute to 
accelerated loss of visual field (VF) in susceptible patients (5).  Lastly, the combination of these 
factors has been shown to increase the cost of patient care due to more rapid disease progression. 
Therefore, an alternative treatment using an extended-release delivery system with an improved 
safety/efficacy profile would be a welcome addition to the current pharmacological 
armamentarium.  To date, there are no approved anti-glaucoma therapies that provide an 
extended-release of a pharmacological agent directly to the site of action.  Development of an 
extended-release PGA formulation administered directly into the anterior chamber would likely 
improve both compliance and the adverse event (AE) profile of current PGA and other IOP 
lowering therapies. 
ENV515 (travoprost) Intracameral Implant is a biodegradable, extended-release formulation 
containing travoprost (1, 2) in a poly(D,L-lactide) (PLA) biodegradable polymer drug delivery 
system.  Studies in preclinical models with ENV515 formulations have shown sustained IOP 
lowering efficacy lasting up to 8 months following a single dose, combined with acceptable 
safety and tolerability profiles.  This body of knowledge, pointing to a potential for improved 
compliance, ocular surface tolerability, and possibly long-term beneficial outcomes, makes 
ENV515 extended-release travoprost therapy a promising area of research and development. 
1.1. 
Description of Investigational Product 
ENV515 is formulated with travoprost in a biodegradable PLA polymer drug delivery system 
composed of a PLA blend of R203S and R208 polymers.  PLA and its closely related 
(poly(lactic-co-glycolic acid)) PLGA polymers are used in many FDA-approved products and 
are hydrolyzed in the body to lactic acid and glycolic acid. 


 
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Additional information about ENV515, including nonclinical and clinical findings, and known 
and potential risks and benefits to human subjects, may be found in the Investigator’s Brochure.   
The clinical trial formulation is an aseptically produced, single-dose, ENV515 (travoprost) 
Intracameral Implant composed of a biodegradable, extended-release dosage form containing the 
PGA travoprost and biodegradable PLA polymer.  ENV515 is formulated as a solid, rod shaped 
implant in 3 different sizes:  
• ~225 μm x ~225 μm x ~2,925 μm implant with 42.5 µg of travoprost/implant 
referenced as ENV515-1 (used in Cohort 1) 
• ~150 μm x ~150 μm x ~1,500 μm implant with 14.1 µg of travoprost/implant 
referenced as ENV515-3,(used in Cohorts 1 and 2) 
• ~200 μm x ~200 μm x ~1,500 μm implant with 26.1 µg of travoprost/implant 
referenced as ENV515-3-2 (to be used in Cohort 3) 
Based on the results from Cohort 1 in which both ENV515-1 and ENV515-3 implants sizes were 
administered, only the smaller-sized implant with a lower dose of travoprost, ENV515-3, was 
advanced into Cohort 2. ENV515-3 and its variant ENV515-3-2, are studied in the Cohorts 2 and 
3 of this trial, respectively. 
ENV515-3-2 has been formulated to achieve the same efficacy as two ENV515-3 implants with 
just one implant and the efficacy of three ENV515-3 implants with just two implants: 
• Low dose: 28.2 µg via two ENV515-3 implants in Cohorts 1 and 2 or 26.1 µg via one 
ENV515-3-2 implants in Cohort 3 
• High dose: 42.3 µg via three ENV515-3 implants in Cohort 1 or 52.2 µg via two 
ENV515-3-2 implants in Cohort 3 
Thus Cohort 3 was designed to replicate the low dose from Cohort 2 with a single ENV515-3-2 
implant per eye, and to dose escalate from Cohort 2 to a high dose achieved via two ENV515-3-2 
implants per eye. Specifically, while two implants/eye of ENV515-3 dosed in low dose Cohort 2 
delivered 28.2 µg of travoprost/eye, and 1 implant per eye of ENV515-3-2 to be dosed in low 
dose of Cohort 3 will deliver 26.1 µg of travoprost/eye. 2 implants/eye of ENV515-3-2 to be 
dosed in high dose of Cohort 3 will deliver 52.2 µg of travoprost/eye. 
In Cohort 1 of this clinical study, the doses of travoprost in the ENV515 drug product used were: 
• 28.2 µg (two ENV515-3 implants) 
• 42.3 µg (three ENV515-3 implants) 
• 42.5 µg (one ENV515-1 implant) 
• 85.0 µg (two ENV515-1 implants).   
In Cohort 2 of this clinical study, the dose of travoprost in the ENV515-3 investigational product 
used was:  
• 28.2 µg (two ENV515-3 implants). 


 
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In Cohort 3 of this clinical study, the dose of travoprost in the ENV515-3-2 investigational 
product used will be:  
•  26.1 µg (one ENV515-3-2 implant) 
• 52.2 µg (two ENV515-3-2 implants).  
All investigational product implants will be loaded into a single use sterile applicator in a sterile 
field immediately prior to dosing and delivered directly into the anterior chamber of the eye via 
intracameral injection. 
ENV515 investigational product is packaged in a sterile glass vial with an overseal containing 
one implant/vial (ENV515-1, ENV515-3, or ENV515-3-2).  Four or five vials containing 
ENV515 investigational product will be provided in each clinical trial material kit to allow for 
applicator loading overage. One sterile ENV515 implant applicator per each clinical trial 
material kit will be provided in a sterile pouch.  
There is no placebo formulation in this study.  In Cohort 1, the non-study eye was dosed with 
TRAVATAN Z (travoprost ophthalmic solution) 0.004% administered as indicated (one eye 
drop once a day).  TRAVATAN Z was provided in its original packaging.   
In Cohorts 2 and 3, the non-study eye will be dosed with timolol maleate 0.5% ophthalmic 
solution (8), the comparator typically used in registration studies, administered as indicated (one 
eye drop twice a day).  Timolol maleate 0.5% ophthalmic solution will be provided in its original 
packaging. 
1.2. 
Overall Trial Design 
ENV515-01 is a multicenter, open-label, prospective, active-comparator-controlled Phase 2a 
study of ENV515 (travoprost) Intracameral Implant comprising of three stages:  
• The completed Cohort 1 was a 28-day study focused on evaluation of the initial 
safety, efficacy and pharmacokinetic properties of ENV515 conducted in glaucoma 
patients scheduled for cataract removal during which the ENV515 implant is removed 
during the cataract procedure 28 days after implantation; 
• The ongoing Cohort 2 is a 12-month study with a 6-month optional Extension 1 
followed by an additional 3-month optional Extension 2 (for up to a total of 21 
months) which is focused on evaluation of the long-term safety and efficacy in 
glaucoma patients during which the two ENV515-3 implants are followed through 
their biodissolution while the duration of IOP-lowering efficacy is assessed; 
• Cohort 3 is a 12-month study with a 6-month optional Extension 1 focused on 
evaluation of the long-term safety in glaucoma patients during which one or two 
ENV515-3-2 implants per study eye are followed through their biodissolution. 
To date, Cohorts 1 and 2 of the study have been completed for 4 dose levels of ENV515.  
 
 


 
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Figure 1: Overall Study Design 
 
 
1.3. 
Justification for Route of Administration and Dose Selection 
The initial 28-day Cohort 1 was designed to assess the initial safety, tolerability, effect on IOP, 
aqueous humor pharmacokinetics (PK), systemic exposure, and remaining travoprost in ENV515 
implants at 4 dose levels of travoprost: 28.2 µg, 42.3 µg, 42.5 µg, and 85.0 µg/eye.  The 4 dose 
levels were achieved via 2 different implant sizes of the same formulation, with smaller sized 
ENV515-3 and a larger sized ENV515-1.  The Cohort 1 phase of the study was conducted as a 
multicenter, randomized, open-label, parallel-group, dose-ranging, 28-day trial in 21 patients 
with bilateral open-angle glaucoma or ocular hypertension who were scheduled for upcoming 
cataract surgery in a single eye.  ENV515 implants were administered unilaterally in the study 
eye (pre-surgical eye) 4 weeks prior to the planned cataract surgery and were retrieved during 
cataract surgery. 
The actual Cohort 1 treatment groups and dose levels were as follows: 
• Two patients dosed with one ENV515-1 implant (42.5 µg) 
• Two patients dosed with two ENV515-1 implants (85.0 µg)   
• Seven patients dosed with two ENV515-3 implants (28.2 µg)  
• Ten patients dosed with three  ENV515-3 implants (42.3 µg)  
Stage 1: Cohort 1 
Approximately 20 
subjects 
Open-label with 
4 dose levels of 
ENV515 
administered as 
single doses and 
followed for 28 
days 
 
Non-study eye - 
TRAVATAN Z 
 
Implants 
removed on Day 
28 
1 ENV515-1 implant 
(Mid dose - 42.5 µg) 
2 ENV515-3 implants 
(Low dose - 28.2 µg)  
3 ENV515-3 implants 
(Mid dose - 42.3 µg)  
Analysis 
of 
Cohort 
1 
2 ENV515-1 implants 
(High dose - 85.0 µg)  
Cohorts 2 and 3 
Open-label with 
dose levels 
administered as 
single doses of 
ENV515-3 or 
ENV515-3-2 and 
followed for up 
to 21 (Cohort 2 
n=5) or up to 24 
months (Cohort 
3 n=15 in two 
dose levels)  
Non-study eye – 
Timolol maleate 
0.5% 
Cohort 2:  
2 ENV515-3 implants 
(Low dose 28.2 µg) 
Cohort 3:  
1 ENV515-3-2 implant 
 (Low dose 26.1 µg, 
n=6)  
and  
2 ENV515-3-2 implants 
 (High dose 52.2 µg, 
n=9)  
 
 


 
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Following the completion of Cohort 1, the ongoing 12-month Cohort 2 with 6-month optional 
Extension 1 followed by an additional 3-month optional Extension 2 (for up to a total of 21 
months) was initiated to assess the long-term safety, tolerability, effect on IOP, and systemic 
exposure of a single travoprost dose of 28.2 µg achieved via two ENV515-3 implants.  
The actual Cohort 2 treatment group and dose level is as follows: 
• Five patients dosed with two ENV515-3 implant (28.2 µg) 
Following the completion of the interim 6-month analysis of the ongoing Cohort 2, Cohort 3 is 
designed as a two dose level cohort consisting of a low and high dose groups. In Cohort 3, the 
low dose is achieved via a single ENV515-3-2 implant per eye vs. two ENV515-3 implants per 
eye in the low dose in Cohort 2. The high dose in Cohort 3 is achieved via two ENV515-3-2 
implants per eye. Cohort 3 will thus assess the long-term safety, tolerability, effect on IOP, and 
systemic exposure of a single travoprost dose of 26.1 µg with one ENV515-3-2 implant per eye 
(n=~5 to 10) and 52.2 µg with two ENV515-3-2 implants per eye (n=~10).  Cohort 3 of the study 
will be conducted with 15 patients with bilateral open-angle glaucoma or ocular hypertension.  
ENV515-3-2 implants will be administered unilaterally in the study eye and followed for 
12 months. 
The ENV515-01 Phase 2a study design is informed by extensive prior clinical studies of 
ophthalmic travoprost formulations. US FDA approvals of two sterile ophthalmic topical 
formulations containing travoprost (TRAVATAN and TRAVATAN Z), and their subsequent 
clinical use have established travoprost’s safety, tolerability, and IOP-lowering efficacy.  The 
mechanism of action of travoprost has been postulated to occur via increasing of aqueous humor 
outflow through the uveoscleral pathway and potentially also via the TM.  The topical 
administration of currently approved travoprost formulations likely results in only a small 
fraction of the total dose reaching the site of action due to the low efficiency of trans-corneal 
transport.  Additionally, the conversion of the travoprost ester prodrug into its active acid form in 
the cornea and conjunctiva results in a high incidence of hyperemia for all topical PGA-based 
products.   Compliance with the topical route of delivery of travoprost is generally perceived as 
low, thus contributing to more rapid progression of the disease and increased cost of treatment. 
Due to the shortcomings of travoprost-based and, more broadly, PGA-based topical therapies, an 
extended release formulation delivering travoprost directly to the site of action is compelling.  
For ENV515, the intracameral route of delivery was chosen as it elutes travoprost more 
proximally to the site of action of the aqueous humor outflow via both TM and uveoscleral 
pathways.  Additionally, in support of this route of delivery, Ocular pharmacokinetic studies with 
ENV515 in Beagle dogs demonstrated effective conversion of the travoprost ester prodrug into 
its active acid form in the anterior chamber.  Furthermore, this route of delivery bypasses the 
primary transport of the drug through the cornea and conjunctiva and, consequently, creates the 
potential for reduced hyperemia.  Lastly, the intracameral route of delivery has the potential for 
significant dose sparing: in preclinical studies in normotensive Beagle dogs dosed with 121.2 μg 
of travoprost/eye delivered via a single dose of ENV515-1, the full IOP treatment effect of ~30% 
change from baseline was demonstrated over an 8-month period.  Based on previous studies in 
Beagle dogs, more than 400 μg of TRAVATAN or TRAVATAN Z/eye would be necessary to 


 
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achieve a comparable treatment effect for the same period.  This body of knowledge concerning 
ENV515 makes it a promising experimental therapy with the potential to improve IOP control 
and reduce treatment-related AEs in glaucoma patients. 
The three implant sizes of ENV515 were selected to account for the anticipated best anatomical 
fit into the human iridocorneal angle.  The dose range of travoprost proposed in the ENV515-01 
Phase 2a clinical study was established based on pharmacodynamic studies in normotensive 
Beagle dogs.  In these studies, a single dose of one ENV515-3 implant (12.5 μg of travoprost) 
demonstrated a submaximal IOP-lowering effect over a 7-month period and a single dose of 
three ENV515-1 implants (121.2 μg of travoprost) demonstrated a maximal IOP-lowering effect 
over an 8-month period, thus demonstrating significant dose-sparing potential vs. the topical 
travoprost formulations. 
ENV515-1 and ENV515-3 have been evaluated in Good Laboratory Practice (GLP) compliant, 
single-dose, intracameral administration toxicity studies in Beagle dogs, using the intended 
clinical formulation composition covering the ranges of sizes and doses being studied in Cohorts 
1, 2 and 3 of the ENV515-01 Phase 2a clinical study.  ENV515-3 and its closely related, higher 
dose variant ENV515-3-2 are being advanced into Cohorts 2 and 3 of the ENV515-01 Phase 2a 
clinical study, respectively.  Toxicity assessments for ENV515-1 and ENV515-3 are complete 
through 6 months following a single administration in GLP-compliant study that included a 12 
month recovery period.  Repeat-dose cohorts are currently being assessed to support repeat dose 
administration in the clinic in future studies.  In the completed GLP toxicology studies, two, 
three, and six implants of each size were dosed/eye (27 to 82 μg of travoprost/eye for ENV515-3 
and 84 to 252 μg of travoprost/eye for ENV515-1). 
Overall, administration of 2, 3, or 6 ENV515-1 or ENV515-3 travoprost-eluting intracameral 
implants in the GLP toxicology studies was well tolerated in Beagle dogs for 28 days, resulting 
in mild ocular inflammation associated with the presence of implants in the anterior chamber as 
well as pharmacological effects consistent with travoprost in this test system.  Additionally, two, 
three, and six ENV515-3 implants per eye were well tolerated for 6 months and the 12 month 
recovery period.  The implants settled into the iridocorneal angle as the study progressed, 
although their location in the angle varied over time.  At no point were implants observed 
floating in the anterior chamber.  There was no effect on corneal thickness in any group.  Ocular 
findings included conjunctival hyperemia, anterior chamber cells, corneal vessels and edema, 
and limited anterior synechiae.  For ENV515-3, ophthalmic findings were generally very mild or 
not observed in the two and three implant groups, and a dose proportionality was observed in the 
incidence and severity as the dose escalated, with no adverse findings noted in any group.  
Findings included small areas of corneal opacity and small peripheral anterior synechiae at the 
location of the implants.  Findings were localized to the implant location and were generally mild 
in nature, and generally resolved during the course of the study.  Pupil miosis was observed in all 
eyes given active implants as expected in this species, and IOP was reduced approximately 30-
40% compared with baseline in all groups, and remained below baseline values through Month 
12.  Microscopic findings included mild signs of inflammation and foreign body reaction 
surrounding the implants.  ENV515-3 microscopic findings at Month 6 were generally mild in 
nature, particularly in the two and three implant groups, and at Month 12 only small anterior 


 
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synechiae persisted.  Overall findings observed were noted at an increased incidence and severity 
for the larger ENV515-1 implant. Overall findings for ENV515-3 were mild and were often 
similar between placebo and high dose, indicating that the number, size, and shape of implants 
may impact tolerability of ENV515.   
Aqueous humor exposure to travoprost acid peaked on Day 3 for ENV515-1 and Month 6 for 
ENV515-3, and ocular tissue exposure was highest in cornea and iris/ciliary body, with minimal 
exposure in the conjunctiva, and was highest at Day 28 for ENV515-1 and at Month 6 for 
ENV515-3.   
There was no observable systemic toxicity at any dose in the Beagle dogs as determined by 
clinical signs, body weight, food consumption, clinical pathology, and necropsy observations.  
Systemic exposure to ENV515 was very low following intracameral administration in Beagle 
dogs; plasma travoprost levels were detectable above the lower limit of quantitation in the 
high-dose animals generally only at the earliest time points evaluated (30 minutes post-dose), 
and was lower than the levels demonstrated for topical TRAVATAN Z.   
The No Observed Adverse Effect Level (NOAEL) for 28 days in Beagle dogs was 6 ENV515-1 
implants per eye (252.0 μg travoprost per eye) and 6 ENV515-3 implants per eye (82.2 μg 
travoprost per eye).  The NOAEL for ENV515-3 for 6 months in Beagle dogs was 6 ENV515-3 
implants per eye (82.2 μg travoprost/eye). 
The dose levels of travoprost in Cohort 1 of this clinical study, administered via single, unilateral 
intracameral injection of ENV515-1 and ENV515-3 formulations, were 28.2 µg/eye, 42.3 
µg/eye, 42.5 µg/eye, and 85.0 µg/eye.  The four dose levels were achieved via the following 
combinations of numbers and sizes of implants: 28.2 µg (two ENV515-3 implants), 42.3 µg 
(three ENV515-3 implants), 42.5 µg (one ENV515-1 implant), and 85.0 µg (two ENV515-1 
implants). The single, unilateral dose of travoprost dosed in Cohort 2 of this clinical study, 
administered via intracameral injection was two ENV515-3 implants/eye. The proposed single, 
unilateral dose levels of travoprost in Cohort 3 of this clinical study, administered via 
intracameral injection, consist of one or two ENV515-3-2 implants/eye, with approximately 26.1 
µg of travoprost/eye or 52.2 µg travoprost/eye for the low and high doses, respectively. 
Overall, the body of evidence suggests that with careful clinical ophthalmic monitoring and 
intracameral injection technique, the risk of potential serious adverse events (SAEs) in this 
Phase 2a study is low.  Patients in this trial will be carefully monitored by a comprehensive set 
of ophthalmic evaluations. The exposure to the intracameral implant is limited by its 
prospectively scheduled implant removal on Day 28 in Cohort 1 of the study and the option to 
remove the implant in Cohorts 2 and 3.   
1.4. 
Summary of Results from Cohort 1 of ENV515-01 Phase 2a Study 
1.4.1. 
Summary of Disposition of Cohort 1 Patients in ENV515-01 Phase 2a Study 
Patient disposition is presented in Table 9 . A total of 21 patients were enrolled and 
randomized into Cohort 1 across 10 sites.  During the early enrollment stage of the study, 
dosing of ENV515-1 larger size implant was discontinued due to suboptimal anatomical fit into 


 
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the human iridocorneal angle resulting in transient peripheral corneal edema from contact with 
the implant. For this reason, only four patients were randomized and treated with ENV515-1 
while 17 patients were randomized and treated with the smaller size ENV515-3 implant. All 
patients completed the study per protocol and there were no early discontinuations from the 
study. 
Table 9: 
Patient Disposition Table for Cohort 1 of ENV515-01 Phase 2a Study 
 
ENV515-3 
ENV515-1 
All Groups 
 
Group 1  
(low dose) 
n (%) 
Group 2  
(high dose) 
n (%) 
Group 3 
(low dose) 
n (%) 
Group 4 
(high dose) 
n (%) 
All Groups 
n (%) 
Randomized 
7 (100) 
10 (100) 
2 (100) 
2 (100) 
21 (100) 
Treated 
7 (100) 
10 (100) 
2 (100) 
2 (100) 
21 (100) 
Analysis Populations 
    Safety 
7 (100) 
10 (100) 
2 (100) 
2 (100) 
21 (100) 
    Intent-to-
treat 
7 (100) 
10 (100) 
2 (100) 
2 (100) 
21 (100) 
    Per-protocol 
7 (100) 
10 (100) 
2 (100) 
2 (100) 
21 (100) 
Study Completion 
    Completed 
7 (100) 
10 (100) 
2 (100) 
2 (100) 
21 (100) 
   
Discontinued 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
 
1.4.2. 
Summary of Efficacy Results from Cohort 1 of ENV515-01 Phase 2a Study 
In the Cohort 1 intent-to-treat population (ITT), mean decreases from baseline diurnal IOP at 
Day 25 of the study were observed in all 4 dose levels of ENV515 intracameral travoprost 
studied in 21 patients with bilateral open-angle glaucoma or ocular hypertension who were 
scheduled for upcoming cataract surgery in a single eye (the study eye, p-values < 0.05 for all 
dose groups). In general, less robust response was observed in the eyes treated with the ENV515-
1 larger size implants in comparison with the response observed in the ENV515-3 smaller sized 
implants. For the non-study eyes dosed with TRAVATAN Z, the IOP-lowering treatment effect 
was comparable to the high dose of ENV515-3. ENV515-1 dosing was discontinued in the early 
portion of the study and only low dose of the ENV515-3 formulation is progressed into Cohort 2 


 
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of the study. Results of these analyses in the per-protocol population were identical to those in 
the ITT population. 
ENV515-3 change from baseline in average diurnal IOP at Day 25 ITT (14.2.1.1, p 9 of tables): 
• Low dose (28.2 μg travoprost, 2 implants/eye): -5.1 ± 1.7 mmHg or -21.3 ±  8.3% 
(mean ± SD, n=7, p < 0.001) 
• High dose (42.3 μg travoprost, 3 implants/eye): -6.7 ± 2.1 mmHg or -27.9 ±  9.1% 
(mean +/- SD, n=10, p < 0.001) 
ENV515-1 change from baseline in average diurnal IOP at Day 25 ITT (14.2.1.1, p 9 of tables): 
• Low dose (42.5 μg travoprost, 1 implants/eye): -3.2 ± 1.2 mmHg or -12.6 ±  3.2% 
(mean ± SD, n=7, p < 0.025) 
• High dose (85 μg travoprost, 3 implants/eye): -5.7 ± 0.7 mmHg or -21.3 ±  1.1% 
(mean +/- SD, n=10, p < 0.001) 
TRAVATAN Z change from baseline in average diurnal IOP at Day 25 ITT (14.2.1.1, p 9 of 
tables): 
• -6.6 +/- 1.8 mmHg or  -28.0 +/- 7.7 %   (mean ± SD, n=21, p < 0.001)  
1.4.3. 
Summary of Safety Results from Cohort 1 of ENV515-01 Phase 2a Study 
There was no systemic exposure to travoprost based on systemic PK study and none of the non-
ocular adverse events were suspected to be related to the ENV515 (e.g. hernia, oral herpes, and 
pulled hamstring). The ocular adverse events observed in the study were generally mild in 
nature, occurring mostly early in the study (Table 10). The majority of the adverse events were 
related to the dosing procedure which involved intracameral injection of ENV515 (Table 11). In 
one patient, a late occurring case of inferior peripheral corneal edema was observed and 
attributed to a narrow iridocorneal angle via anterior chamber OCT (AODSL = 126 μm). The 
implant was seen to be contact with the peripheral cornea by gonioscopy at the time of the 
edema. The patient was initially classified as having open angle based on gonioscopy evaluation 
(Table 11). For that reason, anterior chamber OCT-based angle evaluation is used as inclusion 
criteria for Cohort 2. During the early enrollment stage of the study, dosing of the ENV515-1 
larger size implant was discontinued due to suboptimal anatomical fit into the human 
iridocorneal angle and high incidence of mild, transient AEs (Table 10) 
One patient in the high dose arm of ENV515-3 (three implants/eye) experienced a SAE related to 
decrease in corneal endothelial cell count, with one additional patient in this dose arm 
experiencing a decrease in corneal endothelial cell count greater than 10% change from baseline, 
which was not classified as an AE. There were no other adverse events associated with the 
decrease in corneal endothelial cell count in these two patients, including no changes in corneal 
thickness or BCVA. No impact on corneal endothelium was observed in the low dose arm of 
ENV515-3 (two implants/eye) nor in the two dose arms of the larger sized ENV515-1 (one and 
two implants/eye, respectively). The observed decrease in the corneal endothelial cell counts was 
observed only in the three implants/eye dose group of ENV515-3 and was attributed to the third 


 
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ENV515-3 implant extending out of the iridocorneal angle (in some cases, in a three implant 
vertical stack), as observed during gonioscopy exams. There was no evidence of progression of 
endothelial cell loss after explantation. 
Table 10: 
Overall Summary of Adverse Events by Patient Classification 
 
ENV515-3 
ENV515-1 
TRAVATAN Z 
Category 
Group 1  
(low 
dose) 
(n=7) 
n (%) 
Group 2  
(high 
dose) 
(n=10) 
n (%) 
Group 3  
(low 
dose) 
(n=2) 
n (%) 
Group 4  
(high 
dose) 
(n=2) 
n (%) 
All Groups (non-
study eye) 
(n=21) 
n (%) 
At least 1 ocular AE 
4 (57) 
7 (70) 
2 (100) 
2 (100) 
7 (33) 
At least 1 ocular AE 
unresolved by last visit 
0 
2 (20) 
0 
0 
0 
At least 1 early ocular AE 
(Day 1-7) 
4 (57) 
7 (70) 
2 (100) 
2 (100) 
3 (14) 
At least 1 late ocular AE 
(Day 19-25) 
0 
1 (10) 
1 (50) 
0 
2 (10) 
Table 11: 
Classification of Adverse Events Occurring in > 1 Patient 
 
ENV515-3 
ENV515-1 
TRAVATAN Z 
Preferred Term 
Group 1  
(low dose) 
(n=7) 
n (%) 
Group 2  
(high dose) 
(n=10) 
n (%) 
Group 3  
(low dose) 
(n=2) 
n (%) 
Group 4  
(high dose) 
(n=2) 
n (%) 
All Groups  
(non-study eye) 
(n=21) 
n (%) 
Ocular hyperemia 
4 (57) 
4 (40) 
2 (100) 
1 (50) 
4 (19) 
Foreign body 
sensation in eyes 
1 (14) 
3 (30) 
2 (100) 
1 (50) 
0 
Punctate keratitis 
3 (43) 
1 (10) 
2 (100) 
1 (50) 
1 (5) 
Anterior chamber 
cell 
1 (14) 
2 (20) 
0 
1 (50) 
0 


