Clinical trial NCT05383209
Conditions: Nonproliferative Diabetic Retinopathy
Keywords: NPDR EYP-1901 EyePoint
Sponsor: EyePoint Pharmaceuticals, Inc.
Start date: 2022-09-28; Completion date: 2024-05-06
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A prospective, randomized, double-masked study that evaluated the ocular efficacy and safety of two doses of the EYP-1901 intravitreal (IVT) insert compared to sham.

Detailed description:
This study evaluated the ocular efficacy and safety of two doses of the EYP-1901 IVT insert compared to sham using a randomized double-masked trial design.

Arms: arm 1: EYP-1901 2060 ug; single injection arm 2: EYP-1901 3090 ug; single injection arm 3: Sham IVT; single injection
Interventions: intervention 1: EYP-1901 intervention 2: Sham IVT
Intervention descriptions: intervention 1: EYP-1901 will be administered to the study eye by a single injection through the pars plana using a pre-loaded applicator with a 22-gauge needle. Each EYP-1901 IVT insert has been designed to deliver vorolanib into the vitreous humor for approximately 6 to 9 months. intervention 2: Sham injections will be used to maintain masking of investigational EYP-1901 therapy for study subjects.

Protocol documents:
Prot_000.pdf: 
EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 1 of 65 
 
 
 
EYP-1901 
(VOROLANIB INTRAVITREAL INSERT) 
 
 
PROTOCOL EYP-1901-204 
 
 
A Phase 2, Multicenter, Prospective, Double-masked, Parallel Study 
of EYP-1901, a Tyrosine Kinase Inhibitor (TKI), compared to Sham 
for the Improvement of Moderately Severe to Severe 
Nonproliferative Diabetic Retinopathy (NPDR) 
 
 
 
 
IND Number 
146448 
Sponsor: 
EyePoint Pharmaceuticals, Inc. 
480 Pleasant Street 
Watertown, MA 02472 USA 
Version: 
Version 3.0: 
 
31 March 2023 
Version 2.0: 
 
10 May 2022 
Original Protocol: 26 Feb 2022 
 
 
 
Confidentiality Statement 
This document contains confidential information, which should not be copied, referred to, released, or 
published without written approval from EyePoint Pharmaceuticals, Inc.  Investigators are cautioned that 
the information given in this study protocol might be subject to change and revision.  Any conclusion 
regarding efficacy and safety must be considered provisional. 
 


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 2 of 65 
 
 
 
PROTOCOL APPROVAL PAGE 
Protocol Title: 
A Phase 2, Multicenter, Prospective, Double-masked, Parallel Study of 
EYP-1901, a Tyrosine Kinase Inhibitor (TKI), compared to Sham for 
the Improvement of Moderately Severe to Severe Nonproliferative 
Diabetic Retinopathy (NPDR) 
 
Protocol Number: 
EYP-1901-204 
 
Version Number:  
Version 3.0 
 
Date:  
 
 
 
31 March 2023 
 
 
This protocol has been reviewed and approved by EyePoint Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
EyePoint Pharmaceuticals, Inc. 
 
Date 
PPD


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 3 of 65 
 
 
 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol, concur that it contains all information necessary to conduct the 
study, and agree to follow the study procedures as outlined in this protocol. 
I agree to comply with United States (US) Food and Drug Administration (FDA) regulations 
(21 CFR Parts 50, 54, 56 and 312) and International Conference on Harmonization (ICH) 
guidelines.  I will not initiate the study until I have obtained written approval by the appropriate 
Institutional Review Board/Ethics Committee and have complied with all financial and 
administrative requirements of the governing body of the clinical institution.  I will obtain 
written informed consent from all study participants prior to performing any screening 
procedures. 
This protocol and related information is subject to the Confidentiality Agreement between myself 
and EyePoint Pharmaceuticals, Inc. and as such must be held in confidence and not disclosed to 
any third party for a period of seven (7) years from the date of the Confidentiality Agreement, or 
until said information shall become a matter of public knowledge, or until a formal written 
agreement for that purpose has been entered into by the parties. 
 
 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
Print Name 
 
 
 
 
 


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 4 of 65 
 
 
 
PERSONNEL CONTACT INFORMATION 
 
Role in Study 
Name 
Address and Telephone Numbers 
Sponsor 
EyePoint Pharmaceuticals, 
Inc. 
EyePoint Pharmaceuticals, Inc. 
480 Pleasant Street 
Watertown, MA 02472 USA 
Phone: (617) 926-5000 
Fax: 
(617) 926-5050 
Principal Investigator 
[n/a] 
[n/a] 
 
 
 
Medical Monitor 
, MD 
 
 
EyePoint Pharmaceuticals, Inc. 
480 Pleasant Street, Suite B300 
Watertown, MA 02472 USA 
Cell:  
 
 
Drug Safety Physician 
, MD, 
MS 
Director, Pharmacovigilance 
EyePoint Pharmaceuticals, Inc. 
480 Pleasant Street, Suite B300 
Watertown, MA 02472 USA 
 
Cell: 
 
Email: 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 5 of 65 
 
 
 
SYNOPSIS 
Name of Sponsor/Company: 
EyePoint Pharmaceuticals, Inc. 
Individual Study Table 
Referring to Part 
of the Dossier 
 
Volume: 
 
Page: 
 
 
(for National Authority 
Use only) 
Name of Investigational Product: 
EYP-1901 (Vorolanib Intravitreal Insert) 
Name of Active Ingredient: 
Vorolanib 
Title of Study:  A Phase 2, Multicenter, Prospective, Double-masked, Parallel Study of EYP-1901, a 
Tyrosine Kinase Inhibitor (TKI), compared to Sham for the Improvement of Moderately Severe to 
Severe Nonproliferative Diabetic Retinopathy (NPDR) 
Protocol Number:  EYP-1901-204 
Phase of Development:  2 
Study Sites:  Approximately 30 sites in the US 
Studied Period:  Up to 48 weeks of follow-up 
Objectives:  The primary objective is to assess the efficacy of EYP-1901 compared to sham treatment 
in the improvement of moderately severe to severe nonproliferative diabetic retinopathy (NPDR). 
The secondary objectives are: 
• 
To characterize the safety of EYP-1901 in subjects with moderately severe to severe NPDR. 
• 
To determine if EYP-1901 will prevent the worsening of diabetic retinopathy and reduce the 
incidence of diabetic macular edema (DME). 
• 
To evaluate the need for additional standard of care intervention due to ocular diabetic 
complications. 
• 
To determine the anatomic effects of EYP-1901 in subjects with moderately severe to severe 
NPDR. 
• 
To determine the systemic exposure to vorolanib and X-297, its main metabolite, measured 
through plasma levels up to Week 48. 
Methodology:  A prospective, randomized, double-masked, multicenter study evaluating the ocular 
efficacy and safety of two doses of the EYP-1901 intravitreal insert compared to sham. 
• 
Subjects with NPDR who meet the study eligibility criteria will be randomly assigned to 
EYP-1901 2060 µg dose, EYP-1901 3090 µg dose, or sham intravitreal (IVT) injection. 
• 
Follow-up examinations will be conducted at Week 4, 12, 24, 36, and 48