 
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ENV515-3 
ENV515-1 
TRAVATAN Z 
Conjunctival 
haemorrhage 
1 (14) 
3 (30) 
0 
0 
1 (5) 
Lacrimation 
increased 
0 
3 (30) 
1 (50) 
0 
0 
Iritis 
0 
2 (20) 
0 
1 (50) 
0 
Photophobia 
0 
2 (20) 
0 
1 (50) 
1 (5) 
Posterior capsule 
opacification 
0 
2 (20)* 
0 
0 
0 
*Occurred after cataract removal and intraocular lens (IOL) implantation 
1.5. 
Interim Summary of Results from Cohort 2 of ENV515-01 Phase 2a 
Study 
1.5.1. 
Summary of Disposition of Cohort 2 Patients in ENV515-01 Phase 2a Study 
Patient disposition is presented in Table 12. A total of five patients were enrolled into the study 
across two sites.  All patients completed the study and there were no early discontinuations. 
Table 12: 
Patient Disposition Table for Cohort 2 of ENV515-01 Phase 2a Study 
 
ENV515-3 
(n=5) 
Category 
n (%) 
    Treated 
5 (100) 
    Safety 
5 (100) 
    Intent-to-
treat 
5 (100) 
    Per-protocol 
4 (100) 
    Completed 
3 months post 
dose 
5 (100) 
   
Discontinued 
0 (0) 


 
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1.5.2. 
Interim Summary of Safety Results from Cohort 2 of ENV515-01 Phase 2a 
Study 
There were no SAEs reported in Cohort 2 of the study. The ocular adverse events observed in the 
study were generally mild in nature and related to the injection procedure. (Table 13 
and Table 14).  
Table 13: 
Overall Summary of Ocular Adverse Events for ENV515-3 Excluding 
Hyperemia 
Reported Events 
(summarized by 
preferred term) 
 
Number of 
Subjects 
n (%) 
Severity by AE 
incidence 
reported 
Causality 
Outcome 
 
Foreign body sensation 
4 (80) 
3 -Mild1- 
Moderate 
4 - Injection Procedure 
1 - ENV515 Implant 
Resolved 
Endothelial cell count 
loss 
2 (40) 
Mild 
ENV515 Implant 
1 - Ongoing 
1 - Resolved 
Punctate keratitis 
2 (40) 
1 – Mild 
1 - Moderate 
1 - Injection Procedure 
1 - Unrelated 
Resolved 
Blurred vision 
2 (40) 
Mild 
1 - ENV515 Implant 
1 - Unrelated 
Resolved 
Anterior chamber cell 
and flare 
1 (20) 
Mild 
Injection Procedure 
Resolved 
Photophobia 
1 (20) 
Mild 
Injection Procedure 
Resolved 
Iritis 
1 (20) 
Mild 
Injection Procedure 
Resolved 
Corneal edema 
1 (20) 
Moderate and 
Mild 
ENV515 Implant 
Resolved 
Focal microcystic 
epithelial edema 
1 (20) 
Mild 
ENV515 Implant 
Resolved 
Trichiatic eyelash  
1 (20) 
Mild 
Unrelated 
Resolved 


 
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Ocular soreness 
1 (20) 
Moderate 
Injection Procedure 
 Resolved 
Eyelid edema 
1 (20) 
Mild 
Injection Procedure 
Resolved 
Ocular discomfort 
1 (20) 
1 – Mild  
1 - Moderate 
Injection Procedure and 
Unrelated 
Resolved 
Worsening of visual 
field 
1 (20) 
Mild 
Unrelated 
Ongoing 
 
Table 14: 
Summary of Hyperemia Adverse Events for ENV515-3 Dose Arm 
Reported 
Adverse 
Events  
 
Number 
of  
Incidences 
Reported  
Study Eye or 
Both Eyes 
Severity 
Causality 
Outcome 
Ocular 
hyperemia 
2 
Study Eye 
Severe 
Injection 
Procedure 
Resolved 
Ocular 
hyperemia 
2 
Study Eye  
Moderate 
Injection 
Procedure 
Resolved 
Ocular 
hyperemia 
1 
Study Eye 
Moderate ENV515 Implant 
Resolved 
Ocular 
hyperemia 
10 
8 – Study Eye 
2 – Both Eyes 
Mild 
6 – Unrelated 
4 – ENV515 
Implant 
Resolved 
Conjunctival 
hyperemia 
1  
Study Eye 
Moderate 
Injection 
Procedure 
Resolved 
1.6. 
Summary of the Known and Potential Risks and Benefits to Human 
Patients 
The potential AEs for human subjects receiving ENV515 may occur due to 1) the use of 
travoprost in general; 2) the intracameral injection procedure; 3) the use of a solid implant in the 
anterior chamber; 4) the use of the PLA biodegradable polymers used for the ENV515 extended 
release delivery system; 5) the combination of 1-4 above; and 6) any additional effects due to 
ENV515.  Summary of relevant existing clinical data across these safety considerations provides 
a useful context for ENV515 clinical evaluation: 
• There is extensive safety, tolerability, and efficacy information on the topical 
administration of travoprost in patients with ocular hypertension or open-angle 
glaucoma, based on the US FDA approval of TRAVATAN and TRAVATAN Z.  The 


 
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most common AEs observed in controlled clinical studies with TRAVATAN and 
TRAVATAN Z are provided in more detail below. 
• Extensive information has also been published on the safety and tolerability of 
intraocular injections, based on the intravitreal administration of LUCENTIS®, 
EYLEA®, and OZURDEX®, which are currently approved and marketed in the US.  
Examples of adverse reactions reported for intravitreal injections include IOP 
increase, conjunctival hemorrhage, eye pain, conjunctival hyperemia, ocular 
hypertension, cataract, vitreous detachment and headache (OZURDEX® package 
insert [6]). Intraocular infections, endophthalmitis, may also occur after intraocular 
injections. 
• Anterior chamber paracentesis is a common procedure for relief of IOP due to acute 
angle closure glaucoma. 
• In addition, there is safety and tolerability information of intracameral injection and 
solid implants localized in the anterior chamber based on, for example, the clinical 
development of SURODEX (7), an anterior chamber dexamethasone PLGA implant. 
Solid implants localized in the anterior chamber may cause loss of corneal endothelial 
cells, corneal edema, corneal opacities, and anterior chamber inflammation (flare, 
cells and iritis). 
• The safety and tolerability of intraocular use of biodegradable PLGA polymers are 
based on the intraocular use of OZURDEX and SURODEX, which are PLGA-based, 
extended release formulations of dexamethasone for intravitreal and intracameral 
injections, respectively. 
• The safety and tolerability information from the completed portions of Cohorts 1 and 
2 of the study provides useful information for Cohort 3 (please see details in 
Section 1.4). The safety profile of ENV515 is related to the size and number of 
ENV515 implants administered per eye. The dose selected for Cohort 2 of this trial, 
two ENV515-3 implants per eye (28.2 μg of travoprost) was associated with only 
mild and transient adverse events related to the insertion procedure of ENV515: 
ocular hyperemia, foreign body sensation, punctate keratitis, anterior chamber cells 
and procedural pain (Table 11 and Table 14). Larger number of ENV515-3 implants 
per eye administered in Cohort 1 (three implants/eye) resulted in loss of corneal 
endothelial cell count in two cases (without vision loss or increase in corneal 
thickness) with no progression after explantation (Section 1.4.3). 
The most common adverse reaction observed in controlled clinical studies with TRAVATAN 
and TRAVATAN Z was ocular hyperemia which was reported in 30 to 50% of patients 
(TRAVATAN Z package insert [2]).  Up to 3% of patients discontinued therapy due to 
conjunctival hyperemia.  Ocular adverse reactions reported at an incidence of 5 to 10% in these 
clinical studies included decreased visual acuity (VA), eye discomfort, foreign body sensation, 
pain and pruritus.  Ocular adverse reactions reported at an incidence of 1 to 4% in clinical studies 
with TRAVATAN or TRAVATAN Z included abnormal vision, blepharitis, blurred vision, 


 
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cataract, conjunctivitis, corneal staining, dry eye, iris discoloration, keratitis, lid margin crusting, 
ocular inflammation, photophobia, subconjunctival hemorrhage and tearing.  Non-ocular adverse 
reactions reported at an incidence of 1 to 5% in these clinical studies were allergy, angina 
pectoris, anxiety, arthritis, back pain, bradycardia, bronchitis, chest pain, cold/flu syndrome, 
depression, dyspepsia, gastrointestinal disorder, headache, hypercholesterolemia, hypertension, 
hypotension, infection, pain, prostate disorder, sinusitis, urinary incontinence, and urinary tract 
infections.  In post-marketing use with prostaglandin analogs, periorbital and lid changes 
including deepening of the eyelid sulcus have been observed. 
Travoprost ophthalmic solution has been reported to cause changes to pigmented tissues.  The 
most frequently reported changes have been increased pigmentation of the iris, periorbital tissue 
(eyelid) and eyelashes.  Iris color change may not be noticeable for several months to years.  
Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery 
of the iris and the entire iris or parts of the iris become more brownish.  Travoprost ophthalmic 
solution may gradually change eyelashes and vellus hair in the treated eye.  These changes 
include increased length, thickness, and number of lashes.  Eyelash changes are usually 
reversible upon discontinuation of treatment.  Travoprost ophthalmic solution should be used 
with caution in patients with active intraocular inflammation (e.g., uveitis) because the 
inflammation may be exacerbated.  Macular edema, including cystoid macular edema, has been 
reported during treatment with travoprost ophthalmic solution.  Travoprost ophthalmic solution 
should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior 
lens capsule, or in patients with known risk factors for macular edema.  Topical travoprost has 
not been evaluated for the treatment of angle-closure, inflammatory or neovascular glaucoma.  
There have been reports of bacterial keratitis associated with the use of multiple-dose containers 
of topical ophthalmic products.  These containers had been inadvertently contaminated by 
patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular 
epithelial surface. 
There are no adequate and well-controlled studies of TRAVATAN Z administration in pregnant 
women.  Because animal reproductive studies are not always predictive of human response, 
TRAVATAN Z should be administered during pregnancy only if the potential benefit justifies 
the potential risk to the fetus.  A study in lactating rats demonstrated that radiolabeled travoprost 
and/or its metabolites were excreted in milk.  It is not known whether this drug or its metabolites 
are excreted in human milk.  Because many drugs are excreted in human milk, caution should be 
exercised when TRAVATAN Z is administered to a nursing woman.  No overall clinical 
differences in safety or effectiveness have been observed between elderly and other adult 
patients.  Travoprost ophthalmic solution 0.004% has been studied in patients with hepatic 
impairment and also in patients with renal impairment.  No clinically relevant changes in 
hematology, blood chemistry, or urinalysis laboratory data were observed in these patients. 
The safety of the use of a solid implant in the anterior chamber may be informed by the current 
studies of minimally invasive glaucoma implants (MIGs).  For the currently approved iStent® 
MIG product that is administered during cataract procedure, the most common post-operative 
AEs reported in the randomized pivotal trial included early post-operative corneal edema (8%), 
BCVA loss of = 1 line at or after the 3 month visit (7%), posterior capsular opacification (6%), 


 
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stent obstruction (4%) early post-operative anterior chamber cells (3%), and early post-operative 
corneal abrasion (3%).  Due to the potential for corneal touch, the potential for damage to the 
corneal endothelium is present. 
Data from GLP toxicology and toxicokinetics studies of ENV515-1 and ENV515-3 in naïve 
male Beagle dogs demonstrate that up to six ENV515-1 and six ENV515-3 implants per eye 
were well tolerated in this model over 28 days and up to six ENV515-3 implants per eye were 
well tolerated in this model over six months. Animals (two to six per group per terminal time 
point) received a single administration of up to six implants per eye (252.0 μg per eye for 
ENV515-1 and 82.2 μg per eye for ENV515-3) and were followed for up to six or 12 (recovery) 
months.  For ENV515-3, ophthalmic findings were generally very mild or not observed in the 
two and three implant groups, and a dose proportionality was observed in the incidence and 
severity as the dose escalated, with no adverse findings noted in the high dose group.  Findings 
included small areas of corneal opacity and small peripheral anterior synechiae at the location of 
the implants.  Findings were localized to the implant location and were generally mild in nature, 
and generally resolved during the course of the study.   Pupil miosis and decreased IOP (30-40% 
decrease in IOP from baseline) were observed throughout the 28-day study period, and IOP 
remained below baseline in most groups through Months 6 or 12.  Systemic exposure to 
travoprost was minimal (Cmax = 46 pg/mL), aqueous humor exposure to travoprost acid peaked 
on Day 3 for ENV515-1 and Month 6 for ENV515-3, and ocular tissue exposure was highest in 
cornea and iris/ciliary body, with minimal exposure in the conjunctiva and was highest at Day 28 
for ENV515-1 and at Month 6 for ENV515-3.  Microscopic findings included mild signs of 
inflammation and foreign body reaction surrounding the implants.  ENV515-3 microscopic 
findings at Month 6 were generally mild in nature, particularly in the two and three implant 
groups, and at Month 12 only small anterior synechiae persisted.  Overall findings observed were 
noted at an increased incidence and severity for the larger ENV515-1 implant, were mild or not 
observed for ENV515-3, and were often similar between placebo and high dose, indicating that 
the number, size, and shape of implants may impact tolerability of ENV515.  The NOAEL for 
28 days in Beagle dogs was six ENV515-1 implants (252.0 μg travoprost per eye, 504.0 µg 
travoprost per animal) and six ENV515-3 implants (82.2 μg travoprost per eye, 164.4 µg 
travoprost per animal).  The NOAEL for ENV515-3 for six months in Beagle dogs in this study 
was six ENV515-3 implants (82.2 μg travoprost/eye). 
Based on the results from the ENV515 nonclinical studies and prior findings of safety and 
efficacy for topical travoprost for TRAVATAN and TRAVATAN Z, it is considered that there 
are no nonclinical ocular or systemic toxicity findings that preclude the use of ENV515 in 
humans as described in the completed Cohort 1, Cohort 2 and Cohort 3 phases of this clinical 
study. 
There is no antidote for ENV515.  However, in cases of suspected overdose or adverse safety 
events, ENV515 implants can be removed.  For this reason, the Cohort 1 phase of ENV515-01 
employed a novel clinical trial design implemented in glaucoma patients scheduled for cataract 
surgery.  If suspected overdose or serious adverse safety event occur, the patient could have 
undergone the cataract procedure at an earlier date during which the ENV515 implants were 
removed through the corneal incision needed for the cataract removal in Cohort 1.  A similar 


 
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implant removal procedure can be used for implant removal in the Cohort 2 and 3 phases of the 
study, which would require a standalone clear corneal incision. 
1.7. 
GCP Compliance 
This clinical trial will be conducted in compliance with the protocol, International Conference 
on Harmonization (ICH), Good Clinical Practice (GCP) guidelines, Code of Federal 
Regulations Title 21 and other applicable guidelines and regulatory requirements. 
1.8. 
Population to Be Studied 
The Cohort 1 study population included 21 patients between 18 and 85 years of age with a 
diagnosis of bilateral ocular hypertension or early primary open-angle glaucoma with the need 
for cataract removal and intraocular lens implantation.   
The Cohort 2 study population included 5patients and Cohort 3 includes 15 patients between 18 
and 85 years of age with a diagnosis of bilateral ocular hypertension or early primary open-
angle glaucoma.   
The patients for all phases have been enrolled at centers across the United States in this Phase 
2a trial with ENV515 (travoprost) Intracameral Implants. 


 
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2. 
TRIAL OBJECTIVES AND PURPOSE, COHORT 1 
The primary objectives of the Cohort 1 phase of this study were to: 
• Evaluate the safety and tolerability of ENV515 (travoprost) Intracameral Implants in 
patients with bilateral ocular hypertension or early primary open-angle glaucoma; 
and 
• Evaluate the efficacy of ENV515 (travoprost) Intracameral Implants in lowering 
IOP in patients with bilateral ocular hypertension or early primary open-angle 
glaucoma. 
The secondary objectives of the Cohort 1 phase of this study were to: 
• Determine the PK levels of travoprost in the aqueous humor at the time of the cataract 
surgery (4 weeks post-implantation); 
• Determine the systemic exposure (levels of travoprost in plasma); and 
• Determine the residual level of travoprost in the implant removed at the time of the 
cataract surgery (4 weeks post-implantation). 


 
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3. 
TRIAL DESIGN, COHORT 1 
The Cohort 1 phase of this study was a multicenter, randomized, open-label, parallel-group, 
dose-ranging, 28-day Phase 2a trial to assess the safety, tolerability, efficacy, aqueous humor PK, 
systemic exposure, and remaining travoprost in ENV515 implants for 4 dose levels of ENV515, 
and was conducted in 21 patients with bilateral open-angle glaucoma or ocular hypertension (see 
inclusion criteria in Section 4.1) who are scheduled for upcoming cataract surgery in a single 
eye.  For the purposes of the Cohort 1 phase of this study, early primary open-angle glaucoma 
was defined as focal non-full thickness rim thinning with no VF changes or small isolated 
nasal step or paracentral scotoma or Seidel’s scotoma with VF mean defect (MD) of MD ≤ -8.0.  
The dose levels of travoprost in the Cohort 1 phase of this clinical study, administered via single, 
unilateral intracameral injection of ENV515-1 and ENV515-3 formulations, were 28.2 µg/eye, 
42.3 µg/eye, 42.5 µg/eye and 85.0 µg/eye.  The 4 dose level groups were achieved via the 
following numbers and sizes of implants: 28.2 µg (2 ENV515-3 implants), 42.3 µg (3 ENV515-3 
implants), 42.5 µg (1 ENV515-1 implant), and 85.0 µg (2 ENV515-1 implants).  ENV515 
implants were administered unilaterally in the study eye (pre-surgical eye) 4 weeks prior to the 
cataract surgery and the implants were retrieved during the cataract surgery.  All non-study eyes 
received open label TRAVATAN Z (travoprost ophthalmic solution), 0.004% per their usual 
treatment regimen (Figure 2). 
Figure 2: 
ENV515 Treatment Arms, Cohort 1 
 
The four ENV515 dose levels were administered in a parallel group design, with each patient 
participating in only one group.  Following Day 25 of the treatment phase (Visit 3/Day 1 to 
Visit 8/Day 25 [±1 day]), analysis of IOP treatment effect at Visit 8/Day 25 (±1 day) as % 
change in diurnal IOP from diurnal IOP baseline was conducted as the primary efficacy outcome 
measure.  Following the completion of the study follow-up (Visit 11/Day 42 to Day 49), all 
safety and tolerability assessments were conducted.  The assessment of safety and tolerability 


 
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included, but was not be limited to, data from the AE reports, corneal thickness, endothelial 
cell morphology, endothelial cell counts, and slit lamp examination. 
The study design included 11 clinic visits over approximately 10 to 12 weeks depending on the 
duration of the variable length screening and follow-up periods.  During the Screening Visit 
(Visit 1/Day -35 to -28), patients were required to washout current glaucoma medication(s) if 
currently using them (Section 16 ).  Patients were required to return for an IOP baseline check 
during the Baseline Visit (Visit 2/Day -7 to -1) following the wash-out period.  Once 
randomized, a single dose of ENV515 was given via intracameral injection during Visit 3/Day 1 
(Figure 3). 
Figure 3: 
Study Design for ENV515-01 (Cohort 1): 4-Week Phase 2a Safety, 
Tolerability, and IOP Lowering Effects of ENV515 in Glaucoma Patients in 
Need of Cataract Surgery 
 
Patients received the assigned dose of ENV515 in the pre-surgical eye on Day 1 and received 
TRAVATAN Z drops to use in the non-study eye once daily (8 p.m. ± 1 hour) from Day 1 to 
Day 25. ENV515 implants were scheduled for removal at Visit 9/Day 28 before cataract 
removal. 
Diurnal IOP curves were measured during two visits (Visit 2/Day -7 to -1 and Visit 8/ 
Day 25 ± 1 day).  During these visits, study patients were expected to remain in the clinic from 
8:00 a.m. to 5:00 p.m.  However, at the discretion of the investigator, patients will be permitted 
to leave the clinic between measurements for a specified period of time outlined by visit in 
Section 5.2 and Section 5.8. 
Throughout the study, patients underwent multiple safety assessments.  A schedule of 
assessments is outlined in the sections below and summarized in Table 1. 
. 


 
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3.1. 
Safety Evaluations, Cohort 1 
3.1.1. 
Review of Safety Data by Medical Monitor, Cohort 1 
A review of unmasked ocular safety data from each patient were performed on an ongoing 
basis by a medical monitor or Envisia designee.  All ocular safety data for each patient was 
provided to the medical monitor as it was generated throughout the trial.  A patient could be 
discontinued at any time during the study at the discretion of the medical monitor for reasons 
referenced in, but not limited to, Section 4.4.  Assessment of safety and tolerability included, 
but was not be limited to, AE reports, corneal thickness, endothelial cell morphology, 
endothelial cell counts, and slit lamp examination.  In addition, a meeting with the Envisia 
project team might be requested by the medical monitor at any time during the study to 
conduct a full evaluation of safety, which may have resulted in a recommendation to terminate 
the study.  
3.2. 
Endpoints, Cohort 1 
The endpoints of the Cohort 1 phase of this study were: 
• Incidence of AEs; 
• Changes in ophthalmic examination parameters (slit-lamp biomicroscopy, corneal 
staining, dilated funduscopic exam, anterior segment photos, pupil measurement, 
ocular symptom questionnaire, and VF as measured by the Humphrey Field Analyzer 
using program 24-2); 
• Changes in endothelial cell count and endothelial cell morphology using specular 
microscopy; 
• Changes in corneal thickness as measured using pachymetry; 
• Changes in IOP, including diurnal curve, as measured using a Goldmann applanation 
tonometer; 
• Changes in VA with manifest refraction using the Early Treatment of Diabetic 
Retinopathy Study (ETDRS) chart; 
• Changes in physical examination, vital signs, and laboratory parameters; 
• Rate of discontinuation from the study; 
• Drug levels (travoprost ester and travoprost free acid) in aqueous humor collected during 
cataract removal; 
• Drug levels (travoprost free acid) in plasma; and 
• Residual amount of travoprost (combined ester and free acid) remaining in the implants 
recovered during cataract surgery. 
 


 
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3.2.1. 
Trial Treatments, Cohort 1 
The 4 ENV515 dose levels were administered in a parallel group design, with each patient 
participating in only one group.  The 4 dose levels were achieved via the following numbers and 
sizes of implants: 28.2 µg (two ENV515-3 implants), 42.3 µg (three ENV515-3 implants), 
42.5 µg (one ENV515-1 implant), and 85.0 µg (two ENV515-1 implants). Two patients per dose 
in the two ENV515-1 dose groups, 5 patients per dose in the 2 implants/eye ENV515-3 dose 
group and 11 patients per dose in the 3 implants/eye ENV515-3 dose group had the active dose 
assigned to the pre-surgical eye that was scheduled for cataract removal, with the non-study eye 
receiving TRAVATAN Z once daily per package insert from Day 1 through Day 25. 
3.3. 
Methods to Minimize Bias in Cohort 1 
To minimize bias, patients were assigned to 1 of the 4 dose levels of ENV515 within each 
investigative site.  The non-study eye will receive TRAVATAN Z. 
The randomization code for this study was generated by Envisia or its designee.  The patients, 
investigators, site staff, and project teams at Envisia, the medical monitor, and the CRO were 
unmasked to treatment assignment. 


 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS, COHORT 1 
4.1. 
Patient Inclusion Criteria, Cohort 1 
Individuals of either gender or any race were eligible for participation in Cohort 1 if they: 
1. Provide written informed consent prior to study procedures. 
2. Are between 18 and 85 years of age. 
3. Have a willingness to comply with the investigator’s instructions, attend study visits, and 
stop prior eye medications to treat glaucoma and/or ocular hypertension. 
4. If female, patient must be non-pregnant and non-lactating, and those of childbearing 
potential must be using an acceptable method of birth control (i.e., an intrauterine 
contraceptive device with a failure rate of <1%, hormonal contraceptives, or a barrier 
method).  If a female patient is abstinent, she must agree to use one of the acceptable 
methods if she becomes sexually active. 
5. Have a diagnosis of bilateral ocular hypertension or mild to moderate primary open-angle 
glaucoma and have open normal appearing anterior chamber angles (Shaffer 
classification Grade 3 or 4, angle of approach 20° or larger). 
6. Are currently treated with topical PGA for ocular hypertension. 
7. At the Baseline Visit after washout (Visit 2), have IOP measurements that meet all of the 
following: 
a. Have an IOP at 8:00 a.m. (±30 minutes) and at 10:00 a.m. (±30 minutes) between 
22-34 mm Hg in both eyes with a ≤4 mm Hg difference between the eyes 
b. Have an IOP at 4:00 p.m. (±30 minutes) between 19-34 mm Hg in both eyes with a 
≤4 mm Hg difference between each eye 
8. Have an IOP ≤34 mm Hg in each eye at all other time points prior to the Baseline Visit 
(Visit 2). 
9. At the Screening Visit (Visit 1), have an IOP in both eyes that is considered to be safe, so 
that clinical stability of vision and the optic nerve is likely throughout the trial. 
10. Have endothelial cell counts of at least 2000 cells/mm2 and normal endothelial cell 
morphology at the Screening Visit (Visit 1) as evaluated by central reading center. 
11. Patient is a candidate for and has been scheduled for cataract extraction in a single eye 
within 60 days of Visit 1*. 
* Following cataract removal, the patient may undergo additional procedures (e.g., iStent 
insertion). 


 
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4.2. 
Patient Exclusion Criteria, Cohort 1 
Individuals are not eligible for study participation in Cohort 1 if they: 
1. Are currently diagnosed with closed angle glaucoma, exfoliation syndrome or exfoliation 
glaucoma, and pigment dispersion or secondary glaucoma. 
2. Have a history of glaucoma-related surgery (trabeculectomy, cryotherapy, laser 
iridotomy, etc.). 
3. Have had intraocular conventional surgery, intraocular laser surgery, corneal refractive 
surgery or eyelids surgery within the past 3 months. 
4. Are currently diagnosed with active infectious/noninfectious conjunctivitis, keratitis, 
uveitis, or moderate to severe blepharitis in either eye.  (Chronic mild blepharitis or 
injection related to mild blepharitis, lid lag, mild dry eye or seasonal allergies are 
allowed.) 
5. Are currently taking or have taken corticosteroids (oral, ocular, injectable, IV and/or 
topical) or used dermatology formulations of steroids in the vicinity of eyes in the 
1 month prior to Visit 1 with the exception of inhaled, intranasal, or topical (dermal) 
steroids if on a stable dose; or have a history of chronic ocular corticosteroid (topical or 
intraocular) use within the past year. 
6. Have a requirement for any ocular medications that are specifically disallowed in this 
protocol for any condition during the study or within the specified timeframe prior to 
Visit 2. 
7. Have a history of recurrent corneal erosion syndrome, multiple corneal abrasions, or an 
abrasion that was slow to heal. 
8. Have severe glaucoma with a mean defect (MD) worse than -8.0, central island of vision, 
or otherwise severe glaucoma that would not tolerate a possible short-term increase in 
IOP. 
9. According to the investigator’s best judgment, are at risk for progression of glaucoma, 
VF or VA worsening as a consequence of participation in the trial. 
10. Have any abnormality preventing reliable applanation tonometry in either eye. 
11. Have any corneal opacity or are uncooperative in such a way that restricts adequate 
examination of the ocular fundus or anterior chamber in either eye. 
12. Are unwilling to discontinue use of contact lenses at least 2 days prior to Visit 2 for soft 
lenses and at least 7 days prior to Visit 2 for rigid gas permeable (RGP) lenses through 
completion of the study at Visit 11. 
13. Have progressive retinal or optic nerve disease apart from glaucoma. 
14. Have any clinically significant, serious, or severe medical or psychiatric condition. 


 
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15. Are, in the opinion of the investigator, unable or unwilling to comply with study 
procedures, including attending the scheduled study visits. 
16. Have a history, or a suspected history of drug or alcohol dependence in the preceding 
year. 
17. Are unwilling to limit alcohol ingestion and smoking for the 8-hour period prior to and 
during study appointments after Visit 1. 
18. Have received any investigational product within the past 30 days prior to Visit 1. 
19. Have any history of allergic hypersensitivity or poor tolerance to any components of the 
preparations used in this trial such as travoprost or PLA excipients. 
20. Have a history of insufficient response to PGA topical treatment, i.e., are PGA non-
responders. 
21. Are an employee of the clinical site that is directly involved in the management, 
administration, or support of this study or are an immediate family member of the same. 
22. Have a central corneal thickness greater than 600 micrometers as determined by 
pachymetry at the Baseline Visit (Visit 2). 
23. Had prior intraocular surgery or any ocular or systemic condition that may confound the 
study outcome per the investigator’s recommendation. 
4.3. 
Randomization Criteria, Cohort 1 
At the Randomization Visit (Visit 3/Day 1), an eligible patient must: 
• Continue to meet all inclusion/exclusion criteria as defined in Sections 4.1 and 4.2 
4.4. 
Patient Withdrawal Criteria, Cohort 1 
Any patient who wished to withdraw from the study on his or her own accord for any reason was 
entitled to do so without obligation.  Patients who were withdrawn from the study prior to 
randomization could be replaced.  Any patient could be removed from the study by the 
investigator if it is deemed necessary for the patient’s safety. 
In the event that withdrawal of a randomized patient was medically necessary or requested by the 
patient, the investigator made every attempt to complete all protocol safety assessments and 
visits through the cataract surgery combined with the removal of the ENV515 implant(s), and the 
post-surgery follow-up visits. 
If patient withdrawal was required due to an AE or SAE, the cataract surgery combined with the 
removal of the ENV515 implant(s) should have occurred as soon as possible based on the 
judgment of the investigator and safety of the patient. 
If an AE or SAE was unresolved at the time of the patient’s final study visit, an effort was made 
to follow the patient until the AE or SAE is resolved or stabilized (Section 17), the patient was 


 
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lost to follow-up, or there was some other resolution of the event.  The investigator should have 
made every attempt to follow all SAEs to resolution. 
4.4.1. 
Specific Withdrawal Criteria, Cohort 1 
Following ongoing review of the data by the medical monitor, any individual patient safety 
concerns was discussed between the medical monitor and investigator.  If the investigator 
determined that a patient should be discontinued and withdrawn from the study, the cataract 
surgery and removal of the ENV515 implant(s) should occur as soon as possible based on the 
judgment of the investigator.  Any rescue therapy or procedures should be applied based on the 
judgment of the investigator. 
A patient may be discontinued and withdrawn from the study at any time at the discretion of the 
investigator for any safety reason, including but not limited to those listed below: 
• IOP measurement of 35 mm Hg or greater in either eye at any measurement 
• Any clinically significant pole changes, including but not limited to: 
− Cystoid macular edema (CME) 
− Retinal pigment epithelium (RPE) 
− Disc rim pallor 
• Pachymetry measurement of the central corneal thickness which reveals a change that 
falls outside of the normal variability when compared to the baseline measurement 
− An acute increase of 15% or greater in corneal thickness for a period of <24 hours 
after the instillation of study drug 
− A chronic increase of 10% or greater in corneal thickness for a period of 
>24 hours after the instillation of study drug 
• A >10% decrease in central endothelial cell density as evaluated by the centralized 
reading center 
In the event that study discontinuation and withdrawal of a randomized patient is necessary, the 
investigator should make every attempt to complete all protocol safety assessments and visits 
through the cataract surgery combined with the removal of the ENV515 implant(s), and the 
post-surgery follow-up visits.  The cataract surgery combined with the removal of the ENV515 
implant(s) should occur as soon as possible based on the judgment of the investigator.  Unless 
the consent has been withdrawn, any patient is considered to be in the treatment phase of the 
study until the cataract surgery combined with ENV515 implant removal has been completed, 
and such patients should continue to be followed and will be expected to complete all pre- and 
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5. 
PROCEDURE SCHEDULE BY VISIT, COHORT 1 
5.1. 
Visit 1/-35 to -28 days/Screening Evaluation, Cohort 1 
At Visit 1, patients will be screened, and if eligible, enrolled into the study.  Before any study 
specific assessments are performed, written informed consent will be obtained from each patient.  
During the visit, the procedures described below will be performed. 
5.1.1. 
Screening Assessments, Cohort 1 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Obtain written informed consent 
2. Obtain medical history, ocular history, and demographics (can be performed anytime 
during the site visit and does not need to follow the order as written) 
3. Evaluate and record patient’s medication usage (including concomitant medications taken 
within the past 30 days) (can be performed anytime during the site visit and does not need 
to follow the order as written) 
4. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
5. Perform pupil measurement 
6. Perform slit lamp biomicroscopy 
7. Perform corneal staining 
8. Measure IOP 
9. Perform gonioscopy 
10. Perform pachymetry (contact) 
11. Perform specular microscopy (non-contact) 
− Non-contact specular microscopy can be performed anytime during the clinic visit 
and does not need to follow the order as written. 
12. Assess VF 
13. Perform anterior chamber OCT 
14. Perform dilated funduscopic exam 
15. Perform physical examination (can be performed anytime during the site visit and does 
not need to follow the order as written) 


 
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16. Assess vital signs (can be performed anytime during the site visit and does not need to 
follow the order as written) 
17. Collect non-fasting blood and urine for clinical laboratory tests 
18. If female of childbearing potential, perform urine or serum pregnancy test 
19. Verify that patient meets all applicable entry criteria 
20. Query patient about whether or not they have experienced symptoms suggesting an AE.  
AEs will be documented. 
At the end of the examination, patients will be asked to discontinue their current glaucoma 
medication(s).  Section 16.2.2 references the duration of the washout period given different types 
of topical glaucoma therapy.  The patient will be asked to return for the baseline visit after 
4 weeks.  The washout period may be extended up to 2 weeks, if it remains safe for the patient, 
to accommodate the patient’s or the investigator’s schedule. 
5.1.2. 
Patient Instructions, Cohort 1 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the following instructions: 
• Discontinue use of all eye drop medications until the end of the study (if appropriate).  
With your doctor’s approval, you may be able to use artificial tear eye drops. 
• Remember not to use alcohol or tobacco products within 8 hours of your next clinic visit. 
• At Visits 2 and 8, be prepared for a long clinic visit.  You will be expected to have IOP 
measurements at 8:00 a.m., 10:00 a.m., and 4:00 p.m.  You may leave the clinic after the 
10:00 a.m. assessments, with your doctor’s approval. 
• Call your study site if you have any problems. 
• Remember not to wear contact lenses 2 days for soft contact lenses and 7 days for RGP 
lenses prior to next visit 
5.2. 
Visit 2/Day -7 to -1/Baseline, Cohort 1 
Patients will be queried about changes in medications and whether or not they have experienced 
symptoms suggesting an AE.  AEs will be documented. 


 
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5.2.1. 
Baseline Assessments, Cohort 1 
Assessments will be conducted in the following general order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction, the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. (±30 minutes) 
− IOP must be between 22-34 mm Hg in both eyes with a ≤4 mm Hg difference 
between each eye at 8:00 a.m. (±30 minutes) 
6. Perform gonioscopy 
7. Perform pachymetry (contact) 
8. Perform specular microscopy (non-contact) 
− Non-contact specular microscopy can be performed anytime during the site visit 
and does not need to follow the order as written. 
9. Perform anterior chamber OCT 
10. Perform physical examination (can be performed anytime during the site visit and does 
not need to follow the order as written) 
11. Assess vital signs (can be performed anytime during the site visit and does not need to 
follow the order as written) 
12. Collect non-fasting blood and urine for clinical laboratory tests 
13. If female of childbearing potential, perform urine or serum pregnancy test 
14. Measure IOP at 10:00 a.m. (±30 minutes) 
− IOP must be between 22-34 mm Hg in both eyes with a ≤4 mm Hg difference 
between each eye at 10:00 a.m. (±30 minutes) 
15. Measure IOP at 4:00 p.m. (±30 minutes) 
− IOP must be between 19-34 mm Hg in both eyes with a ≤4 mm Hg difference 
between each eye at 4:00 p.m. (±30 minutes) 
16. Perform dilated funduscopic examination 
17. Verify that patient meets all entry criteria 


 
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Patients are expected to remain in the clinic for the completion of all procedures (~8:00 a.m. to 
~5:00 p.m.).  However, at the discretion of the investigator, patients will be permitted to leave 
the clinic after completing the 10:00 a.m.  IOP measurement and will return to the clinic before 
the 4:00 p.m. IOP measurement.  Any patient that leaves the clinic will be instructed to return no 
later than 30 minutes prior to the 4:00 p.m. IOP measurement. 
5.2.2. 
Patient Instructions, Cohort 1 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 5.1.2. 
5.3. 
Visit 3/Day 1/Randomization/Treatment, Cohort 1 
Query patient about changes in medications and whether or not they have experienced symptoms 
suggesting an AE.  AEs will be documented. 
5.3.1. 
Pre-dose Assessments, Cohort 1 
Assessments will be conducted in the following general order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes) 
5. Instill one drop of VIGAMOX into the study eye  
6. If female of childbearing potential, perform urine or serum pregnancy test 
7. Verify that patient meets all entry criteria 
5.3.2. 
Randomization and Study Drug Administration, Cohort 1 
Patients will be assessed to ensure they still qualify to participate in the study based on the 
inclusion/exclusion criteria and randomization criteria (Section 4.3).  The study principal 
investigator will administer the first and only dose of study medication into the pre-surgical 
study eye (see Section 6.1.1. Implantation of ENV515).  The ENV515 experimental medication 
will be delivered at 10:00 a.m. (±30 minutes). TRAVATAN Z will be administered into the 
non-study eye by the patient at 8 p.m. (±30 minutes). 
At the randomization/treatment visit (Visit 3), the patient’s pre-surgical eye will be randomly 
assigned to 1 of the 4 dose levels of ENV515 and patients will receive 1 to 3 ENV515 
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administered via the provided intracameral implant applicator.  The site will receive 
randomization information based on randomization schedule following Visit 2 specifying which 
ENV515 formulation (ENV515-1 or ENV515-3) and how many implants to administer.  The 
randomization code for this open-label study will be computer-generated prior to the study start.  
To randomize a patient (Visit 3), the investigator (or designee) will confirm in the electronic 
Case Report Form (eCRF) that the patient remains qualified for the study.  The eCRF will 
automatically assign the dose and number of implants that the patient should receive based on a 
prospectively prepared computer generated code list. 
5.3.3. 
Post-dose Assessments, Cohort 1 
1. Perform slit lamp biomicroscopy 
2. Dispense TRAVATAN Z to the patient 
Patients are expected to remain in the clinic for the completion of all procedures (~8:00 a.m. to 
~12:00 p.m.); however, at the discretion of the investigator, patients will be permitted to leave 
the clinic following the completion of the dosing. 
5.3.4. 
Patient Instructions, Cohort 1 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the following instructions: 
• Remember to use TRAVATAN Z once daily in the evening (as close to 8:00 p.m. as you 
can) in the eye that is NOT having cataract surgery.  DO NOT PUT TRAVATAN Z in 
the eye that had the ENV515 implant(s).  Continue using TRAVATAN Z only through 
Day 24, one day prior to Visit 8 (Day 25 ± 1 day).  Please remember to bring 
TRAVATAN Z with you to Visit 8 (Day 25 ± 1 day) so that it can be collected from you. 
• Continue to withhold (not use) all your other eye drop medications until the end of the 
study (if appropriate).  With your doctor’s approval, you may be able to use artificial tear 
eye drops. 
• Remember not to use alcohol or tobacco products within 8 hours of your next clinic visit. 
• Call your study site if you have any problems. 
• Please avoid physical activities associated with jarring physical motions, such as 
horseback riding, for the rest of the study. 
5.4. 
Visit 4/Day 3 ± 1 Day/Treatment Period, Cohort 1 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 


 
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Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes) 
5. Perform gonioscopy 
6. Perform anterior chamber OCT 
Patients are expected to remain in the clinic for the completion of all procedures (~8:00 a.m. to 
~10:00 a.m.).  Before patients leave the clinic, they should receive an appointment for their next 
study visit and the instructions provided in Section 5.3.4. 
5.5. 
Visit 5/Day 7 ± 1 Day/Treatment Period, Cohort 1 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes) 
Patients are expected to remain in the clinic for the completion of all procedures (~8:00 a.m. to 
~9:00 a.m.).  Before patients leave the clinic, they should receive an appointment for their next 
study visit and the instructions provided in Section 5.1.2. 
5.6. 
Visit 6/Day 14 ± 1 Day/Treatment Period, Cohort 1 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 


 
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Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. (±30 minutes) 
6. Perform gonioscopy 
7. Perform pachymetry (contact) 
8. Perform specular microscopy (non-contact) 
− Non-contact specular microscopy can be performed anytime during the site visit 
and does not need to follow the order as written. 
9. Perform anterior chamber OCT 
10. Perform dilated funduscopic exam 
11. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK 
Patients are expected to remain in the clinic for the completion of all procedures (~8:00 a.m. to 
~10:00 a.m.).  Before patients leave the clinic, they should receive an appointment for their next 
study visit and the instructions provided in Section 5.3.4. 
5.7. 
Visit 7/Day 21 ± 1 Day/Treatment Period, Cohort 1 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 


 
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4. Measure IOP at 8:00 a.m. (±30 minutes) 
5. Perform gonioscopy 
Patients are expected to remain in the clinic for the completion of all procedures (~8:00 a.m. to 
~10:00 a.m.).  Before patients leave the clinic, they should receive an appointment for their next 
study visit and the instructions provided in Section 5.3.4. 
5.8. 
Visit 8/Day 25 ± 1 Day/Treatment Period, Cohort 1 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented.  Collect TRAVATAN Z 
from the patient. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. (±30 minutes) 
6. Perform gonioscopy 
7. Perform pachymetry (contact) 
8. Perform specular microscopy (non-contact) 
− Non-contact specular microscopy can be performed anytime during the site visit 
and does not need to follow the order as written. 
9. Perform anterior chamber OCT 
10. Measure IOP at 10:00 a.m. (±30 minutes) 
11. Measure IOP at 4:00 p.m. (±30 minutes) 
12. Perform dilated funduscopic examination 
13. Collect TRAVATAN Z from the study patients 
5.8.1. 
Disbursement and First Administration of Pre-Surgical Medications 
Following the completion of all assessments, the patients will receive their pre-surgical anti-
inflammatory and antibiotic medications: PRED FORTE, PROLENSA, and VIGAMOX.  The 


 
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medications will be administered by the patients on Day 26, 27, and 28 twice a day for each 
medication, once in the morning and once in the evening.  Following the removal of the ENV515 
implant (Visit 9/Day 28), it is upon the discretion of the investigator to determine the post-
operative medication regimen.  Patients will be provided with instructions on use of these 
medications and what to do to prepare for their cataract surgery. 
Patients are expected to remain in the clinic for the completion of all procedures (~8:00 a.m. to 
~4:30 p.m.).  However, at the discretion of the investigator, patients will be permitted to leave 
the clinic after completing the 10:00 a.m. IOP measurement and will return to the clinic before 
the 4:00 p.m. IOP measurement.  Any patient that leaves the clinic will be instructed to return no 
later than 30 minutes prior to 4:00 p.m.  Before patients leave the clinic for the day, they should 
receive an appointment for their next study visit and the instructions provided in Section 5.1.2. 
5.9. 
Visit 9/Day 28/Cataract Surgery, Cohort 1 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
5.9.1. 
Pre-surgery Assessment, Cohort 1 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. If dilation is required to properly conduct BCVA (ETDRS) with manifest refraction the 
assessment should be performed after the slit lamp biomicroscopy and IOP measurement. 
3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. (±30 minutes) 
6. Perform gonioscopy to identify the location of the ENV515 implants to facilitate implant 
recovery during the cataract removal procedure 
7. Additional assessment needed prior to cataract removal conducted per discretion of the 
principal investigator 
5.9.2. 
Cataract Removal Procedure Combined with Aqueous Humor Sampling and 
Implant Recovery, Cohort 1 
The cataract surgery and IOL implantation will be conducted according to the discretion of the 
principal investigator per established protocols.  The following study-specific procedures will be 
performed during the cataract surgery: 
1. The implant location(s) are identified by gonioscopy exam conducted during pre-surgery 
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2. Following the creation of the initial incision in the clear cornea, ~100 μL of aqueous 
humor will be sampled from the anterior chamber via provided tuberculin syringe with 
30 ga needle.  The sample will be treated as described in Appendix 1. 
3. After the removal of the aqueous humor sample, implants will be recovered from the 
anterior chamber. 
4. A stream of buffered saline solution (BSS) is directed to the iridocorneal angle location 
where the implant(s) have been identified until implant(s) is/are dislodged from the 
iridocorneal angle and float in the anterior chamber. Utrata forceps or an equivalent 
instrument is used to grasp the implant(s) one at a time and remove the implant(s) 
through the incision in the clear cornea created for cataract removal and IOL 
implantation. 
5. The aqueous humor samples and recovered implants will be treated as described 
in Appendix 1. 
5.9.3. 
Post-Surgical Assessments, Cohort 1 
The post-surgical assessments will be conducted according to the discretion of the principal 
investigator per established protocols.  Any observations associated with a standard cataract 
extraction followed by intraocular lens implantation as conducted by the principal investigator 
per established protocols, such as expected levels of aqueous cells or flare, will be recorded as 
AEs.  Patients are expected to remain in the clinic for the completion of all procedures 
(~8:00 a.m. to ~12:00 p.m.); however, at the discretion of the investigator, patients will be 
permitted to leave the clinic after completing all procedures and assessments.  Before patients 
leave the clinic, they should receive an appointment for their next study visit and the instructions 
provided in Section 5.1.2.  IOP lowering medications can be prescribed per the judgement of the 
principal investigator at this time. 
5.10. 
Visit 10/Day 33 to 38/Follow-up, Cohort 1 
Patients will be queried about changes in medications and whether or not they have experienced 
symptoms suggesting an AE.  AEs will be documented.  Any observations associated with a 
standard cataract extraction followed by intraocular lens implantation as conducted by the 
principal investigator per established protocols, such as expected levels of aqueous cells or flare, 
will be recorded as AEs.   
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
2. Perform pupil measurement 


 
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3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. (±30 minutes) 
6. Perform gonioscopy 
7. Perform pachymetry (contact) 
8. Assess VF 
9. Perform anterior chamber OCT 
10. Perform dilated funduscopic exam 
11. Perform physical examination (can be performed anytime during the site visit and does 
not need to follow the order as written) 
12. Assess vital signs (can be performed anytime during the site visit and does not need to 
follow the order as written) 
13. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK 
14. If female of childbearing potential, perform urine or serum pregnancy test 
Patients are expected to remain in the clinic for the completion of all procedures (~8:00 a.m. to 
~10:00 a.m.).  Before patients leave the clinic, they should receive an appointment for their next 
study visit and the instructions provided in Section 5.3.4. 
5.11. 
Visit 11/Day 42 to 49/Study Exit, Cohort 1 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. Any observations associated 
with a standard cataract extraction followed by intraocular lens implantation as conducted by the 
principal investigator per established protocols, such as expected levels of aqueous cells or flare, 
will be recorded as AEs. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes) 


 
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5. Perform specular microscopy (non-contact) 
− Non-contact specular microscopy can be performed anytime during the site visit 
and does not need to follow the order as written. 
6. Complete the exit form 
7. Discharge the patient from the trial 
Patients are expected to remain in the clinic for the completion of all procedures (~8:00 a.m. to 
~10:00 a.m.).  The patient will exit the trial barring any clinically significant, possibly related or 
related unresolved AEs. 
5.12. 
Unscheduled Visits, Cohort 1 
Patients may need to be seen at other times than the scheduled study visits for additional safety 
assessments or to follow-up, as medically necessary, on changes in clinical status or to follow-up 
on clinical laboratory or other findings.  If an additional study visit occurs, the date and nature of 
the visit will be documented. 
During unscheduled visits, query patient about changes in concomitant medications and whether 
or not they have experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Only study eye will be evaluated at the 
listed ophthalmic assessments, with additional evaluations carried out as deemed necessary per 
the investigator’s discretion: 
1. Assess BCVA (ETDRS) with manifest refraction 
− If dilation is required to properly conduct BCVA (ETDRS) with manifest 
refraction the assessment should be performed after the slit lamp biomicroscopy 
and IOP measurement. 
2. Measure IOP at 8:00 a.m. (±30 minutes) or when feasible 
 


 
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6. 
TREATMENT OF PATIENTS, COHORT 1 
6.1. 
Treatments to be Administered, Cohort 1 
6.1.1. 
Implantation of ENV515, Cohort 1 
Treatment consisted of a single intracameral injection of ENV515 (travoprost) Intracameral 
Implant(s) into a pre-surgical eye that was scheduled for cataract removal.  A single drop of 
TRAVATAN Z was administered into the non-study eye as indicated daily from Visit 3 (Day 1) 
to Day 24, one day prior to Visit 8 (Day 25 ± 1 day).  TRAVATAN Z was collected from the 
patients during Visit 8 (Day 25, ± 1 day). 
At the randomization/treatment visit (Visit 3), patient’s pre-surgical eye was assigned to 1 of the 
dose levels of ENV515 and patients received 1 to 3 ENV515 (travoprost) Intracameral 
Implant(s) into the pre-surgical eye via intracameral injection administered via the provided 
intracameral implant applicator.  All investigators were trained in implant loading, 
administration and retrieval by Envisia.  The site received randomization information based on 
randomization schedule following Visit 2 specifying which ENV515 formulation (ENV515-1 or 
ENV515-3) and how many implants to administer.  The randomization code for this open-label 
study was computer-generated.  To randomize a patient (Visit 3), the investigator (or designee) 
confirmed in the eCRF that the patient remains qualified for the study.  The eCRF automatically 
assigned the dose and number of implants that the patient was to receive based on a 
prospectively prepared computer generated code list. 
The study treatment assignment of 1 of 4 dose levels of ENV515 to be administered was 
determined by the randomization code.  ENV515-1 and ENV515-3 (travoprost) Intracameral 
Implant(s) were supplied in sterile glass vials with 1 implant per vial.  The sterile implant 
applicator was provided in a Tyvek® pouch.  The packages were opened and the implant 
applicator and the implants were placed into a sterile field.  The implants were loaded into the 
implant applicator by the investigator immediately prior to dosing.  The implant size (ENV515-1 
or ENV515-3) and the number of implants to load into the implant applicator was determined 
based on the randomization code identifying 1 of 4 dose levels described in Section 3.2.1.  
Additionally, the study eye was administered topical antibiotic VIGAMOX following the 
completion of the pre-dose assessments (Section 5.3.1) and immediately before and after the 
ENV515 implant administration as described below.  The following instructions were distributed 
with the ENV515 implants and implant applicator: 
Opening Instructions, Cohort 1 
1. Use sterile technique in sterile field to open primary packaging for the applicator and 
ENV515 implants. 
2. Open ENV515 Phase 2a Implant Applicator packaging and place the sterile ENV515 
applicator into sterile field. 
3. Do not open glass vial containing implants until ready to load into the applicator. 


 
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Instructions for Loading the Implant into the Applicator by the Principal Investigator, 
Cohort 1 
1. Load ENV515 implant(s) into the ENV515 Phase 2a implant applicator in a sterile field 
using sterile technique via insertion through the beveled needle end.  The implant type 
(ENV515-1 or ENV515-3) and the number of implants will be specified in the 
randomization code. 
Instructions for Administration by Principal Investigator, Cohort 1 
1. Treat subject’s ocular surface with topical anesthetic (proparacaine 0.5% or equivalent). 
2. Treat subject’s ocular surface, periocular skin, eyelid margins and eyelashes with 
povidone iodine and wait 2 minutes. 
3. Insert lid speculum. 
4. Instill one drop of VIGAMOX into the study eye. 
5. Administer the implant(s) into the anterior chamber via intracameral injection through 
clear, peripheral cornea.  The needle should be advanced parallel with the iris, ~1 mm 
anterior to the limbus with the subject sitting at the slit lamp, or with the subject supine 
under the operating scope. 
6. Instill one drop of VIGAMOX into the study eye. 
One implant applicator and 5 glass vials with one ENV515-1 or ENV515-3 implant/vial will be 
packaged in an appropriately labeled carton.  The label on the package will minimally contain 
the following information: each package contains no less than 5 glass vials with either one 
ENV515-1 or ENV515-3 implant/vial and one ENV515 implant applicator; study ENV515-01, 
storage temperature, and “Caution: Limited by Federal (or United States) Law to Investigational 
use”.  An unmasked disclosure panel will be displayed on the bottle label of the study medication 
and will minimally contain the following information: ENV515-01, and name of product.  The 
study medications will be stored in a secure area with limited access to study personnel under 
refrigerated storage at approximately 2 to 8°C. 
6.1.2. 
TRAVATAN Z for Non-Study Eye, Cohort 1 
TRAVATAN Z will be provided for the non-study eye with its original packaging, labeling, and 
instructions for use (non-study eye only). 


 
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7. 
ASSESSMENT OF EFFICACY, COHORT 1 
Assessments of efficacy included: 
• IOP measurements completed at all visits.  A diurnal curve of IOP measurements will be 
completed on Visit 2/Baseline and Visit 8/Treatment Day 25. 
The IOP assessments and their timing are outlined in Table 1 and Section 5. 
8. 
ASSESSMENT OF SAFETY, COHORT 1 
8.1. 
Safety Parameters, Cohort 1 
Safety and tolerability of ENV515 were evaluated using the following assessments: 
• Specular microscopy (non-contact) 
• Slit-lamp biomicroscopy 
• Corneal staining 
• Dilated fundus examination 
• Gonioscopy exam 
• Anterior chamber OCT exam 
• Pupil measurement 
• Pachymetry (contact) 
• BCVA 
• VF 
• Physical examination 
• Vital signs 
• Non fasting clinical laboratory tests (chemistry and hematology) 
• Serum or urine pregnancy tests for females of childbearing potential 
• AEs 
These assessments and their timing are outlined in Table 1 (Cohort 1 Time and Events 
Schedule) and Section 5.  Compliance with study drug administration was also be assessed 
(Section 16.3). 
  


 
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9. 
TRIAL OBJECTIVES AND PURPOSE, COHORTS 2 AND 3 
The primary objective of the Cohort 2 and 3 phases of this study is to: 
• Evaluate in a dose escalating design the long-term safety and tolerability of a single, 
unilateral low dose of two ENV515-3 (travoprost) intracameral implants/eye in 
Cohort 2; and low and high doses of one and two ENV515-3-2 (travoprost) 
intracameral implants/eye, respectively, in Cohort 3 in patients with bilateral ocular 
hypertension or primary open-angle glaucoma; and 
 


 
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10. 
TRIAL DESIGN, COHORTS 2 AND 3 
Cohorts 2 (5 patients) and 3 (15patients) are 12-month, prospective, open-label, active-
comparator-controlled, multicenter, dose escalating cohorts of this Phase 2a trial. Cohort 2 had a 
6-month optional Extension 1 followed by an additional 3-month optional Extension 2 (for up to 
a total of 21 months), increasing the total study duration to approximately 23 months.  Cohort 3 
has a 6-month optional Extension 1 followed by an additional 6-month optional Extension 2 (for 
a total of 24 months), increasing the total study duration to approximately 26 months.  Cohorts 2 
and 3 were designed to assess the long-term safety, tolerability, and systemic exposure to 
travoprost after a single low dose (ENV515-3) in Cohort 2; and single low or high doses of 
(ENV515-3-2) in Cohort 3 in patients with bilateral open-angle glaucoma or ocular hypertension 
(see inclusion criteria in Section 11.1).  For the purposes of the Cohorts 2 and 3, patients are 
eligible if in the opinion of the investigator they have an IOP in both eyes that is considered to be 
adequately controlled at the screening visit, can be safely withdrawn from IOP medications in 
both eyes during the washout period, and are not considered to be at significant risk for disease 
progression throughout the trial.  The dose levels of travoprost in Cohorts 2 and 3 of this study 
are achieved by administration of a single, unilateral intracameral injection of each formulation 
with 28.2 µg travoprost/eye in Cohort 2; and 26.1 µg and 52.2 µg travoprost/eye in Cohort 3. 
These dose levels will be achieved via two implants per eye for low dose of ENV515-3 in Cohort 
2; and one and two implants per eye for the low and high doses of ENV515-3-2, respectively, in 
Cohort 3.  The study eye is prospectively defined as the eye with higher IOP or the left eye if 
IOP values are equal in both eyes on Dosing Visit (Day 1). All non-study eyes will receive open-
label timolol maleate 0.5% ophthalmic solution administered twice a day (Figure 4 and 
Figure 5). 
 
Figure 4: 
ENV515 Treatment, Cohort 2 
 


 
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Figure 5: ENV515 Treatment, Cohort 3 
 
On the Day 1 Dosing (Visit 3), low dose of ENV515-3 in Cohort 2, or low or high doses of 
ENV515-3-2 in Cohort 3 will be administered. Following Day 84 of the treatment phase 
(Dosing Visit 3/Day 1 to Treatment Visit 7/Day 84 [±7 days]), an analysis of IOP treatment 
effect as a change in mean diurnal IOP from mean diurnal IOP baseline will be conducted as the 
primary efficacy outcome measure.  Following the completion of the rest of the study treatment 
period Month 4 (Visit 8) to Exit/Early Exit (Visit 16, Visit 22, or Visit 25) for the Cohort 2 
alone, all safety and tolerability analyses will be conducted (Figure 6).   
Figure 6: 
Study Design for ENV515-01 (Cohorts 2 and 3) 
 
 
For Cohort 2, the study design included up to 26 clinic visits over approximately 23 months (12 
months of Cohort 2, 6-month optional Extension 1, and 3-month optional Extension 2). For 
Cohort 3, the study design includes up to 28 clinic visits over approximately 26 months (12 
months of Cohort 3,6-month optional Extension 1, and 6-month optional Extension 2). 
Following the Screening Visit, patients will be required to washout current glaucoma 
medication(s) (Section 16.1) for 4 weeks with up to an additional 2-week extension or 6 weeks 


 
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depending on Cohort.  Patients will be required to return for an IOP baseline check during the 
Baseline Visit (Visit 2/Day -7 to -1) following the wash-out period.  A single dose of ENV515-3 
(two implants/eye) or ENV515-3-2 (one or two implant(s)/eye) will be given via intracameral 
injection during Dosing Visit 3/Day 1. 
Patients will receive the following investigational product doses in the study eye on Day 1 
Dosing (Visit 3) and will receive timolol maleate 0.5% ophthalmic solution to use in the non-
study eye twice daily starting on the evening of Day 1 and continuing through the day prior to 
Month 12 (Visit 16), Month 18 (Visit 22), or Month 21 (Visit 25) for Cohort 2 or Month 24 
(Visit 28) for Cohort 3.  
• Cohort 2 low dose level: two implants/eye of ENV515-3 (28.2 µg/eye)  
• Cohort 3 low and high dose levels: 
− one implant/eye of ENV515-3-2 (26.1 µg/eye)  
− two implants/eye of ENV515-3-2 (52.2 µg/eye)  
Diurnal IOP curves will be measured at select study visits with the exception of the abbreviated 
visits at the Screening Visit (Days -49 to -42 for Cohort 2 and Days -56 to -42 for Cohort 3) 
Dosing Visit 3 (Day 1), Treatment Visit 4 (Day 2), and Treatment Visit 5a (Day 28), and selected 
visits depending on the Cohort and Extension(s). 
Throughout the study, patients will undergo multiple safety assessments.  A schedule of 
assessments is outlined in the sections below and in Table 1, Table 2, Table 3, Table 4, 
Table 5, Table 6, and Table 7. 
10.1. 
Safety Evaluations, Cohorts 2 and 3 
10.1.1. 
Review of Safety Data by Medical Monitor, Cohorts 2 and 3 
A review of unmasked ocular safety data from each patient will be performed on an ongoing 
basis by a medical monitor.  All ocular safety data for each patient will be provided to the 
medical monitor as it is generated throughout the trial.  A patient may be discontinued at any 
time during the study at the discretion of the medical monitor for reasons referenced in, but not 
limited to Section 15.2.1.  In addition, a meeting with the Envisia project team may be 
requested by the medical monitor at any time during the study to conduct a full evaluation of 
safety, which may result in a recommendation to terminate the study. 
10.2. 
Safety Endpoints, Cohorts 2 and 3 
The safety endpoints of the Cohorts 2 and 3 phases of this study are: 
• Incidence of AEs; 
• Changes in ophthalmic examination parameters (slit-lamp biomicroscopy, corneal 
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ocular symptom questionnaire, and VF as measured by the Humphrey Field Analyzer 
using program 24-2); 
• Changes in endothelial cell count and endothelial cell morphology using specular 
microscopy; 
• Changes in corneal thickness as measured using pachymetry; 
• Changes in IOP, including diurnal curve, as measured using a Goldmann applanation 
tonometer; 
• Changes in BCVA with manifest refraction using the ETDRS chart; 
• Changes in body systems assessment, vital signs, and laboratory parameters; 
• Rate of discontinuation from the study; and 
• Drug levels (travoprost free acid) in plasma. 
10.3. 
Endpoints, Cohorts 2 and 3 
10.3.1. 
Trial Treatments, Cohorts 2 and 3 
The single low dose of 28.2 µg travoprost/eye will be achieved via two ENV515-3 implants/eye 
in Cohort 2. Single low and high doses of 26.1 and 52.2 µg/eye travoprost will be achieved 
via one or two ENV515-3-2 implants/eye, respectively, in Cohort 3 dosed into the study eye, 
with the non-study eye receiving timolol maleate 0.5% ophthalmic solution dosed twice a day. 
10.3.2. 
Study Eye Selection 
The central reading centers will determine eligibility of one or both eyes based on inclusion 
criteria related to corneal endothelial cell counts and anterior chamber angles assessed at 
Screening (Visit 1).  At least one of the eyes must meet both inclusion criteria of cell counts and 
angle in addition to the other eligibility criteria.   If both eyes are eligible, the study eye is 
defined as the eye with the higher mean diurnal IOP at Baseline (Visit 2) or the left eye if the 
mean diurnal IOP values are equal for both eyes at Baseline (Visit 2). 
10.4. 
Methods to Minimize Bias in Cohorts 2 and 3 
Patients were prospectively assigned to one dose of ENV515-3 in Cohort 2. In Cohort 3 
ENV515-3-2 will be administered into the study eye, starting with the high dose level first (n=9) 
and proceeding to the low dose (n=6).  The study eye is prospectively assigned based on 
predefined criteria (Section 11.3 and Section 11.4). The non-study eye will receive timolol 
maleate 0.5% ophthalmic solution.  The patients, investigators, site staff, and project teams at 
Envisia, and the medical monitor, will be unmasked to treatment assignment. 


 
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11. 
SELECTION AND WITHDRAWAL OF PATIENTS, COHORTS  
2 AND 3 
11.1. 
Patient Inclusion Criteria, Cohort 2 
Individuals of either gender or any race will be eligible for study participation in Cohort 2 if 
they: 
1. Are male or female between 18 and 85 years of age. 
2. Have a diagnosis of bilateral ocular hypertension or primary open-angle glaucoma. 
3. Normal appearing anterior chamber angles (Shaffer classification Grade 3 or 4, with an 
angle of at least 20° determined by gonioscopy, and confirmed to have an open angle as 
determined by anterior chamber OCT evaluated by a central reading center prior to 
dosing). 
4. Are currently treated with topical PGA for ocular hypertension in both eyes. 
5. Patients who in the opinion of the investigator: have an IOP in both eyes that is 
considered to be adequately controlled at the Screening Visit (Visit 1); can be safely 
withdrawn from IOP medications in both eyes during the washout period, and who are 
not considered to be at significant risk for disease progression throughout the trial. 
6. At the Baseline Visit after washout (Visit 2), have IOP measurements that meet all of the 
following: 
a. Have an IOP at 8:00 a.m. (±30 minutes) and at 10:00 a.m. (±30 minutes) between 22 
and 34 mm Hg in both eyes with a ≤4 mm Hg difference between the eyes 
b. Have an IOP at 4:00 p.m. (±30 minutes) between 19 and 30 mm Hg in both eyes with 
a ≤4 mm Hg difference between each eye 
7. At the Dosing Visit (Visit 3), have IOP measurement that is between 22 and 34 mm Hg in 
both eyes with a ≤4 mm Hg difference between the eyes. 
8. Have endothelial cell counts of at least 2000 cells/mm2 and normal endothelial cell 
morphology prior to dosing as evaluated by central reading center. 
9. If female, patients must be incapable of pregnancy because of hysterectomy, tubal 
ligation or have been amenorrheic for at least 2 years.  Female patients much have a 
negative pregnancy test and not be nursing.  If female patient is capable of pregnancy, 
she must use effective (e.g. double barrier) method of birth control for the duration of the 
study. 
10. Must be able to provide a written informed consent to participate in the study, in 
accordance with the international Conference on Harmonization (ICH) Good Clinical 
Practice (GCP) guidelines, and local regulations, before initiating any study-related 
procedures. 


 
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11.2. 
Patient Exclusion Criteria, Cohort 2  
Individuals of either gender or any race will not be eligible for study participation in Cohorts 2 if 
they: 
1. Are diagnosed with closed angle glaucoma, exfoliation syndrome or exfoliation 
glaucoma, pigment dispersion or secondary glaucoma. 
2. Are insufficiently responsive to PGA topical treatment, i.e., are PGA non-responders. 
3. Have a history of glaucoma-related surgery (e.g., trabeculectomy, cryotherapy, laser 
iridotomy and minimally invasive procedures including shunts/stents). 
4. Have severe glaucoma with a mean defect (MD) worse than -8.0, a central island of 
vision, or otherwise severe glaucoma that would not tolerate a short-term increase in IOP. 
5. According to the investigator’s best judgment, are at risk for progression of glaucoma, 
VF or VA worsening as a consequence of participation in the trial. 
6. Have any abnormality preventing reliable applanation tonometry in either eye. 
7. Have a central corneal thickness less than 500 micrometers or greater than 600 
micrometers as determined by pachymetry at the Screening Visit (Visit 1). 
8. Have a history of recurrent corneal erosion syndrome, multiple corneal abrasions, or an 
abrasion that was slow to heal. 
9. Have had intraocular conventional surgery, intraocular laser surgery, corneal refractive 
surgery or eyelids surgery within the past 3 months. Complicated cataract surgery that 
resulted in intraocular lens placement outside the capsular bag or a break in the posterior 
capsule is not allowed. 
10. Are currently diagnosed with active infectious/noninfectious conjunctivitis, or moderate 
to severe blepharitis in either eye.  (Chronic mild blepharitis or injection related to mild 
blepharitis, lid lag, mild dry eye or seasonal allergies are allowed.) 
11. Are currently taking or have taken corticosteroids (oral, ocular, injectable, IV) or used 
dermatology formulations of steroids in the vicinity of eyes in the 1 month prior to Visit 
1; have a history of chronic ocular corticosteroid (topical or intraocular) use within the 
past year. Inhaled, intranasal, or topical (dermal) steroids not in the vicinity of the eyes is 
permissible if on a stable dose for at least 1 month prior to Visit 1. 
12. Have any media opacity or are uncooperative in such a way that restricts adequate 
examination of the ocular fundus or anterior chamber in either eye. 
13. Are unwilling to discontinue use of contact lenses for the duration of their study 
participation. 
14. Have progressive retinal or optic nerve disease apart from glaucoma or history of uveitis 
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15. Have any history of allergic hypersensitivity or poor tolerance to any components of the 
preparations used in this trial such as travoprost or poly-lactic acid or similar excipients, 
topical anesthetic (proparacaine 0.5% or equivalent), iodine, timolol maleate and 
VIGAMOX® (or generic equivalent). 
16. Have a requirement for any ocular medications that are specifically disallowed in this 
protocol for any condition during the study or within the specified timeframe prior to 
Visit 2. 
17. Have a history, or a suspected history of drug or alcohol dependence in the preceding 
year. 
18. Currently using or used marijuana in the past 30 days prior to Visit 1. 
19. Have received any investigational product within the past 30 days prior to Visit 1. 
20. Are an employee of the clinical site that is directly involved in the management, 
administration, or support of this study or are an immediate family member of the same 
21. Patients who, per investigator’s judgment, are not good clinical trial candidates due to 
personal (e.g., perceived willingness or ability to comply with protocol, significant 
traveling distance to medical center) and/or medical (i.e. mental illness, other non-ocular 
medical conditions, or laboratory abnormalities that might negatively impact trial 
participation or outcome) conditions that would likely impede the patient’s successful 
study completion or planned analyses. 
11.3. 
Patient Inclusion Criteria, Cohort 3 
Individuals of either gender or any race will be eligible for study participation in Cohort 3 if 
they: 
1. Are male or female between 18 and 85 years of age. 
2. Have a diagnosis of bilateral ocular hypertension or primary open-angle. 
3. Normal appearing anterior chamber angles (Shaffer classification Grade 3 or 4, with an 
angle of at least 20° determined by gonioscopy, and confirmed to have an open angle as 
determined by anterior chamber OCT evaluated by a central reading center prior to 
dosing in the study eye). 
4. Are currently treated with topical PGA for ocular hypertension in both eyes. (Dual 
therapy (i.e. PGA and another IOP lowering agent) is acceptable) 
5. In the opinion of the investigator, the non-study eye can be adequately controlled with 
timolol maleate 0.5% ophthalmic solution BID. 
6. Patients who in the opinion of the investigator, have an IOP in both eyes that is 
considered to be adequately controlled at Screening (Visit 1), can be safely withdrawn 
from IOP medications in both eyes during the washout period, and who are not 
considered to be at significant risk for disease progression throughout the trial. 


 
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7. At Baseline (Visit 2) after washout, have IOP measurements that meet all of the 
following: 
a. Have an IOP at 8:00 a.m. (±30 minutes) and at 10:00 a.m. (±30 minutes) between 22 
and 34 mm Hg in both eyes with a ≤4 mm Hg difference between the eyes 
b. Have an IOP at 4:00 p.m. (±30 minutes) between 19 and 30 mm Hg in both eyes with 
a ≤4 mm Hg difference between each eye 
c. Demonstrate an 8 AM IOP increase of at least 4 mmHg in each eye Baseline (Visit 2) 
compared to the Screening (Visit 1) IOP measurements.  
8. At Dosing (Visit 3), have IOP measurement that is between 22 and 34 mm Hg in both 
eyes with a ≤4 mm Hg difference between the eyes. 
9. Have endothelial cell counts of at least 2000 cells/mm2 and normal endothelial cell 
morphology at Screening (Visit 1) as evaluated by central reading center in the study eye. 
10. If female, patients must either be incapable of pregnancy because of hysterectomy, tubal 
ligation or have been amenorrheic for at least 2 years or must use effective (e.g., double 
barrier) method of birth control for the duration of the study.  Female patients must have 
a negative pregnancy test, and not be nursing  
11. Must be able to provide a written informed consent to participate in the study, in 
accordance with the international Conference on Harmonization (ICH) Good Clinical 
Practice (GCP) guidelines, and local regulations, before initiating any study-related 
procedures. 
11.4. 
Patient Exclusion Criteria, Cohort 3  
Individuals of either gender or any race will not be eligible for study participation in Cohort 3 if 
they: 
1. Are diagnosed with closed angle glaucoma, exfoliation syndrome or exfoliation 
glaucoma, pigment dispersion or secondary glaucoma in either eye. 
2. Are insufficiently responsive to PGA topical treatment, i.e., are PGA non-responders in 
either eye. 
3. Have a history of glaucoma-related surgery (e.g., Selective Laser Trabeculoplasty (SLT), 
Argon Laser Trabeculoplasty (ALT), trabeculectomy, cryotherapy, laser iridotomy and 
minimally invasive procedures including shunts/stents) in the study eye. 
4. Have severe glaucoma with a mean defect (MD) worse than -8.0, a central island of 
vision, or otherwise severe glaucoma that would not tolerate a short-term increase in IOP 
including advanced cupping in either eye. 
5. Have manifest refraction BCVA worse than 20/80 Snellen in either eye as measured 
using an ETDRS chart in. 
6. Have hyperemia score of 1 or greater at Baseline (Visit 2). 


 
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7. According to the investigator’s best judgment, are at risk for progression of glaucoma, 
VF or VA worsening as a consequence of participation in the trial in either eye. 
8. Have any abnormality preventing reliable applanation tonometry in either eye. 
9. Have a central corneal thickness less than 500 micrometers or greater than 600 
micrometers as determined by pachymetry at Screening (Visit 1) in either eye. 
10. Have a history of recurrent corneal erosion syndrome, multiple corneal abrasions, or an 
abrasion that was slow to heal in either eye. 
11. Have had intraocular conventional surgery, intraocular laser surgery, corneal refractive 
surgery or eyelids surgery within the past 3 months in the study eye. Complicated 
cataract surgery that resulted in intraocular lens placement outside the capsular bag or a 
break in the posterior capsule in the study eye is not allowed. 
12. Are currently diagnosed with active infectious/noninfectious conjunctivitis, or moderate 
to severe blepharitis in either eye.  (Chronic mild blepharitis or injection related to mild 
blepharitis, lid lag, mild dry eye or seasonal allergies are allowed.) 
13. Are currently taking or have taken corticosteroids (oral, ocular, injectable, IV) or used 
dermatology formulations of steroids in the vicinity of eyes in the 1 month prior to 
Screening (Visit 1); have a history of chronic ocular corticosteroid (topical or intraocular) 
use within the past year. Inhaled, intranasal, or topical (dermal) steroids not in the 
vicinity of either eye is permissible if on a stable dose for at least 1 month prior to 
Screening (Visit 1). 
14. Have any medial opacity or are uncooperative in such a way that restricts adequate 
examination of the ocular fundus or anterior chamber in either eye. 
15. Are unwilling to discontinue use of contact lenses for the duration of their study 
participation. 
16. Have progressive retinal or optic nerve disease apart from glaucoma or history of uveitis 
or keratitis in either eye.  
17. Have any history of allergic hypersensitivity or poor tolerance to any components of the 
preparations used in this trial such as travoprost or poly-lactic acid or similar excipients, 
topical anesthetic (proparacaine 0.5% or equivalent), iodine, timolol maleate, and 
VIGAMOX® (or generic equivalent). 
18. Have a requirement for any ocular medications that are specifically disallowed in this 
protocol for any condition during the study or within the specified timeframe prior to 
Baseline (Visit 2). 
19. Have a history, or a suspected history of illicit drug or alcohol dependence in the 
preceding year. 
20. Currently using or used marijuana in the past 30 days prior to Screening (Visit 1). 


 
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21. Have received any investigational product within the past 30 days prior to Screening 
(Visit 1) or have ever been previously implanted in the anterior segment with 
experimental therapies. 
22. Are an employee of the clinical site that is directly involved in the management, 
administration, or support of this study or are an immediate family member of the same 
23. Patients who, per investigator’s judgment, are not good clinical trial candidates due to 
personal (e.g., perceived willingness or ability to comply with protocol, significant 
traveling distance to medical center) and/or medical (e.g., mental illness, other non-ocular 
medical conditions, or laboratory abnormalities that might negatively impact trial 
participation or outcome) conditions that would likely impede the patient’s successful 
study completion or planned analyses. 
11.5. 
Dosing Criteria, Cohorts 2 and 3 
At the Dosing Visit (Visit 3/Day 1), an eligible patient must: 
• Continue to meet all inclusion/exclusion criteria as defined in Section 11.1, 
Section 11.2, Section 11.3, and Section 11.4 depending on cohort. 
11.6. 
Patient Rescue Criteria, Cohorts 2 and 3 
For Cohort 2 and its Extensions 1 and 2, rescue therapy may be allowed in the study eye if in the 
opinion of the investigator the IOP is not well controlled on any two visits after Day 1 that are 
separated by at least 4 weeks.  If IOP is well controlled, rescue therapy should be discontinued 
and the patient should resume regular study visit schedule. Each patient can be subjected to up to 
two rescue treatments. If rescue therapy is needed after 2 prior rescue therapy periods or after 7 
months post-dose, the patient should be permanently rescued until the completion of the study. 
For Cohort 2 and its Extensions 1 and 2, AZOPT® (brinzolamide ophthalmic suspension) 1% 
will be used for rescue therapy. Patients will be given four weeks of AZOPT treatment 3 times 
daily and evaluated at their next study visit. If IOP is well controlled, rescue therapy should be 
discontinued and patients should resume the regular study visit schedule per protocol. At the 
investigator’s discretion, the patient can be brought in for an unscheduled visit two weeks 
following the discontinuation of AZOPT for an IOP assessment. The investigator can choose to 
measure IOP at 8 AM or full diurnal. If the IOP is well controlled during the unscheduled visit, 
the patient should resume the regular study visit schedule. If the patient’s IOP is not well 
controlled during the unscheduled visit, the patient should be permanently rescued with Timolol 
maleate 0.5% ophthalmic solution twice a day until the completion of the study. Thus, each 
patient can be subjected to only one AZOPT rescue treatment. Notwithstanding the above, both 
the study and non-study eyes may be rescued at any time, at the investigator’s discretion, if it is 
considered to be in the best interest of the patient. 
For Cohort 3 and its Extension 1, rescue therapy may be allowed in the study eye if, in the 
opinion of the investigator, the IOP is not well controlled on any two visits after Month 3 (Day 
84) that are separated by at least 4 weeks (+/- 7 days).  Timolol maleate 0.5% ophthalmic 


 
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solution administered BID daily will be used for rescue therapy. The patient should be 
permanently rescued with Timolol maleate 0.5% ophthalmic solution twice a day until the 
completion of the study. Notwithstanding the above, both the study and non-study eyes may be 
rescued at any time, at the investigator’s discretion, if it is considered to be in the best interest of 
the patient. 
11.7. 
Patient Withdrawal Criteria, Cohorts 2 and 3 
Any patient who wishes to withdraw from the study on his or her own accord for any reason is 
entitled to do so without obligation.  Patients who are withdrawn from the study prior to dosing 
will be replaced.  Any patient may be removed from the study by the investigator if it is deemed 
necessary for the patient’s safety. 
In the event that withdrawal of a dosed patient is medically necessary or requested by the patient, 
the investigator should make every attempt to complete all assessments indicated at the Early 
Exit/Exit (Visit 16 for Cohorts 2 and 3, Visit 22 for Cohort 2 Extension 1, Visit 25 for Cohort 2 
Extension 2; and Visit 22 for Cohort 3 Extension 1). 
If patient withdrawal is required due to a treatment related AE or SAE and the implant removal 
is necessary prior to its biodissolution, the removal of the ENV515-3 or ENV515-3-2 implant(s) 
should occur as soon as possible based on the judgment of the investigator and safety of the 
patient. 
If an treatment related AE or SAE is unresolved at the time of the patient’s final study visit, an 
effort will be made to follow the patient until the AE or SAE is resolved or stabilized 
(Section 17), the patient is lost to follow-up, or there is some other resolution of the event.  The 
investigator should make every attempt to follow all SAEs to resolution. 
Following ongoing review of the data by the medical monitor, any individual patient safety 
concerns will be discussed between Envisia representative and investigator.  If the investigator 
determines that a patient should be discontinued and withdrawn from the study, the removal of 
the ENV515 implants should occur as soon as possible based on the judgment of the investigator.   
A patient may be discontinued and withdrawn from the study at any time at the discretion of the 
investigator for any safety reason, including but not limited to those listed below: 
• IOP measurement of 35 mm Hg or greater in either eye at any measurement 
• Any clinically significant pole changes, including but not limited to: 
− Progressive VF loss or optic nerve changes 
− CME 
− Other significant disease such as AMD or vascular occlusion 
• Pachymetry measurement of the central corneal thickness which reveals a change that 
falls outside of the normal variability when compared to the baseline measurement 


 
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− An acute increase of 15% or greater in corneal thickness for a period of <24 hours 
after the instillation of study drug 
− A chronic increase of 10% or greater in corneal thickness for a period of 
>24 hours after the instillation of study drug 
• A ≥30% decrease in central endothelial cell density as evaluated by the centralized 
reading center 
In the event that study discontinuation and withdrawal of a subject is necessary, the investigator 
should make every attempt to complete all protocol safety assessments and visits.  Unless 
consent has been withdrawn, any subject is considered to be in the treatment phase of the study 
until the completion of the study, and such subjects should continue to be followed and will be 
expected to complete all safety assessments and visits.  
11.8. 
Early Exit Criteria, Cohorts 2 and 3 
Patients may also exit the study sooner than their exit visit if all of the following are true: 
• They have received rescue therapy 
• Their IOP in the study eye is well controlled 
• No implant remnants are visible by gonioscopy on two consecutive visits 
• No treatment related adverse events are present that require continued monitoring. 


 
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12. 
PROCEDURE SCHEDULE BY STUDY VISIT, COHORT 2 
12.1. 
Visit 1/-49 to -29 days/Screening Evaluation, Cohort 2  
At Visit 1, patients will be screened, and if eligible, enrolled into the study.  Before any study 
specific assessments are performed, written informed consent will be obtained from each patient.  
Screening procedures can be conducted over several visits but should be completed within a 7 
day period.  During the visit, the procedures described below will be performed. 
12.1.1. 
Screening Assessments 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Obtain written informed consent 
2. Obtain medical history, ocular history, and demographics (can be performed anytime 
during the visit) 
3. Evaluate and record patient’s medication usage (including concomitant medications taken 
within the past 30 days) (can be performed anytime during the visit) 
4. Assess BCVA (ETDRS) with manifest refraction 
5. Perform pupil measurement 
6. Perform slit lamp biomicroscopy 
7. Perform corneal staining 
8. Measure IOP at 8 a.m. 
9. Perform gonioscopy 
10. Perform pachymetry (contact) 
11. Perform specular microscopy, non-contact (can be performed anytime during the visit 
beyond the pachymetry exam) 
12. Assess VF 
13. Perform anterior chamber OCT 
14. Perform dilated funduscopic exam 
15. Perform body system assessment (can be performed anytime during the site visit) 
16. Assess vital signs (can be performed anytime during the site visit) 
17. Collect non-fasting blood and urine for clinical laboratory tests (can be performed any 
time after the 10 a.m. IOP measurements) 
18. If female of childbearing potential, perform urine pregnancy test 
19. Verify that patient meets all applicable entry criteria 


 
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20. Begin washout of patient’s current PGA therapy.  
21. Query patient about whether or not they have experienced symptoms during the exam 
procedures suggesting an AE.  AEs will be documented. 
The patient will be asked to return for the baseline visit after 4 weeks.  The washout period may 
be extended up to two additional weeks if it remains safe for the patient, and to accommodate the 
patient’s or the investigator’s schedule. 
Before subjects leave the clinic, they should receive an appointment for their next study visit and 
the following instructions: 
• Discontinue use of all eye drop medications until the end of the study (if appropriate).  
With your doctor’s approval, you may be able to use artificial tear eye drops. 
• At all visits except Visit 3 and Visit 4, be prepared for a long clinic visit.  You will be 
expected to have IOP measurements at 8:00 a.m., 10:00 a.m., and 4:00 p.m.  You may 
leave the clinic after the 10:00 a.m. assessments with your doctor’s approval. 
• Call your study site if you have any problems. 
• Remember not to wear contact lenses  
12.2. 
Visit 2/Day -7 to -1/Baseline, Cohort 2  
Patients will be queried about changes in medications and whether or not they have experienced 
symptoms suggesting an AE.  AEs will be documented. 
12.2.1. 
Baseline Assessments 
Assessments will be conducted in the following general order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. 
− IOP must be between 22-34 mm Hg in both eyes with a ≤4 mm Hg difference 
between each eye at 8:00 a.m. (±30 minutes) 
− IOP must increase of at least 4 mmHg in each eye compared to the pre-washout 
baseline  
6. Perform gonioscopy 
7. Perform pachymetry (contact) 
8. Perform specular microscopy (non-contact) (can be performed anytime during the visit) 


 
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9. Assess vital signs (can be performed anytime during the site visit) 
10. Measure IOP at 10:00 a.m. (±30 minutes) 
− IOP must be between 22-34 mm Hg in both eyes with a ≤4 mm Hg difference 
between each eye at 10:00 a.m. (±30 minutes) 
11. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK (can be 
performed after the 10 a.m. IOP) 
12. If female of childbearing potential, perform urine pregnancy test 
13. Measure IOP at 4:00 p.m. (±30 minutes) 
− IOP must be between 19-30 mm Hg in both eyes with a ≤4 mm Hg difference 
between each eye at 4:00 p.m. (±30 minutes) 
14. Perform dilated funduscopic examination 
15. Verify that patient meets all entry criteria 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~5:00 p.m.).  However, at the discretion of the investigator, patients will be permitted to leave 
the clinic after completing the 10:00 a.m. IOP measurement and will return to the clinic before 
the 4:00 p.m. IOP measurement.  Any patient that leaves the clinic will be instructed to return no 
later than 30 minutes prior to the 4:00 p.m. IOP measurement. 
12.3. 
Visit 3/Day 1/Dosing/Treatment, Cohort 2  
Query patient about changes in medications and whether or not they have experienced symptoms 
suggesting an AE.  AEs will be documented. 
12.3.1. 
Pre-dose Assessments 
Assessments will be conducted in the following general order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at between 6:00 a.m. and 10:00 a.m. a.m. (±30 minutes) 
5. Perform gonioscopy 
6. Perform pachymetry (contact) 
7. Perform specular microscopy (non-contact) study eye only 
8. Instill one drop of VIGAMOX into the study eye 
9. Verify that patient meets all entry criteria 


 
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12.3.2. 
Study Eye Assignment and Study Drug Administration 
Patients will be assessed to ensure they still qualify to participate in the study based on the 
inclusion/exclusion criteria (Section 11.3 and Section 11.4 ).  The patient’s study eye will be 
assigned to receive 2 ENV515-3 (travoprost) Intracameral Implant(s) into the study eye via 
intracameral injection administered via the provided intracameral implant applicator. The study-
trained investigator will administer the dose of study medication into the study eye between 6:00 
a.m. and 10:00 a.m. (±30 minutes).  Timolol maleate 0.5% ophthalmic solution will be 
administered into the non-study eye by the patient at 8 p.m. (±60 minutes) on the day of Visit 3.  
12.3.3. 
Post-dose Assessments 
1. Perform slit lamp biomicroscopy 
2. Dispense bottle of timolol maleate 0.5% ophthalmic solution to the patient 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~12:00 p.m.); however, at the discretion of the investigator, patients will be permitted to leave 
the clinic following the completion of the dosing. 
12.3.4. 
Patient Instructions 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the following instructions: 
• Remember to use timolol maleate 0.5% ophthalmic solution twice daily (as close to 
8:00 a.m. and 8:00 p.m. as you can ± 60 minutes) in the non-study eye.  DO NOT 
PUT timolol maleate 0.5% ophthalmic solution in the eye that received the ENV515 
implants.  Continue using timolol maleate 0.5% ophthalmic solution until one day 
prior to the last study visit, Visit 16 (Month 12 ± 7 days).  Please remember to bring 
timolol maleate 0.5% ophthalmic solution with you to at each subsequent visit so that 
it can be administered after the 8:00 a.m. IOP measurement. It will need to be 
collected from you before issuing a new bottle at applicable visits. 
• Continue to withhold (not use) all your other eye drop medications until the end of 
the study (if appropriate).  With your investigator’s approval, you may be able to use 
artificial tear eye drops. 
• Remember not to wear contact lenses 
• Call your study site if you have any problems 
• Please avoid physical activities associated with jarring physical motions, such as 
horseback riding, for the rest of the study. 
12.4. 
Visit 4/Day 2 + up to 3 Days/Treatment Period, Cohort 2 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 


 
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Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise noted: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
5. Perform gonioscopy   
6. Perform pachymetry (contact) 
7. Perform specular microscopy (non-contact) study eye only 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~10:00 a.m.).  Before patients leave the clinic, they should receive an appointment for their next 
study visit and the instructions provided in Section 12.3.4. 
12.5. 
Visit 5/Day 14 ± 3 Days/Treatment Period, Cohort 2  
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise noted: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement)  
5. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4:00 p.m. IOP measurement) 
6. Perform pachymetry (contact) 
7. Perform specular microscopy (non-contact)  
8. Measure IOP at 10:00 a.m. (±30 minutes) 
9. Measure IOP at 4:00 p.m. (±30 minutes) 
10. If female of childbearing potential, perform urine pregnancy test 
11. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK (can be 
performed after the 10 a.m. IOP) 


 
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12. Patients are expected to remain in the clinic for the completion of all procedures (~7:30 
a.m. to ~5:00 p.m.).  However, at the discretion of the investigator, patients will be 
permitted to leave the clinic after completing the 10:00 a.m.  IOP measurement and will 
return to the clinic before the 4:00 p.m. IOP measurement.  Any patient that leaves the 
clinic will be instructed to return no later than 30 minutes prior to the 4:00 p.m. IOP 
measurement. Before patients leave the clinic, they should receive an appointment for 
their next study visit and the instructions provided in Section 12.3.4. 
12.6. 
Visit 5a/Day 28 ± 3 Days/Treatment Period, Cohort 2 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise noted: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
5. Perform gonioscopy 
6. Perform pachymetry (contact) 
7. Perform specular microscopy (non-contact) study eye only 
Patients are expected to remain in the clinic for the completion of all procedures (~8:00 a.m. to 
~10:00 a.m.).   
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 12.3.4. 
12.7. 
Visit 6/Day 42 ± 3 Days/Treatment Period, Cohort 2 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes), please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement 


 
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5. Perform gonioscopy  (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4 :00 p.m. IOP measurement) 
6. Perform pachymetry (contact) 
7. Perform specular microscopy (non-contact) study eye only (can be performed anytime 
during the visit) 
8. Measure IOP at 10:00 a.m. (±30 minutes) 
9. Measure IOP at 4:00 p.m. (±30 minutes) 
10. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK (can be 
performed after the 10 a.m. IOP) 
11. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~5:00 p.m.).  However, at the discretion of the investigator, patients will be permitted to leave 
the clinic after completing the 10:00 a.m.  IOP measurement and will return to the clinic before 
the 4:00 p.m. IOP measurement.  Any patient that leaves the clinic will be instructed to return no 
later than 30 minutes prior to the 4:00 p.m. IOP measurement. 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 12.3.4. 
12.8. 
Visit 7/Day 84 ± 7 Days/Treatment Period, Cohort 2  
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
6. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4 :00 p.m. IOP measurement) 
7. Perform pachymetry (contact) 
8. Perform specular microscopy (non-contact) study eye only(can be performed anytime 
during the site visit) 


 
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9. Perform anterior chamber OCT 
10. Measure IOP at 10:00 a.m. (±30 minutes) 
11. Measure IOP at 4:00 p.m. (±30 minutes) 
12. Perform body system assessment (can be performed anytime during the site visit) 
13. Assess vital signs (can be performed anytime during the site visit) 
14. Perform dilated fundus exam 
15. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK (can be 
performed after the 10:00 a.m. IOP) 
16. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~5:00 p.m.).  However, at the discretion of the investigator, patients will be permitted to leave 
the clinic after completing the 10:00 a.m.  IOP measurement and will return to the clinic before 
the 4:00 p.m. IOP measurement.  Any patient that leaves the clinic will be instructed to return no 
later than 30 minutes prior to the 4:00 p.m. IOP measurement.  
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 12.3.4. 
12.9. 
Visit 8/Month 4 – Visit 15/Month 11 ± 7 Days/Treatment Period, 
Cohort 2 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented.   
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform pupil measurement only at Visit 10/Month 6, and Visit 13/Month 9  
3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
6. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4 :00 p.m. IOP measurement) 
7. Perform pachymetry (contact) only at Visits 8, 9, 10, 12, and 14 
8. Perform specular microscopy (non-contact) study eye only at Visits 8, 9, 10, 12, and 14 
(can be performed anytime during the site visit)  


 
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9. Measure IOP at 10:00 a.m. (±30 minutes) 
10. Measure IOP at 4:00 p.m. (±30 minutes) 
11. Perform body system assessment (can be performed anytime during the site visit) only at 
Visit 10/Month 6 
12. Assess vital signs (can be performed anytime during the site visit) only at Visit 
10/Month 6 and Visit 13/Month 9 
13. Perform dilated funduscopic examination only at Visit 10/Month 6 
14. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK only at 
Visits 10, 11, and 13 for clinical laboratory tests and at all visits for systemic PK  (can be 
performed after the 10 a.m. IOP) 
15. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~5:00 p.m.).  However, at the discretion of the investigator, patients will be permitted to leave 
the clinic after completing the 10:00 a.m.  IOP measurement and will return to the clinic before 
the 4:00 p.m. IOP measurement.  Any patient that leaves the clinic will be instructed to return no 
later than 30 minutes prior to the 4:00 p.m. IOP measurement. 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 12.3.4. 
12.10. 
Visit 16/Month 12 ± 7 Days/Treatment Period Study Exit, Cohort 2 
(if patient chooses not to enroll in Extension 1) 
If a patient discontinues prior to the Visit 16/Month 12, or declines to continue into the Cohort 2 
Study Extension 1 and chooses to exit the study at Visit 16/Month 12, the following procedures 
are to the performed.  If the patient chooses to continue into the Cohort 2 Study Extension 1, 
please follow the procedures in Section 12.11. 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8 am (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 


 
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6. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4 :00 p.m. IOP measurement) 
7. Perform pachymetry (contact) 
8. Perform specular microscopy (non-contact) for both eyes (can be performed anytime 
during the visit) 
9. Assess VF 
10. Perform anterior chamber OCT 
11. Measure IOP at 10:00 a.m. (±30 minutes) 
12. Measure IOP at 4:00 p.m. (±30 minutes) 
13. Perform dilated funduscopic exam 
14. Perform body system assessment (can be performed anytime during the site visit) 
15. Assess vital signs (can be performed anytime during the site visit)  
16. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK (can be 
performed any time after the 10 a.m. IOP) 
17. If female of childbearing potential, perform urine pregnancy test 
18. Collect used timolol maleate 0.5% ophthalmic solution bottle 
19. Complete the exit form 
20. Discharge the patient from the trial 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~5:00 p.m.).  However, at the discretion of the investigator, patients will be permitted to leave 
the clinic after completing the 10:00 a.m.  IOP measurement and will return to the clinic before 
the 4:00 p.m. IOP measurement.  Any patient that leaves the clinic will be instructed to return no 
later than 30 minutes prior to the 4:00 p.m. IOP measurement. 
12.11. 
Visit 16/Month 12 – Visit 21/Month 17 ± 7 Days/Treatment Period, 
Cohort 2 Study Extension 1 (if patient chooses to enroll in Extension 
1) 
 Obtain written consent to participate in Cohort 2, Extension 1 before any study related activities 
begin. 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 


 
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1. Obtain written informed consent before or at Visit 16/Month 12 to participate in Cohort 2 
Extension 1 
2. Assess BCVA (ETDRS) with manifest refraction 
3. Perform pupil measurement only at Visit 16/Month 12, Visit 18/Month 14, and Visit 
20/Month 16 
4. Perform slit lamp biomicroscopy 
5. Perform corneal staining 
6. Measure IOP at 8:00 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
7. Perform gonioscopy  (if gonioscopy images are collected, please conduct the gonioscopy 
after the 8:00 a.m. IOP measurement) 
8. Perform pachymetry (contact) only at Visit 16/Month 12, Visit 18/Month 14, and Visit 
20/Month 16 
9. Perform specular microscopy (non-contact) study eye only at Visit 16/Month 12, Visit 
18/Month 14, Visit 20/Month 16 and Visit 21/Month 17  (can be performed anytime 
during the site visit)  
10. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image only at Visit 16/Month 12 and Visit 21/Month 17. 
11. Perform body system assessment only at Visit 16/Month 12  (can be performed anytime 
during the site visit) 
12. Assess vital signs  only at Visit 16/Month 12 and Visit 19/Month 15 (can be performed 
anytime during the site visit) 
13. Perform dilated funduscopic examination only at Visit 16/Month 12 
14. Collect non-fasting blood and urine for clinical laboratory tests only at Visit 16/Month 12 
15. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~9:00 a.m.).   
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 12.3.4. 


 
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12.12. 
Visit 22/Month 18 ± 7 Days/Treatment Period Study Exit, Cohort 2 
Extension 1 (if patient chooses not to enroll in Extension 2) 
If a patient discontinues prior to the Visit 22/Month 18, or declines to continue into the Cohort 2 
Study Extension 2 the following procedures are to the performed.  If the patient chooses to 
continue into the Cohort 2 Study Extension 2, please follow the procedures in Section 12.13. 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8 am (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
6. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4:00 p.m. IOP measurement) 
7. Perform pachymetry (contact) 
8. Perform specular microscopy (non-contact) for both eyes (can be performed anytime 
during the visit) 
9. Assess VF 
10. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
11. Measure IOP at 10:00 a.m. (±30 minutes) 
12. Measure IOP at 4:00 p.m. (±30 minutes) 
13. Perform dilated funduscopic exam 
14. Perform body system assessment (can be performed anytime during the site visit) 
15. Assess vital signs (can be performed anytime during the site visit)  
16. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK  
17. If female of childbearing potential, perform urine pregnancy test 
18. Collect used timolol maleate 0.5% ophthalmic solution bottle 
19. Complete the exit form 
20. Discharge the patient from the trial 


 
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Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~9:00 a.m.).   
12.13. 
Visit 22/Month 18 – Visit 24/Month 20 ± 7 Days/Treatment Period, 
Cohort 2 Study Extension 2 (if patient chooses to enroll in Extension 
2) 
Obtain written consent to participate in Cohort 2, Extension 2 before any study related activities 
begin. 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Obtain written informed consent before or at Visit 22/Month 18 to participate in Cohort 2 
Extension 2 
2. Assess BCVA (ETDRS) with manifest refraction 
3. Perform pupil measurement 
4. Perform slit lamp biomicroscopy 
5. Perform corneal staining 
6. Measure IOP at 8:00 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
7. Perform gonioscopy  (if gonioscopy images are collected, please conduct the gonioscopy 
after the 8:00 a.m. IOP measurement) 
8. Perform pachymetry (contact) 
9. Perform specular microscopy (non-contact) study eye only 
10. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
11. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~9:00 a.m.).   
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 12.3.4. 
 


 
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12.14. 
Visit 25/Month 21 ± 7 Days/Treatment Period Study Exit, Cohort 2 
Study Extension 2 
If a patient discontinues prior to Visit 25/Month 21, the following procedures are to be 
performed. 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs will be documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy 
4. Perform corneal staining 
5. Measure IOP at 8 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
6. Perform gonioscopy  (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4:00 p.m. IOP measurement) 
7. Perform pachymetry (contact) 
8. Perform specular microscopy (non-contact) for both eyes (can be performed anytime 
during the visit) 
9. Assess VF 
10. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
11. Measure IOP at 10:00 a.m. (±30 minutes) 
12. Measure IOP at 4:00 p.m. (±30 minutes) 
13. Perform dilated funduscopic exam 
14. Perform body system assessment (can be performed anytime during the site visit) 
15. Assess vital signs (can be performed anytime during the site visit)  
16. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK (can be 
performed any time during the site visit) 
17. If female of childbearing potential, perform urine pregnancy test 
18. Collect used timolol maleate 0.5% ophthalmic solution bottle 
19. Complete the exit form 
20. Discharge the patient from the trial 


 
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13. 
PROCEDURE SCHEDULE BY STUDY VISIT, COHORT 3 
At visits with IOP diurnal measurements, patients are expected to remain in the clinic for the 
completion of all procedures (~7:30 a.m. to ~5:00 p.m.).  However, at the discretion of the 
investigator, patients will be permitted to leave the clinic after completing the 10:00 a.m.  IOP 
measurement and will return to the clinic before the 4:00 p.m. IOP measurement.  Any patient 
that leaves the clinic will be instructed to return no later than 30 minutes prior to the 4:00 p.m. 
IOP measurement. 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 13.1.2. 
13.1. 
Visit 1/Day -56 to -42/Screening Evaluation, Cohort 3 
At Visit 1, patients will be screened, and if eligible, enrolled into the study.  Before any study 
specific assessments are performed, written informed consent will be obtained from each patient.  
During the visit, the procedures described below will be performed.  These procedures can occur 
over a seven day window. 
13.1.1. 
Screening Assessments 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Obtain written informed consent 
2. Obtain medical history, ocular history, and demographics (can be performed anytime 
during the visit) 
3. Evaluate and record patient’s medication usage - include concomitant medications taken 
within the past 30 days (can be performed anytime during the visit) 
4. Assess BCVA (ETDRS) with manifest refraction 
5. Perform pupil measurement 
6. Perform slit lamp biomicroscopy 
7. Perform corneal staining 
8. Measure IOP before 10:00 a.m. 
9. Perform gonioscopy 
10. Perform pachymetry (contact) 
11. Perform specular microscopy, non-contact (can be performed anytime during the visit 
beyond the pachymetry exam) 
12. Assess VF 
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14. Perform dilated funduscopic exam 
15. Perform body system assessment (can be performed anytime during the site visit) 
16. Assess vital signs (can be performed anytime during the site visit) 
17. Collect non-fasting blood and urine for clinical laboratory tests (can be performed any 
time after the 10 a.m. IOP measurements) 
18. If female of childbearing potential, perform urine pregnancy test (can be performed 
anytime during the site visit) 
19. Verify that patient meets all applicable entry criteria 
20. Query patient about whether or not they have experienced symptoms during the exam 
procedures suggesting an AE.  AEs will be documented. 
At the end of the examination, patients that have met the eligibility requirements will be asked to 
discontinue their current glaucoma medication(s).   
The patient will be asked to return for the baseline visit after 6 weeks.   
13.1.2. 
Patient Instructions 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the following instructions: 
• Discontinue use of all eye drop medications until the end of the study (if appropriate).  
With your investigator’s approval, you may be able to use artificial tear eye drops. 
• At all visits except Visit 3 and Visit 4, be prepared for a long clinic visit.  You will be 
expected to have IOP measurements at 8:00 a.m., 10:00 a.m., and 4:00 p.m.  You may 
leave the clinic after the 10:00 a.m. assessments with your doctor’s approval. 
• Call your study site if you have any problems. 
• Remember not to wear contact lenses.  
13.2. 
Visit 2/-7 to -1 days/Baseline Assessments, Cohort 3 
Patients will be queried about changes in medications and whether or not they have experienced 
symptoms suggesting an AE.  AEs and concomitant medications will be documented. 
Assessments will be conducted in the following general order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy 
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5. Perform corneal staining 
6. Measure IOP at 8:00 a.m. 
a. IOP must be between 22-34 mm Hg in both eyes with a ≤4 mm Hg difference 
between each eye at 8:00 a.m. (±30 minutes) 
b. IOP must increase of at least 4 mmHg in each eye compared to the pre-washout 
baseline  
7. Perform gonioscopy 
8. Perform pachymetry (contact) 
9. Perform specular microscopy (non-contact), Non-contact specular microscopy can be 
performed anytime during the site visit 
10. Assess vital signs (can be performed anytime during the site visit) 
11. If female of childbearing potential, perform urine pregnancy test (can be performed 
anytime during the site visit) 
12. Measure IOP at 10:00 a.m. (±30 minutes) 
a. IOP must be between 22-34 mm Hg in both eyes with a ≤4 mm Hg difference 
between each eye at 10:00 a.m. (±30 minutes) 
13. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK (can be 
performed after the 10 a.m. IOP) 
14. Measure IOP at 4:00 p.m. (±30 minutes) 
a. IOP must be between 19-30 mm Hg in both eyes with a ≤4 mm Hg difference 
between each eye at 4:00 p.m. (±30 minutes) 
15. Perform dilated funduscopic examination 
16. Verify that patient meets all entry criteria 
13.2.1. 
Patient Instructions 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 13.1.2 . 
13.3. 
Visit 3/Day 1/Dosing/Treatment, Cohort 3 
Query patient about changes in medications and whether or not they have experienced symptoms 
suggesting an AE.  AEs and concomitant medications will be documented. 
13.3.1. 
Pre-dose Assessments 
Assessments will be conducted in the following general order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 


 
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2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at between 6:00 a.m. and 10:00 a.m. (±30 minutes) 
a. IOP must be between 22-34 mm Hg in both eyes with a ≤4 mm Hg difference 
between each eye at 8:00 a.m. (±30 minutes) 
b. IOP must increase of at least 4 mmHg in each eye compared to the pre-washout 
baseline  
5. Perform gonioscopy 
6. Instill one drop of VIGAMOX into the study eye 
7. Verify that patient meets all entry criteria 
13.3.2. 
Study Eye Assignment and Study Drug Administration 
Patients will be assessed to ensure they still qualify to participate in the study based on the 
inclusion/exclusion criteria (Section 11.3 and Section 11.4).  The patient’s study eye will be 
assigned to receive one or two ENV515-3-2 (travoprost) Intracameral Implant(s) into the study 
eye via intracameral injection administered via the provided intracameral implant applicator. The 
study-trained investigator will administer the dose of study medication into the study eye (see 
Section 14.1.1, Implantation of ENV515) between 6:00 a.m. and 10:00 a.m. (±30 minutes).  
Timolol maleate 0.5% ophthalmic solution will be administered into the non-study eye by the 
patient at 8 p.m. (±60 minutes) on the day of Visit 3. 
13.3.3. 
Post-dose Assessments 
1. Perform slit lamp biomicroscopy 
2. Dispense bottle of timolol maleate 0.5% ophthalmic solution to the patient 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~12:00 p.m.); however, at the discretion of the investigator, patients will be permitted to leave 
the clinic following the completion of the dosing. 
13.3.4. 
Patient Instructions 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the following instructions: 
• Remember to use timolol maleate 0.5% ophthalmic solution twice daily (as close to 
8:00 a.m. and 8:00 p.m. as you can ± 60 minutes) in the non-study eye.  DO NOT 
PUT timolol maleate 0.5% ophthalmic solution in the eye that received the ENV515 
implants.  Continue using timolol maleate 0.5% ophthalmic solution until one day 
prior to Visit 16 (Month 12 ± 7 days).  Please remember to bring timolol maleate 
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administered after the 8:00 a.m. IOP measurement. It will need to be collected from 
you before issuing a new bottle at applicable visits. 
• Continue to withhold (not use) all other eye drop medications until the end of the 
study (if appropriate).  With your investigator’s approval, you may be able to use 
artificial tear eye drops. 
• Remember not to wear contact lenses.  
• Please avoid physical activities associated with jarring physical motions, such as 
horseback riding, for the rest of the study.  
• Call your study site if you have any problems. 
13.4. Visit 4/Day 2 + up to 3 Days/Treatment Period, Cohort 3 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise noted: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes) - Please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement. 
5. Perform gonioscopy   
6. Perform pachymetry (contact) 
7. Perform specular microscopy (non-contact) study eye only; Non-contact specular 
microscopy can be performed anytime during the site visit 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~10:00 a.m.).   
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 13.3.4. 
13.5. 
Visit 5/Day 14 ± 3 Days/Treatment Period, Cohort 3 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented. 


 
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Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise noted: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy (if corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study) 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. (±30 minutes) - Please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement. 
6. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4:00 p.m. IOP measurement) 
7. Perform pachymetry (contact) 
8. Perform specular microscopy (non-contact) study eye only; Non-contact specular 
microscopy can be performed anytime during the site visit 
9. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
10. Measure IOP at 10:00 a.m. (±30 minutes) 
11. Measure IOP at 4:00 p.m. (±30 minutes) 
12. Collect blood sample for PK analysis. (can be performed after the 10 a.m. IOP)  
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 13.3.4. 
13.6. 
Visit 5a/Day 28 ± 3 Days/Treatment Period, Cohort 3 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise noted: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy (If corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites.) 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes) - Please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement. 


 
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5. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4:00 p.m. IOP measurement) 
6. Perform pachymetry (contact) 
7. Perform specular microscopy (non-contact) study eye only; Non-contact specular 
microscopy can be performed anytime during the site visit 
8. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
9. Measure IOP at 10:00 a.m. (±30 minutes) 
10. Measure IOP at 4:00 p.m. (±30 minutes) 
11. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
12. Collect blood sample for PK analysis (can be performed after the 10 a.m. IOP)  
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 13.3.4. 
13.7. 
Visit 6/Day 42 ± 3 Days/Treatment Period, Cohort 3 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise noted: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy (If corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites.) 
3. Perform corneal staining 
4. Measure IOP at 8:00 a.m. (±30 minutes) - Please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement. 
5. Perform gonioscopy  (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4 :00 p.m. IOP measurement) 
6. Perform pachymetry (contact) 
7. Perform specular microscopy (non-contact) study eye only; Non-contact specular 
microscopy can be performed anytime during the site visit 
8. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
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9. Measure IOP at 10:00 a.m. (±30 minutes) 
10. Measure IOP at 4:00 p.m. (±30 minutes) 
11. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
12. Collect blood sample for PK analysis (can be performed after the 10 a.m. IOP) 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 13.3.4.  
13.8. 
Visit 7/Day 84 ± 7 Days/Treatment Period, Cohort 3 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise noted: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform pupil measurement 
3. Perform slit lamp biomicroscopy (If corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites.) 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. (±30 minutes) - Please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement. 
6. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4 :00 p.m. IOP measurement) 
7. Perform pachymetry (contact) 
8. Perform specular microscopy (non-contact) study eye only; Non-contact specular 
microscopy can be performed anytime during the site visit 
9. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
10. Measure IOP at 10:00 a.m. (±30 minutes) 
11. Measure IOP at 4:00 p.m. (±30 minutes) 
12. Perform body system assessment (can be performed anytime during the site visit) 
13. Assess vital signs (can be performed anytime during the site visit) 
14. Perform dilated fundus exam 


 
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15. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK (can be 
performed after the 10:00 a.m. IOP) 
16. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 13.3.4. 
13.9. 
Visit 8/Month 4 – Visit 12/Month 8 ± 7 Days/Treatment Period, 
Cohort 3 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented.   
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform pupil measurement  
3. Perform slit lamp biomicroscopy (if corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites) 
4. Perform corneal staining 
5. Measure IOP at 8:00 a.m. (±30 minutes) - Please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement. 
6. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 4 :00 p.m. IOP measurement) 
7. Perform pachymetry (contact)  
8. Perform specular microscopy (non-contact) study eye only (can be performed anytime 
during the site visit)  
9. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
10. Measure IOP at 10:00 a.m. (±30 minutes) 
11. Measure IOP at 4:00 p.m. (±30 minutes) 
12. Perform body system assessment (can be performed anytime during the site visit) only at 
Visit 10 (Month 6) and Visit 13 (Month 9) 
13. Assess vital signs (can be performed anytime during the site visit) only at Visit 10 
(Month 6) and Visit 13 (Month 9) 


 
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14. Perform dilated funduscopic examination only at Visit 10 (Month 6) and Visit 13 
(Month 9) 
15. Collect non-fasting blood and urine for clinical laboratory tests at Month 6 (Visit 10) 
(should be performed any time after the 10:00 am IOP measurement)   
16. Collect systemic PK at all visits (should be performed any time after the 10:00 am IOP 
measurement)   
17. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
Patients are expected to remain in the clinic for the completion of all procedures (~7:30 a.m. to 
~5:00 p.m.).  However, at the discretion of the investigator, patients will be permitted to leave 
the clinic after completing the 10:00 a.m.  IOP measurement and will return to the clinic before 
the 4:00 p.m. IOP measurement.  Any patient that leaves the clinic will be instructed to return no 
later than 30 minutes prior to the 4:00 p.m. IOP measurement. 
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 13.3.4. 
13.10. 
Visit 13/Month 9 – Visit 15/Month 11 ± 7 Days/Treatment Period, 
Cohort 3 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented.   
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy (if corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites) 
3. Measure IOP at 8:00 a.m. (±30 minutes) - Please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement. 
4. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 8:00 a.m. IOP measurement) 
5. Perform pachymetry (contact)  
6. Perform specular microscopy (non-contact) study eye only (can be performed anytime 
during the site visit)  
7. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
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8. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
Patients are expected to remain in the clinic for the completion of all procedures.  Before patients 
leave the clinic, they should receive an appointment for their next study visit and the instructions 
provided in Section 13.3.4 . 
13.11. 
Visit 16/Month 12 ± 7 Days/Treatment Period Study Exit, Cohort 3 
(if patient chooses not to enroll in Cohort 3 Extension 1) 
The following procedures are to be performed during an exit visit or during an early exit visit if a 
patient discontinues prior to Visit 16 (Month 12).   
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy (if corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites.) 
3. Measure IOP at 8 am (±30 minutes) - Please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement. 
4. Perform gonioscopy (if gonioscopy images are collected, please conduct the gonioscopy 
after the 8:00 a.m. IOP measurement) 
5. Perform pachymetry (contact)   
6. Perform specular microscopy (non-contact), can be performed anytime during the site 
visit 
7. Assess VF 
8. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
9. Perform dilated funduscopic exam 
10. Perform body system assessment (can be performed anytime during the site visit) 
11. Assess vital signs (can be performed anytime during the site visit)  
12. Collect non-fasting blood and urine for clinical laboratory tests and systemic PK (can be 
performed any time after the 10 a.m. IOP)  
13. If female of childbearing potential, perform urine pregnancy test 


 
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14. Collect used timolol maleate 0.5% ophthalmic solution bottle 
15. Complete the exit page in eCRF  
16. Discharge the patient from the trial 
 
13.12. 
Visit 16/Month 12 – Visit 21/Month 17 ± 7 Days/Treatment Period, 
Cohort 3 Study Extension 1 (if patient chooses to enroll in Cohort 3 
Extension 1) 
Obtain written consent to participate in Cohort 3, Extension 1 before any study extension related 
activities begin. 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Obtain written informed consent before or at Visit 16/Month 12 to participate in Cohort 3 
Extension 1 
2. Assess BCVA (ETDRS) with manifest refraction 
3. Perform slit lamp biomicroscopy (if corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites.) 
4. Measure IOP at 8:00 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
5. Perform gonioscopy  (if gonioscopy images are collected, please conduct the gonioscopy 
after the 8:00 a.m. IOP measurement) 
6. Perform pachymetry (contact) 
7. Perform specular microscopy (non-contact) study eye only 
8. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
9. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
Patients are expected to remain in the clinic for the completion of all procedures.   
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 12.3.4. 


 
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13.13. 
Visit 22/Month 18 ± 7 Days/Treatment Period Study Exit, Cohort 3 
Study Extension 1 (if patient chooses not to enroll in Cohort 3 
Extension 2) 
The following procedures are to be performed during an exit visit or during an early exit visit if a 
patient discontinues prior to Visit 22 (Month 18).   
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy (if corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites.) 
3. Measure IOP at 8 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
4. Perform gonioscopy  (if gonioscopy images are collected, please conduct the gonioscopy 
after the 8:00 a.m. IOP measurement) 
5. Perform pachymetry (contact) 
6. Perform specular microscopy (non-contact) for both eyes (can be performed anytime 
during the visit) 
7. Assess VF 
8. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
9. Perform dilated funduscopic exam 
10. Perform body system assessment (can be performed anytime during the site visit) 
11. Assess vital signs (can be performed anytime during the site visit)  
12. Collect non-fasting blood and urine for clinical laboratory tests  
13. If female of childbearing potential, perform urine pregnancy test 
14. Collect used timolol maleate 0.5% ophthalmic solution bottle 
15. Complete the exit form 
16. Discharge the patient from the trial 


 
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13.14. 
Visit 23/Month 19 – Visit 27/Month 23 ± 7 Days/Treatment Period, 
Cohort 3 Study Extension 1 (if patient chooses to enroll in Cohort 3 
Extension 2) 
Obtain written consent to participate in Cohort 3, Extension 2 before any study extension related 
activities begin. 
Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Obtain written informed consent before or at Visit 16/Month 12 to participate in Cohort 3 
Extension 2 
2. Assess BCVA (ETDRS) with manifest refraction 
3. Perform slit lamp biomicroscopy (if corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites.) 
4. Measure IOP at 8:00 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
5. Perform gonioscopy  (if gonioscopy images are collected, please conduct the gonioscopy 
after the 8:00 a.m. IOP measurement) 
6. Perform pachymetry (contact) 
7. Perform specular microscopy (non-contact) study eye only 
8. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
9. Collect used timolol maleate 0.5% ophthalmic solution bottle and distribute new bottle to 
patient 
Patients are expected to remain in the clinic for the completion of all procedures.   
Before patients leave the clinic, they should receive an appointment for their next study visit and 
the instructions provided in Section 12.3.4. 
13.15. 
Visit 28/Month 24 ± 7 Days/Treatment Period Study Exit, Cohort 3 
Study Extension 2 
The following procedures are to be performed during an exit visit or during an early exit visit if a 
patient discontinues prior to Visit 28 (Month 24).   


 
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Query patient about changes in concomitant medications and whether or not they have 
experienced symptoms suggesting an AE.  AEs and concomitant medications will be 
documented. 
Assessments will be conducted in the following order.  Both eyes will be evaluated at all 
ophthalmic assessments unless otherwise indicated: 
1. Assess BCVA (ETDRS) with manifest refraction 
2. Perform slit lamp biomicroscopy (if corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites.) 
3. Measure IOP at 8 a.m. (±30 minutes, please make sure that timolol maleate 0.5% 
ophthalmic solution is administered after the IOP measurement) 
4. Perform gonioscopy  (if gonioscopy images are collected, please conduct the gonioscopy 
after the 8:00 a.m. IOP measurement) 
5. Perform pachymetry (contact) 
6. Perform specular microscopy (non-contact) for both eyes (can be performed anytime 
during the visit) 
7. Assess VF 
8. Perform anterior chamber OCT with the ENV515 implant(s) in the field of view of at 
least one OCT image 
9. Perform dilated funduscopic exam 
10. Perform body system assessment (can be performed anytime during the site visit) 
11. Assess vital signs (can be performed anytime during the site visit)  
12. Collect non-fasting blood and urine for clinical laboratory tests  
13. If female of childbearing potential, perform urine pregnancy test 
14. Collect used timolol maleate 0.5% ophthalmic solution bottle 
15. Complete the exit form 
16. Discharge the patient from the trial 
17.  
13.16. 
Unscheduled Visits, Cohorts 2 and 3 
Patients may need to be seen at other times than the scheduled study visits for additional safety 
assessments or to follow-up, as medically necessary, on changes in clinical status or to follow-up 
on clinical laboratory or other findings.  If an additional study visit occurs, the date and nature of 
the visit will be documented. 


 
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During unscheduled visits, query patient about changes in concomitant medications and whether 
or not they have experienced symptoms suggesting an AE.  AEs and concomitant medications 
will be documented. 
Mandatory assessments will be conducted in the following order.  Only study eye will be 
evaluated at the listed ophthalmic assessments, with additional evaluations carried out as deemed 
necessary per the investigator’s discretion: 
1. Perform slit lamp biomicroscopy (If corneal opacity is observed, please collect corneal 
photograph at each visit until opacity has resolved or patient is exited from the study at 
selected sites.) 
2. Assess BCVA (ETDRS) with manifest refraction 
3. Measure IOP at 8:00 a.m. (±30 minutes) or when feasible 
4. Perform pachymetry (contact)   
5. Perform specular microscopy (non-contact), can be performed anytime during the site 
visit 
6. Adverse Event assessment 
7. Concomitant medication assessment 


 
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14. 
TREATMENT OF PATIENTS, COHORTS 2 AND 3 
14.1. 
Treatments to be Administered, Cohorts 2 and 3 
14.1.1. 
Implantation of ENV515, Cohorts 2 and 3 
Treatment will consist of a single intracameral injection of low dose ENV515-3 (travoprost) 
Intracameral Implants in Cohort 2, and a single intracameral injection of low or high dose of 
ENV515-3-2 (travoprost) Intracameral Implants in Cohort 3 into the study eye, defined as the 
qualifying eye with higher mean diurnal IOP during the Baseline Visit or the left eye if both eyes 
have the same mean diurnal IOPs at the Baseline Visit.  The study eye will be selected during the 
Dosing Visit (Visit 3). All investigators will be trained in implant loading, administration, and 
retrieval (if necessary) by Envisia. Timolol maleate 0.5% ophthalmic solution will be 
administered into the non-study eye once on Day 1 at 8:00 p.m. Starting on Day 2 patients will 
administer timolol maleate 0.5% ophthalmic solution twice a day (8 a.m. and 8 p.m. ± 60 
minutes) until the night prior to Visit 16 (Month 12) in the non-study eye. 
ENV515-3 and ENV515-3-2 (travoprost) Intracameral Implants will be supplied in sterile glass 
vials with 1 implant per vial.  The sterile implant applicator will be provided in a Tyvek® pouch.  
The packaging will be opened and the implant applicator and the implants will be placed into a 
sterile field.  Implants will be loaded into the implant applicator by the trained investigator or 
trained Envisia staff member immediately prior to dosing.  Additionally, the study eye will be 
administered 3 doses of topical antibiotic VIGAMOX:  first dose following the completion of the 
pre-dose assessments (Section 12.3.1 and Section 13.3.1) and immediately before and after the 
ENV515 implant administration as described below.  The following instructions will be 
minimally distributed with the ENV515 implants and implant applicator: 
Opening Instructions, Cohorts 2 and 3 
1. Use sterile technique in sterile field to open primary packaging for the applicator and 
ENV515 implants. 
2. Open ENV515 Implant Applicator packaging and place the sterile ENV515 applicator 
into sterile field. 
3. Do not open glass vial containing implants until ready to load into the applicator. 
Instructions for Loading the Implant into the Applicator by the Investigator, Cohorts 2 
and 3 
1. Load two ENV515-3 implants in Cohort 2, and one or two ENV515-3-2 implant(s) in 
Cohort 3 into the ENV515 Implant Applicator in a sterile field using sterile technique via 
insertion through the beveled needle end. 
Instructions for Administration by Principal Investigator, Cohorts 2 and 3 
1. Instill second dose of VIGAMOX into the study eye (first dose is administered during 
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2. Treat patient’s ocular surface with topical anesthetic (proparacaine 0.5% or equivalent). 
3. Treat patient’s ocular surface with 5% povidone iodine and wait 2 minutes. 
4. Insert lid speculum. 
5. Administer the implant(s) into the anterior chamber via intracameral injection through 
clear, peripheral cornea.  The needle should be advanced parallel with the iris, ~1 mm 
anterior to the limbus with the patient sitting at the slit lamp, or with the patient supine 
under the operating scope. 
6. Instill third dose of VIGAMOX into the study eye. 
One implant applicator and 4 glass vials with 1 ENV515-3 or 5 glass vials with 1 ENV515-3-2 
implant/vial will be packaged in appropriately labeled cartons in Cohorts 2 and 3, respectively.  
The label on the package will minimally contain the following information: each package 
contains no less than 4 glass vials with 1 ENV515-3 or 5 glass vials with 1 ENV515-3-2 
implant/vial, 1 ENV515 implant applicator; study ENV515-01, storage temperature, and 
“Caution: Limited by Federal (or United States) Law to Investigational use.”  An unmasked 
disclosure panel will be displayed on the bottle label of the study medication and will minimally 
contain the following information: ENV515-01, and name of product.  The study medications 
will be stored in a secure area with limited access to study personnel under refrigerated storage at 
approximately 2 to 8°C. 
14.1.2. 
Timolol maleate 0.5% Ophthalmic Solution for Non-Study Eye, Cohorts 2 and 3 
Timolol maleate 0.5% ophthalmic solution will be provided for the non-study eye with its 
original packaging, labeling, and instructions for use (non-study eye only). 
 


 
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15. 
PROCEDURE DESCRIPTION 
15.1. 
Measurements and Evaluations, Cohorts 1, 2 and 3 
15.1.1. 
Best-Corrected Distance VA With Manifest Refraction Guidelines 
VA will be measured using the ETDRS chart.  VA should be taken with the patient’s best-
correction for distance at designated visits (method of correction should be consistent across 
visits).  It is important to take time for careful refraction of those patients with reduced VA.  
Spectacle correction is not allowed.  A consistent distance to the chart and method of 
measurement should be used throughout the trial.  The VA will be measured in the following 
way. 
1. When performing visual acuities it is recommended that the lighting should be at 
approximately office levels, be approximately uniform between the patient and the chart, 
and is used consistently the same way throughout the trial. 
2. For manifest refraction, use “Chart R.”  For actual vision testing, use “Chart 1” for the 
right eye and “Chart 2” for the left eye. 
3. The technician should ask the patient to read each letter slowly from the top of the chart 
and down as far as possible.  Do not point to letters. 
4. The patient should try no longer than 1 minute to see any 1 line.  If the patient has 
difficulty reading a letter, they should be encouraged to guess.  When the patient can read 
no further, the technician should ask the patient twice to read to the line below where the 
last correct letter was recognized.  When a letter is read correctly, the examiner will 
record this on a score sheet with a layout identical to that of the chart. 
5. The total number of letters missed will be recorded on the worksheet and entered in the 
eCRF. 
To record the Logarithm of the Minimum Angle of Resolution (LogMAR) VA: 
• Record the last line from which at least one letter is read correctly; this is the Base 
LogMAR. 
• Record the total number of letters missed.   
15.1.2. 
Slit Lamp Biomicroscopy Exam Guidelines 
Slit lamp biomicroscopy will be performed using the investigator’s standard procedure.  This 
procedure will be the same for all patients observed at an investigator’s site.  Observations 
should be graded as normal or abnormal.  In the event of abnormal observations, all findings 
should be noted and specified as clinically significant or not clinically significant and graded on 
a 5 point scale (0 = None, 0.5 = Trace, 1.0 = Mild, 2.0 = Moderate, 3.0 = Severe). Observations 
for each eye should be made of the following variables: 
• Eyelid erythema 


 
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• Chemosis 
• Corneal Staining 
• Corneal edema 
• Corneal opacity (At Visit 2 (Baseline) and if corneal opacity is observed, please 
collect corneal photograph at each visit until opacity has resolved or patient is exited 
from the study at selected sites.) 
• Hyphema 
• Anterior synechiae 
• Posterior synechiae 
• Lens 
• Conjunctival hyperemia (Hyperemia should be evaluated on a seven point scale [0, 
0.5, 1, 1.5, 2, 2.5, 3] against the provided Ora Calibra™ Redness Scale #6.0b. 
Findings should be noted as diffuse or injection site). 
• Conjunctiva (findings other than hyperemia) 
Anterior Chamber Cells Grading Scale – evaluated against the SUN Scale (9) 
0 = <1 cell in field 
.5+ = 1-5 cells in field 
1+ = 6-15 cells in field 
2+ = 16-25 cells in field 
3+ = 26-50 cells in field 
4+ = 50+ cells in field 
Anterior Chamber Flare Grading Scale - evaluated against the SUN Scale (9)  
0 = None 
1+ = Faint 
2+ = Moderate (Iris/lens details clear) 
3+ = Marked (Iris/lens details hazy) 
4+ = Intense (fibrin/plastic aqueous) 
15.1.3. 
Corneal Staining 
The cornea will be stained with non-preserved 2% fluorescein.  When conducting all assessments 
room temperature and humidity should be relatively consistent throughout each visit and 
throughout the study.  Observations should be graded as normal or abnormal.  In the event of 


 
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abnormal observations, all findings should be noted and specified as clinically significant or not 
clinically significant and graded for severity on a 0-5 scale. 
15.1.4. 
Binocular Indirect Ophthalmoscopy (Dilated Fundus Exam) Guidelines 
Dilated ophthalmoscopy will be performed according to the investigator’s preferred procedure.  
This procedure will be the same for all patients observed at an investigator’s site.  Observations 
should be graded as normal or abnormal.   All findings should be noted and specified as 
clinically significant or not clinically significant and graded for severity on a 0 - 5 scale.  The 
fundus will be examined thoroughly and the following variables examined: 
• Retina 
• Macula 
• Choroid 
• Vitreous 
• Optic nerve/disc 
• Cup/disc ratio 
15.1.5. 
Body System Review 
Abbreviated body system review examinations will be performed and include the following 
examinations.   
• General appearance 
• Skin 
• Lymphatic 
• Head and Neck 
• Ears Nose and Throat 
• Chest and Lungs 
• Cardiovascular 
• Abdomen 
• Extremities 
• Musculoskeletal 
• Neuromuscular 
 


 
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15.1.6. 
Vital Signs 
Vital sign assessments will include measurements of heart rate, blood pressure, and respiration 
rate. 
15.1.7. 
Laboratory Safety Assessments and Systemic Exposure to Travoprost 
Laboratory samples will be collected as indicated in the Times and Events schedules.  Labs 
should be non-fasting however, if not, please indicate on the lab requisition form as well as in the 
patient’s chart. Chemistry, hematology and urinalysis will be assessed according to the central 
laboratory procedures manual.  A urine pregnancy test will be performed on all females of 
childbearing potential. 
15.1.8. 
Anterior Chamber Optical Coherence Tomography (OCT) 
Anterior chamber OCT images will be acquired per instructions provided in the OCT manual. 
Images will be evaluated for angle opening distance at a central reading center.  Additional 
details about collection, handling and interpretation of images will be provided in the OCT 
manual. At least one collected anterior chamber OCT image should include the ENV515 
implant(s) in the field of view at each visit.  
15.1.9. 
Gonioscopy 
Gonioscopy will be performed to grade the iridocorneal angle according to the Shaffer 
gonioscopy scale.  Gonioscopy will also be used to monitor the implant location. The Shaffer 
scale should be used to describe the angle created between the plane of the iris and the cornea as 
follows: 
• Grade 4:  35 to 45 degrees, wide open, closure improbable 
• Grade 3:  20 to 35 degrees, moderately narrow, closure possible 
• Grade 2:  <20 degrees, extremely narrow, closure probable 
• Grade 1:  partly or totally closed, closure present 
The orientation of the implants will need to be indicated on source documents for each patient. In 
Cohorts 2 and 3 select sites will collect gonioscopy images. If gonioscopy images are collected, 
please conduct the gonioscopy after the last IOP measurement. Photographs will be taken at 
visits post dose starting a Visit 5 and continue at visits until the patient is exited from the study. 
15.1.10. 
Visual Field (Humphrey Program 24-2 SITA-Standard Strategy) 
The VF assessment will be performed on the Humphrey Field Analyzer using the program 
24-2.  All VF examinations will be performed with the patient’s best correction for 33 cm.  
The pupil should be at least 3 mm in diameter.  If not, pharmacologic dilation should be used 
for VF testing.  Quantified single threshold perimetry may be used if desired.  Swedish 
Interactive Threshold Algorithms (SITA), Fastpac, or a similar program may be used.  SITA 
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15.1.11. 
Intraocular Pressure 
All IOPs will be measured with a Goldmann applanation tonometer.  The calibration of the 
tonometer will be checked at least monthly and recorded in a log.  Diurnal curves will be 
recorded at specified visits.  The time of tonometry will be recorded on the source document for 
all visits. 
IOP should be measured only after the biomicroscopic exam is completed and must be measured 
prior to pupil dilation.  Measurements will be taken by two qualified independent study site 
personnel using a Goldmann applanation tonometer affixed to a slit lamp with the patient seated.  
One person will adjust the dial in masked fashion and a second person will read and record the 
value.  The patient and slit lamp should be adjusted so that the patient’s head is firmly positioned 
on the chin rest and against the forehead rest without leaning forward or straining.  Both eyes 
will be tested, with the right eye preceding the left eye.  Each IOP measurement is to be 
recorded. 
One person (“the measurer”) looks through the binocular viewer of the slit lamp at low power.  
The tension knob is pre-set at a low pressure value (4 to 6 mmHg).  The measurer follows the 
image of the fluorescein-stained semicircles while he/she slowly rotates the tension knob until 
the inner borders of the fluorescein rings touch each other at the midpoint of their pulsation in 
response to the cardiac cycle.  When this image is reached, the measurer takes his/her fingers off 
the tension knob and the second person (“the reader”) records the IOP reading along with the 
date and time of day in the source document, thus maintaining a masked IOP reading. 
For Cohorts 1 and 2, three consecutive measurements will be taken to determine IOP in the 
manner described above.  All three measurements will be recorded and the median IOP of the 
three measurements will be recorded and used in the analysis. 
For Cohort 3, only two measurements are necessary if the pressure measurements are the same.  
If the two measurement are not identical, a third measurement is required. 
15.1.12. 
Pachymetry (Contact) 
Following IOP measurements, the central corneal thickness of each eye will be measured with 
the patient seated and visualizing fixation. 
An ultrasonic pachymeter equipped with a solid tip probe must be used. 
Center the probe tip on the cornea and take a measurement when it is correctly positioned. 
Obtain 3 measurements (displayed in microns) for each eye and average the values to obtain the 
corneal thickness measurement. 
15.1.13. 
Specular Microscopy (Non-contact) 
Perform assessment according to the manufacturer’s specified instructions.  The image analysis 
will be conducted by centralized reading center. Detailed instructions for submission of images 
will be provided in a manual from the reading center. 


 
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For Cohort 2, specular microscopy is needed for all study eyes on Visits 1 through 10, 12, 14, 
and 16.  For non-study eyes, it is collected only during Visits 1 and 16 for Cohort 2.  Cohort 3 
requires for non-study eyes images to be collected at Visits 1 and 2.  Non-contact specular 
microscopy can be performed anytime during the study visit. 
15.1.14. 
Pupil Measurement 
Pupil diameter will be measured in a room (not at the slit lamp) with lighting that is used 
consistently the same way throughout the trial.  Instruct the patient to gaze into the distance, and 
then compare the pupil diameter to a standardized schematic.  A standardized schematic will be 
provided by the sponsor. 
15.1.15. 
Implant Recovery and Aqueous Humor Sampling 
In Cohort 1, the cataract surgery and intraocular lens (IOL) implantation will be conducted 
according to the discretion of the principal investigator per established protocols.  The implant 
removal will be conducted during the cataract surgery.  The implant removal procedure as 
described below was used in nonclinical studies of ENV515.  Based on observations in 
nonclinical studies of ENV515 in Beagle dogs, the implants retain their original size and shape, 
do not disintegrate for at least 2 months in situ at the iridocorneal angle in vivo, and do not 
disintegrate when manipulated via instruments such as utrata forcepts after 2 months in situ in 
vivo.  The following study-specific procedures will be performed during the cataract surgery: 
1. The implant location(s) are identified by gonioscopy exam conducted during pre-surgery 
assessments.  
2. Following the creation of the initial incision in the clear cornea, ~100 μL of aqueous 
humor will be sampled from the anterior chamber via provided tuberculin syringe with 
30 gauge needle.  The sample will be treated as described in Appendix 1. 
3. After the removal of the aqueous humor sample, implants will be recovered from the 
anterior chamber. 
4. A stream of buffered saline solution (BSS) is directed to the iridocorneal angle location 
where the implants have been identified until implants are dislodged from the 
iridocorneal angle and float in the anterior chamber.  Utrata forceps or equivalent 
instrument is used to grasp the implant and remove the implant(s) through the incision in 
the clear cornea created for cataract removal and IOL implantation. 
5. Recovered implants will be treated as described in Appendix 1. 
In Cohorts 2 and 3, patients are not scheduled for cataract surgery. However, steps 1 through 5 
can be used to remove implants if absolutely necessary. 


 
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15.2. 
Stopping Rules 
15.2.1. 
Stopping Rules for the Study 
The medical monitor will evaluate safety data (e.g. AE reports) on a regular basis.  Consultation 
with the principal investigators will occur as appropriate.   
The trial or parts of the trial may be discontinued by Envisia at the recommendation of the 
medical monitor. This may be based on a significant number of AEs of a similar nature that 
warrant such action. The medical monitor may request at any time a meeting with the Envisia 
project team for the purposes of conducting a full evaluation of safety. This evaluation may 
result in a recommendation by the medical monitor to Envisia to terminate the study.  If the 
medical monitor recommends to Envisia to terminate the study, Envisia will evaluate the 
recommendation, and make a decision whether to continue the study, make any changes to the 
study including but not limited to stopping further dosing, or discontinue the study. An Envisia 
representative will inform the FDA, the medical monitor, and all participating clinical sites and 
their principal investigators of the medical monitor’s recommendation and Envisia decision 
within 48 hours from the recommendation to stop the study.  
In the event that study discontinuation is necessary (i.e. no more patients are being dosed), the 
investigator should make every attempt to complete all protocol safety assessments and visits for 
patients who have been dosed in Cohorts 2 and 3.   For Cohort 1, the cataract surgery combined 
with the removal of the implant(s) should occur as soon as possible based on the judgment of the 
investigator and safety of the patient.  Unless consent has been withdrawn, any patient is 
considered to be in the treatment phase of the study until the cataract surgery combined with 
ENV515 implant removal, and such patients should continue to be followed and will be 
expected to complete all pre- and post- surgery safety assessments and visits for Cohort 1 or 
until study is completed for Cohorts 2 and 3. 


 
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16. 
WASHOUT MEDICATIONS, CONCOMITANT MEDICATIONS, 
DRUG ACCOUNTABILITY, AND MAINTENANCE OF 
RANDOMIZATION 
16.1. 
Washout Medications 
During the Screening Visit, patients will be asked to discontinue their current glaucoma 
medication(s), for the appropriate time period. The patient will be asked to return for the 
Baseline Visit within 4 weeks for Cohorts 1 and 2.  Patients will be scheduled to return for an 
interim IOP check if their washout period will be longer than 4 weeks.  The washout period will 
be extended up to 2 additional weeks (if medically safe) to accommodate the patient’s or 
investigator’s schedule.  Patients will be washed out for 6 weeks for all glaucoma medications in 
Cohort 3.  Patients should discontinue the use of any glaucoma medication(s) with the exception 
of study medication for the duration of the study. 
16.2. 
Concomitant Medications 
16.2.1. 
Permitted Medications 
Medications permitted include systemic medications with the exception of oral, ocular, or IV 
steroids.  Only non-preserved artificial tears will be allowed to be administered as an ocular 
treatment. Medications not specifically excluded in Section 16.2.2 may be taken as necessary. 
The use of topical non-steroidal anti-inflammatory agents (e.g. PROLENSA, ACULAR, 
ILEVRO or others) is allowed per the discretion of the investigator for 1 to 2 days prior to and 7 
days immediately following ENV515-3-2 administration via intracameral injection.  
All medications taken by a patient 30 days prior to Visit 1 through the end of the study will be 
recorded in the eCRF and the patient’s medical chart.  This includes all ocular medications 
given on the day of dosing.  The generic name (if known, otherwise the trade name) of the drug, 
dose, route of administration, duration of treatment (including start and stop dates), frequency, 
and indication will be recorded for each medication. 
Topical medications that are administered to all patients as part of conducting safety assessments 
or routine procedures are not required to be recorded in the eCRF.  For example, topical 
medications used for the following are not required to be recorded in the eCRF: 
• Dilating agents 
• Anesthesia 
• Staining (i.e., fluorescein) 
16.2.2. 
Medications Not Permitted 
The use of medical marijuana and corticosteroids (oral, ocular, injectable, or IV) are disallowed 
with the exception of inhaled, intranasal or topical (dermal) steroids if on a stable dose. 


 
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In the event that a subject requires the initiation of one or more of these medications during the 
study, the investigator must consult with the sponsor regarding the proper action that should be 
taken. 
16.3. 
Investigational Product Accountability 
Investigational product (IP), including the provided injectors, will not be shipped to any 
investigational site until the site has fulfilled all requisite regulatory requirements.  
Accountability of IP, ENV515 and TRAVATAN Z for the non-study eye in Cohort 1 and 
ENV515 and timolol maleate 0.5% ophthalmic solution for Cohorts 2 and 3, will be conducted 
by the Envisia monitor or designee.  Accountability will be ascertained by performing 
reconciliation between the amount of drug sent to the site, the amount used and the amount 
unused at the time of reconciliation. 
Clinical trial materials will be shipped to the investigational sites under sealed conditions.  IP 
shipment records will be verified by comparing the shipment inventory sheet to the actual 
quantity of drug received at the site.  Accurate records of receipt and disposition of the study 
drug (e.g., dates, quantity, patient number, dose dispensed, returned, etc.) must be maintained by 
the investigator or his/her designee.  IP will be stored under refrigerated storage at approximately 
2 to 8°C.  This area should be limited controlled access.  
Patient’s compliance with administration of the control arm medication (TRAVATAN Z or 
timolol maleate 0.5%) will be assessed by the site staff upon return of the study medication to the 
site.  If bottle(s) were unopened or clearly unused between visits or if the patient reports a 
significant time frame of 5 or more days of not using their control arm medications prior to the 
study visit, a note should be made in the drug accountability log, in the patient’s source 
document (patient chart) and in the eCRF.   
At the end of the study, all study materials, including used and unused study drug (ENV515, 
TRAVATAN Z and timolol maleate 0.5%) are to be returned to Envisia (or designee) or 
destroyed under the direction of the same.  The removed implants will be retained per 
instructions in Appendix 1.  The study monitor or designee will verify drug accountability.  All 
drug accounting procedures must be completed before the study is considered complete. 
16.4. 
Maintenance of Randomization 
For Cohort 1, a randomization code for the patient assignment to 1 of 4 dose levels of ENV515 
will be computer-generated by either Envisia or its designee.  Randomization team members will 
work independently of other team members.  Study personnel, study patients, and project teams 
at Envisia, the medical monitor, and the CRO involved in the study will be unmasked to 
treatment assignments.  To randomize a patient (Visit 3), the investigator (or designee) will 
confirm in the eCRF that the patient remains qualified for the study.  The eCRF will 
automatically assign the dose and number of implants that the patient should receive based on a 
prospectively prepared computer generated code list. 


 
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In the event of a medical need during Cohort 1, the investigator treated each patient as needed.  
The study design allowed for removal of the ENV515 intracameral implant by scheduling the 
subject for cataract surgery at an earlier date as determined by the medical need during which the 
ENV515 implant(s) was/were removed. 
For Cohorts 2 and 3, no randomization was conducted as these are open-label, single arm 
cohorts. 


 
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17. 
SAFETY REPORTING 
17.1. 
Adverse Events Reporting 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment.  AEs will be monitored throughout the study and will be recorded on the 
eCRF with the date and time of onset, date and time of resolution, intensity, seriousness, 
causality (relationship to study medication), and treatment required. From point of consent but 
prior to dosing, AEs and SAEs are classified as Medical Event. 
To elicit AEs, simple questions with minimal connotations should be used as the initial questions 
at all evaluation points during the trial.  For example: 
• How have you felt since your last assessment? 
• Have you had any health problems since your last assessment? 
The severity of each AE should be categorized as mild, moderate, or severe.  Severity of an AE 
is defined as a qualitative assessment of the degree of intensity of an AE as determined by the 
investigator or reported to him/her by the patient.  The assessment of severity is made 
irrespective of relationship to investigational product or seriousness of the event and should be 
evaluated according to the following scale: 
• Mild:  Event is noticeable to the patient, but is easily tolerated and does not interfere 
with the patient’s daily activities. 
• Moderate:  Event is bothersome, possibly requiring additional therapy, and may 
interfere with the patient’s daily activities. 
• Severe:  Event is intolerable, necessitates additional therapy or alteration of therapy, 
and interferes with the patient’s daily activities. 
The causality of the study treatment in relation to the AE will be assessed by the principal 
investigator after careful medical consideration and categorized as not related, possibly related, 
or related. 
The expectedness of each AE should be determined based upon existing safety information about 
the investigational product using these explanations: 
• Unexpected:  An AE that is not listed in the IB or Report of Prior Investigations 
(ROPI) or is not listed at the specificity or severity that has been observed. 
• Expected:  An AE that is listed in the IB at the specificity and severity that has been 
observed. 
• Not applicable: An AE unrelated to the investigational product. 


 
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The relationship of each AE to the investigational product and the administration procedure 
should be determined by the investigator using these explanations: 
• Suspected:  A reasonable possibility exists that the investigational product caused the AE. 
• Not Suspected: A reasonable possibility does not exist that the investigational product 
caused the AE. 
For Cohorts 2 and 3, causality of AEs were further assessed using the following selections: 
• Unrelated to any study procedure or any study medications 
• ENV515 implant 
• Comparator 
• Injection Procedure 
• Other study procedure(s) 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
investigational product caused the AE.  “Reasonable possibility” means there is evidence to 
suggest a causal relationship between the investigational product and the AE.  Types of evidence 
that would suggest a causal relationship between the investigational product and the AE include:  
a single occurrence of an event that is uncommon and known to be strongly associated with 
investigational product exposure; one or more occurrences of an event that is not commonly 
associated with investigational product exposure, but is otherwise uncommon in the population 
exposed to the investigational product; an aggregate analysis of specific events observed in a 
clinical trial (such as known consequences of the underlying disease or condition under 
investigation or other events that commonly occur in the study population independent of drug 
therapy) that indicates those events occur more frequently in the investigational product-
treatment group than in a concurrent or historical control group. 
AEs that are mentioned in the Investigator’s Brochure occurring with a class of products or as 
anticipated from the pharmacological/ mechanical (or other) properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation are to be 
considered unexpected.   The sponsor will classify the expectedness of an AE with a final review 
by the Medical Monitor. 
If an AE occurs, the investigator will institute support and/or treatment as deemed appropriate.  
If a serious or treatment-related AE is unresolved at the time of the last day of the study, an effort 
will be made to follow up until the AE is resolved or stabilized, the patient is lost to follow-up, 
or there is some other resolution of the event.  The investigator should make every attempt to 
follow SAEs to resolution. 
 


 
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17.2. 
AEs of Special Interest and Their Reporting 
An adverse event of special interest (AESI) is one of scientific and medical concern specific to 
the sponsor’s product or program, for which ongoing monitoring and rapid communication by 
the investigator to the sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. AESIs for the this study include any 
corneal events including corneal edema detected via slit lamp or pachymetry, corneal opacity, 
and any suspected changes in corneal endothelial cell counts determined by the central reading 
center of 30% or greater change from baseline (V2) as determined via specular microscopy. 
If  AESI of corneal edema or corneal opacity occur, the investigators or their designees should 
report all such AESIs to Envisia within 24 hours of the event being brought to the investigators’ 
or their staffs’ attention.  Should any decrease in corneal endothelial cell count equal or greater 
than 30% change from study baseline occur, the investigators will be promptly notified by the 
Envisia team and/or the centralized reading center. 
17.3. 
Prospective Definitions of Select AEs 
Selected events are classified further via the use of a prospective AE definition to provide 
investigators additional medically relevant considerations and to improve patient safety. Such 
definitions are provided below for this study: 
Adverse Event of Corneal Endothelial Cell Loss: Any decrease in corneal endothelial cell 
count equal or greater than 30% change from study baseline count of corneal endothelial cells 
(Visit 2, Study Baseline) is considered an adverse event. The corneal endothelial cell counts are 
evaluated via an independent centralized reading center. Should any decrease in corneal 
endothelial cell count equal or greater than 30% change from study baseline occur, the 
investigators will be promptly notified by the Envisia team and/or the centralized reading center.  
Additional medically relevant considerations are provided for the classification of mild, 
moderate and severe instances for AE of corneal endothelial cell loss: 
• Mild AE of corneal endothelial cell loss: patient’s corneal endothelial cell counts are in 
the range from greater than 1,200 cells/mm2 to less than or equal to 30% change from 
baseline (dependent on individual patient’s baseline)   
[1,200 cells/mm2 < mild AE cell count ≤ 30% change from patient’s baseline] 
• Moderate AE of corneal endothelial cell loss: patient’s corneal endothelial cell counts are 
in the range from greater than 900 cells/mm2 to less than or equal to 1,200 cells/mm2 
[900 cells/mm2 < moderate AE cell count ≤ 1,200 cells/mm2] 
• Severe AE of corneal endothelial cell loss: cell counts are in the range of greater than 600 
cells/mm2 to less than or equal to 900 cells/mm2 
[600 cells/mm2 < severe AE cell count ≤ 900 cells/mm2] 


 
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Any corneal endothelial cell loss leading to cell counts at or below 600 cells/mm2 should be 
classified as Serious Adverse Event (SAE, see Section 17.5 for additional medically relevant 
considerations for classifying a corneal endothelial cell loss as SAE). 
17.4. 
Serious Adverse Event Reporting 
It is the responsibility of the investigators or their designees to report any SAE to Envisia within 
24 hours of the event being brought to the investigators’ or their staffs’ attention.  It is also the 
responsibility of the investigator to report all SAEs reported at their site to their Institutional 
Review Board (IRB), as required.  If an unexpected SAE, determined to be related or possibly 
related to study medication occurs in any study involving ENV515, all sites will be notified by 
Envisia and they should report it to their IRB.  The investigator should make every attempt to 
follow all SAEs to resolution. 
An SAE is any adverse drug experience occurring at any dose that results in any of the following 
outcomes: 
• death; 
• a life-threatening adverse drug experience (i.e., the patient was, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred); 
• inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• a congenital anomaly/birth defect; or 
• other important medical events not meeting the above criteria that, based on appropriate 
medical judgment, may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the above outcomes. 
The following information should be provided when an SAE is reported to Envisia: 
1. Protocol number 
2. Site number 
3. Patient initials 
4. Patient number 
5. Patient demographic information, including: 
• Date of birth 
• Sex 
• Race 


 
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6. Study drug start date (TRAVATAN Z and ENV515 implant date for Cohort 1, timolol 
maleate 0.5% ophthalmic solution for Cohorts 2 and 3, ENV515-3 for Cohort 2 and 
ENV515-3-2 for Cohort 3) 
7. Date of last dose of TRAVATAN Z or ENV515 implant removal date for Cohort 1 and 
date of the last dose of timolol maleate 0.5% ophthalmic solution for Cohorts 2 and 3 
8. SAE information, including: 
• Description of SAE/narrative 
• Diagnosis only (if known) or serious signs/symptoms 
• Date/time of onset 
• Frequency 
• Severity 
• Date/time of resolution or death (if duration <24 hours) 
• Relationship to study drug 
• Action taken 
9. Criteria for classifying the event as serious, including whether the SAE resulted in any of 
the following: 
• Death 
• Life-threatening 
• Disabling or incapacitating 
• Hospitalization required or prolonged 
• Congenital anomaly 
• Other - investigator must specify 
10. Concomitant medications 
11. Relevant history 
12. Copy of the Adverse Event page from the eCRF 
17.5. 
Additional Medically Relevant Considerations for Defining Corneal 
Endothelial Cell Loss as an SAE 
Serious Adverse Event of Corneal Endothelial Cell Loss: If an event meets any of the three 
criteria described below, it is considered a serious adverse event of corneal endothelial cell loss. 
Should any decrease in corneal endothelial cell count equal or greater than 30% change from 
study baseline occur, the investigators will be promptly notified by the Envisia team and/or the 
centralized reading center.  


 
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AE of corneal endothelial cell loss is considered “serious” (SAE) if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 
• Corneal endothelial cell loss occurs that results in a cell count < 600 cells/mm2  
• Corneal endothelial cell loss of > 70% that results in persistent change in BCVA of three 
lines of vision (15 letters) compared to study eye baseline and non-study eye 
• Corneal endothelial cell loss of any magnitude that necessitates corneal endothelium 
keratoplasty 


 
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18. 
STATISTICS 
18.1. 
Statistical Methods 
The primary objective of Cohort 1 was to evaluate the safety and tolerability of 4 dose levels of 
ENV515 (travoprost) Intracameral Implant in patients with bilateral ocular hypertension or early 
primary open angle glaucoma.  Patients were evenly randomized (two patients per dose in the 
2 ENV515-1 dose groups, 7 patients per dose in the two implants/eye ENV515-3 dose group and 
11 patients per dose in the 3 implants/eye ENV515-3 dose group for a total of 20 patients) to 
active treatment, with one study pre-surgical eye selected to receive study medication and the 
other non-study eye receiving TRAVATAN Z.  All arms will be enrolled in parallel. 
The primary objective of Cohort 2 is to evaluate the long-term safety, and tolerability of one 
dose level of ENV515-3 (travoprost) Intracameral Implant. In Cohort 3 the primary objective is 
to evaluate the long-term safety, and tolerability of two dose levels of ENV515-3-2 (travoprost) 
Intracameral Implant achieved via one or two ENV515-3-2 implant(s) per eye for low and high 
doses of ENV515-3-2, respectively. Both Cohorts study patients with bilateral ocular 
hypertension or early primary open angle glaucoma.  Patients will be assigned to active 
treatment, with one study eye selected to receive study medication and the other non-study eye 
receiving timolol maleate 0.5% ophthalmic solution.  Study eye will be determined based on the 
diurnal IOP measurement at the Baseline Visit:  the qualifying eye with the higher mean diurnal 
IOP value at the Baseline Visit will be assigned as the study eye, or the left eye will be assigned 
as the study eye if the mean diurnal IOP values are the same. 
Assessment of safety and tolerability occurring on a weekly or monthly basis (e.g. AE reports). 
Since this study has not been powered to allow formal hypothesis testing of toxicity rates or 
efficacy between dose groups for Cohort 1 or treatments for Cohort 2, any examination of 
treatment differences will be exploratory in nature.  For all analyses, patient-level covariates will 
be summarized within each group by treatment for Cohort 1 (Table 15) or by treatment for 
Cohorts 2 and 3 (Table 17).  Eye-level covariates will be summarized for each cell in the final 
row of Table 16 for Cohort 1 and Table 18 for Cohorts 2 and 3. 
Table 15: 
Patient-level Analyses, Cohort 1 
 
Group 1 
Group 2 
Group 3 
Group 4 
2 implants ENV515-3 
(28.2 μg travoprost) 
3 implants ENV515-3 
(42.3 μg travoprost) 
1 implant ENV515-1 
(42.5 μg travoprost) 
2 implants ENV515-1 
(85.0 μg travoprost) 
 
 


 
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Table 16: Eye-level Analyses, Cohort 1 
Group 1 
Group 2 
Group 3 
Group 4 
2 implants ENV515-3 
(28.2 μg travoprost) 
3 implants ENV515-3 
(42.3 μg travoprost) 
1 implant ENV515-1 
(42.5 μg travoprost) 
2 implants ENV515-1 
(85.0 μg travoprost) 
ENV515-3 
SE 
TRAVA-
TAN Z 
NSE 
ENV515-3 
SE 
TRAVA-
TAN Z 
NSE 
ENV515-1 
SE 
TRAVA-
TAN Z 
NSE 
ENV515-1 
SE 
TRAVA-
TAN Z 
NSE 
SE: Study-eye; NSE: Non-study eye 
 
Table 17: 
Patient-level Analyses, Cohorts 2 and 3 
Cohort 2 
Low Dose Cohort 3 
High Dose Cohort 3 
2 implants ENV515-3 
(28.2 μg travoprost) 
1implant ENV515-3-2 
(26.1 μg travoprost) 
2 implants ENV515-3-2 
(52.2 μg travoprost) 
 
Table 18: 
Eye-level Analyses, Cohort 2 and 3 
Cohort 2 
Low Dose Cohort 3 
High Dose Cohort 3 
2 implants ENV515-3 
(28.2 μg travoprost) 
1 implant ENV515-3-2 
(26.1 μg travoprost) 
2 implants ENV515-3-2 
(52.2 μg travoprost) 
ENV515-3 
SE 
Timolol 
maleate 
0.5% NSE 
ENV515-3-2 SE 
Timolol 
maleate 0.5% 
NSE 
ENV515-3-2 SE 
Timolol maleate 
0.5% NSE 
SE: Study-eye; NSE: Non-study eye 
18.1.1. 
Patient Disposition, Demographic and Background Characteristics 
Baseline demographic characteristics such as age and gender and clinical characteristics 
including VA, IOP, gonioscopy, and corneal thickness will be summarized using descriptive 
statistics.  Baseline will be defined as the last measurement prior to administration of the first 
dose of study drug. 
18.1.2. 
Analysis of Safety 
Safety endpoints include AEs, corneal thickness, VA, endothelial cell count and morphology, slit 
lamp biomicroscopy exam findings, corneal staining, binocular indirect ophthalmoscopy, VF 
assessment, anterior segment photos, pupil measurement, vital signs, clinical laboratory values, 
physical exam findings, and rate of discontinuation from the study.  Compliance with study drug 
administration will also be collected. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
categorized by system organ class using preferred terms.  Events will be tabulated with respect to 


 
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their intensity and relationship to the study drug.  Changes in corneal thickness, VA, endothelial 
cell count and morphology, slit lamp biomicroscopy exam findings, binocular indirect 
ophthalmoscopy, VF assessment, anterior segment photos, and pupil measurement will be 
summarized and compared between treated study eyes and across study arms for Cohort 1 and 
between study eyes for Cohorts 2 and 3 using descriptive statistics.  Continuous clinical 
laboratory values will be summarized using mean and standard deviation for reported and change 
from baseline values.  Categorical clinical laboratory values will be summarized using shift 
tables displaying the frequencies of patients with abnormal or normal results.  In addition, patient 
specific data listings will be provided for all safety measurements. 
All SAEs and other significant events, including withdrawals due to AEs will be individually 
summarized in the clinical study report. 
18.2. 
Sample Size Estimation 
Since this trial is primarily a dose-finding safety and tolerability study and the first study of 
ENV515 in patients for Cohort 1, and the first study of the full duration of IOP-lowering effect 
of ENV515-3 for Cohort 2, sample size estimation was not performed.  This study will enroll up 
to four arms of 2 to11 patients each treated unilaterally for approximately 20 patients for Cohort 
1 and 5 patients in a single arm for Cohort 2, and 15 patients in Cohort 3. 
The proposed number of patients is typical for a Phase 1/2a clinical trial and should be sufficient 
to assess the safety and tolerability of the study drug.  Assuming that 5 patients receive pooled 
active drug within Cohort 1, the probability of failing to observe a toxicity can be determined for 
various true underlying toxicity rates from the binomial distribution (Table 19).  For example, for 
a true underlying toxicity rate of 30%, the probability of failing to observe toxicity with 
5 patients would be 0.17.  For a true toxicity rate of 40%, the probability of failing to observe 
toxicity would be 0.08. For Cohort 3, the probability of failing to observe toxicity was 
determined for n=5 and n = 10 patients to provide powering information for the minimum power 
in this cohort targeting 15 patients in low (n=~5-10) and high (n=~10) dose groups, respectively 
(Table 19 and Table 20). 
Table 19: 
Toxicity Probabilities (n = 5), Cohorts 1, 2, and 3 
True Toxicity Rate (%) 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of Failing to 
Observe Toxicity 
0.59 
0.33 
0.17 
0.08 
0.03 
0.01 
0.002 <0.001 <0.001 
Table 20: 
Toxicity Probabilities (n = 10), Cohort 3 
True Toxicity Rate (%) 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of Failing to 
Observe Toxicity 
0.35 
0.11 
0.03 
0.006 0.001 <0.001 <0.001 <0.001 <0.001 
Due to the study design and discontinuation criteria in the protocol, patients who receive the 
ENV515 dose of study treatment and discontinue from the study for any reason may be replaced. 


 
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18.3. 
Level of Significance 
All exploratory statistical tests will be 2-sided and nominal significance will be determined at the 
0.05 level. 
18.4. 
Procedure for Accounting for Missing, Unused, or Spurious Data 
Any missing, unused, or spurious data will be noted in the final statistical report. 
18.5. 
Procedure for Reporting Deviations from the Statistical Plan 
Any deviations from the statistical analysis plan will be described and a justification given in the 
final clinical study report. 
18.6. 
Patients to be Included in the Analysis 
AEs and other safety parameters will be analyzed for all patients receiving at least one dose of 
study medication in the study (Safety population). 


 
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19. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator will permit trial-related monitoring, audits, Institutional Review Board (IRB) 
review, and regulatory inspection(s) by providing direct access of source data and documents 
(such as tests performed as a requirement for participation in the study and other medical records 
required to confirm information contained in the case report form such as medical history) to the 
appropriate authorized persons conducting such reviews. 
 


 
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20. 
QUALITY CONTROL 
The progress of the study will be monitored by on-site, written, email, and telephone 
communications between personnel at the study center and the sponsor (or designated monitor).  
The investigator will allow Envisia monitors or designee to inspect all case report forms; patient 
records (source documents); signed informed consent forms; records of study medication receipt, 
storage, and disposition, and regulatory files related to the study. 
 


 
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21. 
ETHICS 
21.1. 
Institutional Review Board (IRB) 
This protocol and the informed consent form (ICF) must be approved by the appropriate IRB and 
the approvals made available to Envisia or designee prior to the start of the enrollment into the 
study based on these items.  Materials used to recruit patients will be approved by the 
appropriate IRB and the approvals made available to Envisia or designee prior to their use.  In 
addition, the IB should be submitted to the IRB.  Written IRB approval must adequately identify 
the protocol and informed consent form.  Copies of all approved materials, all correspondence 
with the IRB, and written approval from the IRB must be made available to Envisia Therapeutics 
Inc. (or designated monitor). 
Any modification of study procedures or amendments to the protocol must be approved by the 
IRB prior to implementation.  In the event that a modification or amendment is considered by the 
investigator to be immediately necessary to ensure patient safety, the investigator will promptly 
notify their IRB and Envisia Therapeutics Inc. 
Investigators will promptly report all SAEs occurring at their site to their IRB. 
21.2. 
Informed Consent Requirements 
It is the responsibility of the investigator to obtain signed written informed consent from each 
potential study patient prior to the conduct of any screening or other study procedures.  This 
written informed consent will be obtained after the methods, objectives, and potential risks of the 
study have been fully explained to the potential patient.  The investigator must explain to each 
patient that he or she is completely free to refuse to enter the study or to withdraw from it at any 
time. 
The patient should also be asked in the informed consent form for permission for the principal 
investigator or his/her designee to contact the patient’s other personal physicians, as appropriate, 
concerning participation in the study. 
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of Human 
Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) regulations, and all 
other applicable regulatory requirements.  A properly executed written ICF shall be read, signed, 
and dated by each patient prior to entering the trial or prior to performing any study procedure.  
The original signed and dated ICF will be kept on file at the study site.  Patients will be given a 
copy of the signed ICF and will be informed of any new developments during the course of the 
study that might influence their continued participation in the study. 
The investigator or a qualified designee will be available to answer each patient’s questions 
throughout the study, and all questions must be answered to their satisfaction.  If the protocol is 
amended and a revised ICF is introduced during the study, each patient’s further consent must be 
obtained.  The new version of the ICF must be approved by the EC/IRB prior to subsequently 
obtaining each patient’s consent. 


 
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Receipt of written informed consent will be documented in each patient’s eCRF.  The signed ICF 
must remain in each patient’s study file and must be available for verification by study monitors 
at all times. 
21.3. 
Maintaining Privacy and Confidentiality 
In order to maintain patient privacy, all eCRFs, study drug accountability records, and other 
documents, including communications between the study site and Envisia, will identify patients 
in a fully anonymized manner, for example using only their initials and/or their assigned study 
identification numbers If required, the investigator will grant monitors and auditors from Envisia 
or its designee and/or regulatory authority’s access to patients’ original medical records for 
verification of the data gathered on the eCRFs and to audit the data collection process.  Patients’ 
confidentiality will be maintained and will not be made publicly available unless mandated by 
applicable laws and regulations. 


 
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22. 
DATA HANDLING AND RECORDKEEPING 
All procedures for the handling and analysis of data will be conducted using good clinical 
practices meeting ICH guidelines and US Food and Drug Administration regulations for the 
handling and analysis of data for clinical trials. 
22.1. 
Data Quality Control and Reporting 
Unless otherwise specified, procedures, data collection and evaluation will be conducted as per 
the Standard Operating Procedures (SOPs) of Envisia and the contracted CRO(s).  The 
investigator will assume the responsibility of ensuring the completeness and accuracy of the 
clinical data.  All data will be verified for quality control and will also be subject to audits from 
Envisia or designee to ensure quality. 
All laboratory results will be analyzed by an accredited and licensed clinical laboratory facility.  
Clinical laboratory data will be transferred from the central laboratory to the clinical database 
maintained by the CRO.  
All qualified central reading centers will collect, maintain and analyze study data in accordance 
to their standard operation procedures.  Their data will be transferred to the clinical database. 
The responsible clinical study monitor(s) will check data at the monitoring visits to the clinical 
study site.  The investigator will ensure that the data collected are accurate, complete, and 
legible.  Any changes made to the clinical data will be documented with a full audit trail. 
Aspects of the clinical and statistical phases of the study, including all associated documentation, 
may be reviewed by the Quality Assurance Unit of the CRO using a risk-assessment approach.  
The final clinical and statistical report will be audited to ensure that, as far as can be reasonably 
established, the methods described and the results reported accurately reflect the raw data 
generated during the study. 
22.2. 
Records Retention 
Study site files for the retention of regulatory documents will be established at the beginning of 
the study, maintained for the duration of the study, and retained according to FDA and ICH/GCP 
guidelines and applicable regulatory requirements.  The records maintained must be adequate to 
fully document appropriate protection of study patients, the validity of the study, the integrity of 
the data, and the manner in which the study was conducted. 
The investigator’s site file, copies of protocols, CRFs, originals of test result reports, drug 
disposition logs, correspondence, records of written informed consent, and other paper or 
electronic documents pertaining to the conduct of the study must be kept on file by the 
investigator and in readily accessible order for at least 2 years after the last approval of a 
marketing application, until at least 2 years have elapsed after formal discontinuation of the 
clinical development of the investigational product, or according to local regulatory 
requirements.  No study document may be destroyed without prior written consent from Envisia 
or its designee.  Should the investigator wish to withdraw from the responsibility of keeping the 
study records, custody must be transferred to a person willing to accept the responsibility.  


 
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Envisia must be notified in writing in advance if a custodial change is to occur.  It is important 
that the investigator remain ready to provide background information from the archived study 
records on request. 
The sponsor or designee will maintain adequate study records for at least 2 years after the last 
approval of a marketing application or for at least 2 years after clinical development of the study 
drug for the indication being studied has been discontinued.  After that period, the sponsor will 
be contacted to determine whether the study records will be forwarded to the sponsor, destroyed, 
or kept at the location of the designee or another facility for a longer period of time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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23. 
PUBLICATION POLICY 
The institutions and investigators participating in this trial shall have no right to publish or 
present the results of this study without the prior written consent of Envisia. 


 
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24. 
REFERENCES 
 
1. TRAVATAN® (travoprost ophthalmic solution) Package Insert. Alcon Laboratories, 
Inc. Fort Worth, TX 2004. 
2. TRAVATAN Z® (travoprost ophthalmic solution) Package Insert. Alcon Laboratories, 
Inc. Fort Worth, TX. 2013. 
3. Quigley HA, Vitale S. Models of open-angle glaucoma prevalence and incidence in the 
United States. Invest Ophthalmol & Visual Sci. 1997;38(1):83-91. 
4. Quigley HA. Glaucoma Macrocosm to microcosm. Invest Ophthalmol & Visual Sci. 
2005;46(8):2663-2670. 
5. Caprioli J, Rohit V. Intraocular Pressure: Modulation as treatment for Glaucoma. Am J 
Ophthalmol. 2011;152(3):340-344. 
6. OZURDEX® (dexamethasone intravitreal implant) Package Insert. Allergan, Inc. Irvine, 
CA 2014. 
7. Chang DF, Wong V. Two clinical trials of an intraocular steroid delivery system for 
cataract surgery. Trans Am Ophthalmol Soc.1999;97:261-74. OZURDEX® 
(dexamethasone intravitreal implant) Package Insert. Allergan, Inc. Irvine, CA 2014. 
8. Timolol Maleate Ophthalmic Solution, USP (0.5% Sterile Ophthalmic Solution) 
Package Insert. Akorn, Inc. Lake Forest, IL  
9. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature 
(SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical 
data. Results of the First International Workshop. Am J Ophthalmol 2005;140:509-516. 


 
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APPENDIX 1 
Blood/Plasma Sample Collection and Processing, Cohorts 1, 2 and 3 
Chemistry and hematology collection and processing instructions can be found in the ACM lab 
manual. 
Plasma samples will be processed as follows: 
Collect whole blood into vial K2EDTA provided by ACM. Centrifuge for 15 minutes at 2,000 x 
g to deplete platelets in the plasma sample. The resulting supernatant is designated plasma. 
Immediately transfer the liquid component (plasma) into a plasma cyrovial provided by ACM 
using a Pasteur pipette. The samples should be maintained at 2-8°C while handling. The plasma 
should be aliquoted into a primary and secondary cryovials, stored, and transported at –20°C or 
lower. It is important to avoid freeze-thaw cycles. 
No plasma samples should be shipped on Fridays. If plasma samples are collected on a Friday, 
please store in a controlled -80°C to -70°C freezer if you have one.  If you do not have a -80°C to 
-70°C freezer, please fill the shipment container to capacity with dry ice and hold shipment over 
the weekend.  Replenish the dry ice on Monday and ship samples overnight for Tuesday 
delivery.  *Do not put dry ice in a -20°C freezer.   
Aqueous Humor Sample Collection and Processing, Cohort 1 
Aqueous humor will be collected as follows: 
Following the creation of the initial incision in the clear cornea, ~100 µL of aqueous humor will 
be sampled from the anterior chamber via provided 1 ml syringe with 30 gauge needle.  Samples 
will be dispensed into pre-labeled amber scintillation vial.  Place sample in dry ice for shipment 
to Intertek on the same day. 
Target Volume:  ~0.1 mL 
Aqueous humor samples will be collected and processed.  
If implants are removed from patients in Cohorts 2 or 3, utilize the collection of aqueous humor 
collection and processing above. 
No aqueous humor samples should be shipped on Fridays. If aqueous humor samples are 
collected on a Friday, please store in a controlled -80°C to -70°C freezer if you have one.  If you 
do not have a -80°C to -70°C freezer, please fill the shipment container to capacity with dry ice 
and hold shipment over the weekend.  Replenish the dry ice on Monday and ship samples 
overnight for Tuesday delivery.  *Do not put dry ice in a -20°C freezer.   
Implant Removal and handling, Cohort 1 
The recovered implants recovery is described in this study protocol. The recovered implants will 
be collected and handled as by the following procedure: 


 
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After removal of the aqueous humor sample, implants will be recovered from the anterior 
chamber.  A stream of Buffered Saline Solution (BSS) is directed to the iridocorneal angle 
location where the implant(s) was identified during gonioscopy.  Dislodge the implants using the 
stream of BSS.  Implants will float within the fluid on the anterior chamber.  Utrata forceps or 
equivalent instrument is used to grasp implant(s) and remove through the incision.  Place 
implant(s) in salinized glass vials and store at 2-8ºC until shipment.  Samples should be shipped 
the same day as recovery. 
If implants are removed from patients in Cohorts 2 or 3, utilize the removal and handling 
proceeds above. 
No recovered implants should be shipped on Fridays. If recovered implants are collected on a 
Friday, please store in a controlled 2°C to 8°C refrigerator.   
 
 

SAP_001.pdf: 




































































Version: DRAFT 
 
STATISTICAL ANALYSIS PLAN 
January 21, 2019 
 
 
 
 
A Multi-Center, Three-Stage, Open-Label, Prospective, Active-
Comparator-Controlled Phase 2a Study of ENV515 (travoprost) 
Intracameral Implant in Patients with Bilateral Ocular Hypertension or 
Early Primary Open Angle Glaucoma 
 
 
 
 
PROTOCOL NUMBER ENV515-01 
 
 
 
 
 
 
 
SPONSORED BY 
 
Envisia Therapeutics Inc. 
PO Box 110065 
Research Triangle Park, NC 27709 
919-219-6448 
 
 
PREPARED BY 
 
Rho, Inc. 
6330 Quadrangle Drive 
Chapel Hill, NC 27517 
Telephone:  (919) 408-8000 
Fax:  (919) 408-0999 
 
 
 
This document is confidential and proprietary to Envisia Therapeutics Inc..  Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be reproduced, 
published, or otherwise disclosed without the prior written approval of Envisia Therapeutics Inc., except 
that this document may be disclosed to appropriate Institutional Review Boards under the condition that they 
keep the information confidential. 


Envisia Therapeutics Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 2 of 21 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
0.1 
19 December 2018 
DRAFT 
1.0 
21 January 2019 
Final 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Envisia Therapeutics Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 3 of 21 
APPROVALS 
Approved: 
 
Date: 
 
 
Marcus Herman-Giddens 
Biostatistician 
Rho, Inc. 
 
 
 
 
Date: 
 
 
Steven Neilson, MS 
Consultant, Clinical Operations 
 
 


Envisia Therapeutics Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 4 of 21 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 5 
1. 
PURPOSE OF THE ANALYSES .............................................................................. 6 
2. 
PROTOCOL SUMMARY .......................................................................................... 7 
2.1 
Study Objectives ........................................................................................... 7 
2.2 
Overall Study Design and Plan ..................................................................... 7 
2.3 
Study Population ........................................................................................... 9 
2.4 
Treatment Regimens..................................................................................... 9 
2.5 
Treatment Group Assignments or Randomization ....................................... 10 
2.6 
Sample Size Determination ......................................................................... 10 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS.................................. 11 
4. 
ANALYSIS POPULATIONS ................................................................................... 12 
5. 
STUDY PATIENTS ................................................................................................. 13 
5.1 
Disposition of Patients ................................................................................. 13 
5.2 
Protocol Deviations ..................................................................................... 13 
5.3 
Medical History ........................................................................................... 13 
5.4 
Prior and Concomitant Medications ............................................................. 13 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 14 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................ 15 
8. 
EFFICACY EVALUATION ..................................................................................... 16 
8.1 
Primary Efficacy Analysis ............................................................................ 16 
9. 
SAFETY EVALUATION ......................................................................................... 17 
9.1 
Overview of Safety Analysis Methods ......................................................... 17 
9.2 
Extent of Exposure ...................................................................................... 17 
9.3 
Adverse Events ........................................................................................... 17 
9.4 
Clinical Laboratory Evaluation ..................................................................... 17 
9.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 17 
9.5.1 
Vital Signs .......................................................................................... 17 
9.5.2 
Physical Examinations ....................................................................... 18 
9.5.3 
Visual Acuity (VA) .............................................................................. 18 
9.5.4 
Other Safety Parameters ................................................................... 18 
10. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 19 
11. LIST OF PLANNED TABLES ................................................................................ 20 
12. LIST OF PLANNED DATA LISTINGS ................................................................... 21 
 


Envisia Therapeutics Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 5 of 21 
LIST OF ABBREVIATIONS 
AE 
adverse event 
CSR 
clinical study report 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
IND 
Investigational New Drug Application 
IOP 
intraocular pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSE 
non-study eye 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
study eye 
VA 
visual acuity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Envisia Therapeutics Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 6 of 21 
1. 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) contains detailed information to aid in the implementation 
of the statistical analysis and reporting of the study data for use in the abbreviated clinical 
study report (CSR).  An abbreviated CSR is being created because the Investigational New 
Drug Application (IND) is being withdrawn.  This SAP will address the analysis for 
Cohorts 2 and 3 of the study.  A separate SAP was created for Cohort 1. 
 


Envisia Therapeutics Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 7 of 21 
2. 
PROTOCOL SUMMARY 
ENV515-01 is a multicenter, open-label, prospective, active-comparator-controlled 
Phase 2a study of ENV515 (travoprost) Intracameral Implant comprising three stages: 
• The completed Cohort 1 was a 28-day study focused on evaluation of the initial 
safety, efficacy, and pharmacokinetic properties of ENV515 conducted in 
glaucoma patients scheduled for cataract removal during which the ENV515 
implant is removed during the cataract procedure 28 days after implantation.  This 
cohort was covered in a separate SAP and no further mention of this cohort will 
be made in this SAP. 
 
• Cohort 2 is a 12-month study with a 6-month optional Extension 1 followed by an 
additional 3-month optional Extension 2 (for a total of up to 21 months) that is 
focused on evaluation of the long-term safety and efficacy in glaucoma patients 
during which the two ENV515-3 implants are followed through their 
biodissolution while the duration of intraocular pressure (IOP)-lowering efficacy 
is assessed. 
 
• Cohort 3 is a 12-month study with a 6-month optional Extension 1 followed by an 
additional 6-month optional Extension 2 (for a total of up to 24 months) that is 
focused on evaluation of the long-term safety in glaucoma patients during which 
one or two ENV515-3-2 implants per study eye are followed through their 
biodissolution. 
 
 
2.1 
Study Objectives 
Evaluate in a dose-escalating design the long-term safety and tolerability of a single, 
unilateral low dose of two ENV515-3 (travoprost) intracameral implants/eye in Cohort 2; 
and low and high doses of one and two ENV515-3-2 (travoprost) intracameral 
implants/eye, respectively, in Cohort 3 in patients with bilateral ocular hypertension or 
primary open-angle glaucoma. 
 
2.2 
Overall Study Design and Plan 
Cohorts 2 (5 patients) and 3 (15 patients) are 12-month, prospective, open-label, 
active-comparator-controlled, multicenter, dose-escalating cohorts of this Phase 2a trial.  
Cohort 2 had a 6-month optional Extension 1 followed by an additional 3-month optional 
Extension 2 (for up to a total of 21 months), increasing the total study duration to 
approximately 23 months.  Cohort 3 has a 6-month optional Extension 1 followed by an 
additional 6-month optional Extension 2 (for a total of 24 months), increasing the total 
study duration to approximately 26 months.  Cohorts 2 and 3 were designed to assess the 
long-term safety, tolerability, and systemic exposure to travoprost after a single low dose 
(ENV515-3) in Cohort 2, and single low or high doses (ENV515-3-2) in Cohort 3 in 


Envisia Therapeutics Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 8 of 21 
patients with bilateral open-angle glaucoma or ocular hypertension (see Inclusion Criteria 
in Section 11.1 of the protocol).  For the purposes of the Cohorts 2 and 3, patients are 
eligible if in the opinion of the investigator they have an IOP in both eyes that is 
considered to be adequately controlled at the screening visit, can be safely withdrawn 
from IOP medications in both eyes during the washout period, and are not considered to 
be at significant risk for disease progression throughout the trial.  The dose levels of 
travoprost in Cohorts 2 and 3 of this study are achieved by administration of a single, 
unilateral intracameral injection of each formulation with 28.2 μg travoprost/eye in 
Cohort 2; and 26.1 μg and 52.2 μg travoprost/eye in Cohort 3.  These dose levels will be 
achieved via two implants per eye for low dose of ENV515-3 in Cohort 2, and one and 
two implants per eye for the low and high doses of ENV515-3-2, respectively, in 
Cohort 3.  The study eye is prospectively defined as the eye with higher IOP or the left 
eye if IOP values are equal in both eyes on Dosing Visit (Day 1).  All non-study eyes will 
receive open-label timolol maleate 0.5% ophthalmic solution administered twice a day 
(Figure 1 and Figure 2). 
Figure 1: ENV515 Treatment, Cohort 2 
 
Figure 2: ENV515 Treatment, Cohort 3 
 
On the Day 1 Dosing (Visit 3), low dose of ENV515-3 in Cohort 2, or low or high doses 
of ENV515-3-2 in Cohort 3 will be administered.  Following the completion of the rest of 
the study treatment period Month 4 (Visit 8) to Exit/Early Exit (Visit 16, Visit 22, or 
Visit 25) for the Cohort 2 alone, all safety and tolerability analyses will be conducted 
(Figure 3). 


Envisia Therapeutics Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 9 of 21 
Figure 3: Study Design for ENV515-01 (Cohorts 2 and 3) 
 
 
For Cohort 2, the study design included up to 26 clinic visits over approximately 
23 months (12 months of Cohort 2, 6-month optional Extension 1, and 3-month optional 
Extension 2).  For Cohort 3, the study design includes up to 28 clinic visits over 
approximately 26 months (12 months of Cohort 3, 6-month optional Extension 1, and 
6-month optional Extension 2).  Following the Screening Visit, patients will be required 
to washout current glaucoma medication(s) for 4 weeks with up to an additional 2-week 
extension or 6 weeks depending on Cohort.  Patients will be required to return for an IOP 
baseline check during the Baseline Visit (Visit 2/Day -7 to -1) following the wash-out 
period.  A single dose of ENV515-3 (two implants/eye) or ENV515-3-2 (one or two 
implant(s)/eye) will be given via intracameral injection during Dosing Visit 3/Day 1. 
Diurnal IOP curves will be measured at select study visits with the exception of the 
abbreviated visits at the Screening Visit (Days -49 to -442 for Cohort 2 and Days -56 
to -42 for Cohort 3), Dosing Visit 3 (Day 1), Treatment Visit 4 (Day 2), Treatment 
Visit 5a (Day 28), and selected visits depending on the cohort and extensions(s). 
 
2.3 
Study Population 
This study enrolled subjects between 18 and 85 years of age with a diagnosis of bilateral 
ocular hypertension or primary open-angle glaucoma.  For additional information on 
inclusion and exclusion criteria, see Section 11 of the protocol. 
 
2.4 
Treatment Regimens 
Patients will receive the following investigational product doses in the study eye on 
Day 1 Dosing (Visit 3) and will receive timolol maleate 0.5% ophthalmic solution to use 
in the nonstudy eye twice daily starting on the evening of Day 1 and continuing through 
the day prior to Month 12 (Visit 16), Month 18 (Visit 22), or Month 21 (Visit 25) for 
Cohort 2 or Month 24 (Visit 28) for Cohort 3. 


Envisia Therapeutics Inc. 
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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 10 of 21 
• Cohort 2 low dose level: two implants/eye of ENV515-3 (28.2 µg/eye) 
• Cohort 3 low and high dose levels: 
o One implant/eye of ENV515-3-2 (26.1 µg/eye) 
o Two implants/eye of ENV515-3-2 (52.2 µg/eye) 
 
2.5 
Treatment Group Assignments or Randomization 
No randomization was conducted as these are open-label cohorts. 
 
2.6 
Sample Size Determination 
Since this trial is primarily a dose-finding safety and tolerability study and the first study 
of the full duration of IOP-lowering effect of ENV515-3 for Cohort 2, sample size 
estimation was not performed.  This study will enroll 5 patients in a single arm for 
Cohort 2, and 15 patients in Cohort 3. 
 


Envisia Therapeutics Inc. 
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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 11 of 21 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following is a list of general analysis and reporting conventions to be applied for this 
study. 
• Categorical variables will be summarized using counts (n) and percentages (%) 
and will be presented in the form “n (xx.x)”.  To ensure completeness, summaries 
for categorical and discrete variables will include all categories, even if no 
subjects had a response in a particular category. 
• Continuous variables will be summarized using mean, standard deviation (SD), 
minimum, maximum, median, and number of subjects.  The mean and median 
will be reported to one more level of precision than the original observations, and 
the SD will be reported to 2 more levels of precision than the original 
observations.  The minimum and maximum will be the same precision as the 
original data. 
• All analyses will be performed using SAS® System version 9.4 or higher. 
• Dates will be displayed as ddmmmyyyy (e.g., 24Jan2005). 
Patient-level analyses will be presented with the following columns: 
Cohort 2 
Low Dose Cohort 3 
High Dose Cohort 3 
2 implants ENV515-3 
(28.2 µg travoprost) 
1 implant ENV515-3-2 
(26.1 µg travoprost) 
2 implants ENV515-3-2 
(52.2 µg travoprost) 
Eye-level analyses will be presented with the following columns: 
Cohort 2 
Low Dose Cohort 3 
High Dose Cohort 3 
2 implants ENV515-3 
(28.2 µg travoprost) 
1 implant ENV515-3-2 
(26.1 µg travoprost) 
2 implants ENV515-3-2 
(52.2 µg travoprost) 
ENV515-3 
SE 
Timolol 
maleate 
0.5% NSE 
ENV515-3 
SE 
Timolol 
maleate 
0.5% NSE 
ENV515-3 
SE 
Timolol 
maleate 
0.5% NSE 
Note: SE=study eye, NSE=non-study eye 
 


Envisia Therapeutics Inc. 
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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 12 of 21 
4. 
ANALYSIS POPULATIONS 
The safety population will be defined as any patient receiving at least one dose of study 
medication in the study.  The safety population will be used for all analyses. 
 


Envisia Therapeutics Inc. 
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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 13 of 21 
5. 
STUDY PATIENTS 
5.1 
Disposition of Patients 
The disposition of subjects will be summarized for all subjects enrolled in Cohorts 2 and 
3.  The number and percentage of subjects in the safety population, the number and 
percentage of subjects who complete the study, as well as the number and percentage that 
discontinue the study and the reasons for study discontinuation will be summarized by 
cohort dose. 
 
5.2 
Protocol Deviations 
All protocol deviations will be reported in listings.  Protocol deviations will be defined 
prior to locking the database. 
 
5.3 
Medical History 
All medical history data will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.0 and presented in listings. 
 
5.4 
Prior and Concomitant Medications 
All prior and concomitant medications will coded using WHO Drug Enhanced version 
2016.01 and be presented in listings. 


Envisia Therapeutics Inc. 
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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 14 of 21 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Age, gender, race, ethnicity, and iris color will be summarized by cohort dose.  All 
demographics data will be presented in subject listings. 
 


Envisia Therapeutics Inc. 
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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 15 of 21 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
In this study, the principal investigator administers the investigational treatment into the 
study eye on the day of randomization.  As a result, compliance with the investigational 
product will be 100%.  Compliance information will not be collected for the active 
control. 
 


Envisia Therapeutics Inc. 
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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 16 of 21 
8. 
EFFICACY EVALUATION 
8.1 
Primary Efficacy Analysis 
The primary efficacy endpoint for this study is the change from baseline in time-matched 
IOP measurements for the study and non-study eye.  Intraocular pressure is collected at 8 
am.  Values for IOP and change from baseline will be summarized by visit and time, 
cohort dose group, and eye as specified in Section 3.  Baseline will be defined as the last 
IOP measurement prior to implantation and will be time-matched.  No formal statistical 
testing will be done. 


Envisia Therapeutics Inc. 
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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 17 of 21 
9. 
SAFETY EVALUATION 
9.1 
Overview of Safety Analysis Methods 
Adverse events, clinical laboratory results, vital signs, and physical exam findings will be 
tabulated at the subject level.  All other safety measurements will be made at the eye 
level.  Unless otherwise noted, baseline will be defined as the last measurement prior to 
receiving the implant. 
 
9.2 
Extent of Exposure 
The number of days from implant insertion to implant dissolution or removal will be 
summarized descriptive statistics.  All other exposure data will be available in subject 
listings.  Exposure will be calculated only for the study eye.  No exposure information for 
the TRAVATAN Z eye will be collected. 
 
9.3 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 18.0 and categorized by system organ class using preferred terms.  
Events will be tabulated overall and by ocular/non-ocular status.  Treatment related 
adverse events and severe adverse event will also be summarized.  Serious adverse events 
will be summarized. 
 
9.4 
Clinical Laboratory Evaluation 
Continuous clinical laboratory values will be summarized using descriptive statistics for 
reported and change from baseline values. Baseline will be the last measurement prior to 
implantation.  Categorical clinical laboratory values will display the frequencies of 
patients with abnormal and normal results. 
 
9.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.5.1 
Vital Signs 
Vital sign assessments include measurements of heart rate, blood pressure, and 
respiration rate.  Vital signs will be summarized using descriptive statistics by study visit 
and treatment group.  All vital sign data will be presented in subject listings. 
 


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Protocol No. ENV515-01 
 
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Page 18 of 21 
9.5.2 
Physical Examinations 
All physical examination data will be presented in listings. 
 
9.5.3 
Visual Acuity (VA) 
Visual acuity will be measured using the Early Treatment Diabetic Retinopathy Study 
(ETDRS) chart according to the manufacturer’s specifications.  The number of letters 
missed will be collected and summarized by cohort group and eye for each visit.  Visual 
acuity data, including best corrected distance, will be presented in subject listings. 
 
9.5.4 
Other Safety Parameters 
Safety data were also collected for anterior chamber optical coherence tomography, 
gonioscopy, specular microscopy, corneal thickness, endothelial cell count and 
morphology, slit lamp biomicroscopy exam findings, corneal staining, binocular indirect 
ophthalmoscopy, visual field assessment, and pupil measurements.  These data will be 
presented in data listings. 
 
 
 
 
 
 
 


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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 19 of 21 
10. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
This analysis plan is for an abbreviated CSR.  Therefore, the primary endpoint will be 
summarized, but no formal statistical testing will be done.  There will be no summaries 
for secondary endpoints.  The planned summaries in the protocol for changes in corneal 
thickness, VA, endothelial cell count and morphology, slit lamp biomicroscopy exam 
findings, binocular indirect ophthalmoscopy, visual field assessment, anterior segment 
photos, and pupil measurement will not be created.  These data will instead be available 
in listings. 
 


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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 20 of 21 
11. 
LIST OF PLANNED TABLES 
Rho Table 
Identifier 
Table No. Title 
Population 
DS-TAA 
14.1.1 
Disposition 
Safety 
DM-TAA 
14.1.2 
Demographics 
Safety 
EF-TAA 
14.2.1 
Summary of Intraocular 
Pressure by Visit and Time 
Point 
Safety 
AE-TAA 
14.3.1.1 
Summary of Adverse Events Safety 
AE-TAB 
14.3.1.2 
Summary of Adverse Events 
by System Organ Class and 
Preferred Term 
Safety 
AE-TAC 
14.3.1.3 
Summary of Ocular Adverse 
Events by System Organ 
Class and Preferred Term 
Safety 
AE-TAD 
14.3.1.4 
Summary of Related 
Adverse Events 
Safety 
AE-TAE 
14.3.1.5 
Summary of Severe Adverse 
Events 
Safety 
AE-TAF 
14.3.1.6 
Summary of Serious 
Adverse Events 
Safety 
LB-TAA 
14.3.2.1 
Summary of Chemistry by 
Visit 
Safety 
LB-TAB 
14.3.2.2 
Summary of Hematology by 
Visit 
Safety 
LB-TAC 
14.3.2.3 
Summary of Urinalysis by 
Visit 
Safety 
VS-TAA 
14.3.3.1 
Summary of Vital Signs by 
Visit 
Safety 
VA-TAA 
14.3.4.1 
Summary of Visual Acuity 
Safety 
EX-TAA 
14.3.5.1 
Summary of Exposure  
Safety 
 
 
 
 


Envisia Therapeutics Inc. 
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Statistical Analysis Plan 
Protocol No. ENV515-01 
 
21 January 2019 
Version:  ENV515-01 Cohorts 2-3 SAP Clean 
 
Page 21 of 21 
12. 
LIST OF PLANNED DATA LISTINGS 
Listing No. 
Title 
16.1.1 
Disposition 
16.1.2 
Demographics 
16.1.3 
Protocol Deviations 
16.1.4 
Prior and Concomitant Medications 
16.1.5 
Medical History 
16.2.1 
Intraocular Pressure 
16.3.1 
Adverse Events 
16.3.2.1 
Chemistry 
16.3.2.2 
Hematology 
163.2.3 
Urinalysis 
16.3.3 
Vital Signs 
16.3.4.1 
Visual Acuity 
16.3.4.2 
Endothelial Cell Count and Morphology 
16.3.4.3 
Slit Lamp Biomicroscopy 
16.3.4.4 
Pupil Measurements 
16.3.4.5 
Dilated Fundus Examination 
16.3.4.6 
Visual Field 
16.3.4.7 
Anterior Segment 
16.3.4.8 
Gonioscopy 
16.3.4.9 
Specular Microscopy 
16.3.4.10 
Corneal Thickness 
16.3.4.11 
Pupil Measurements 
16.4.5 
Exposure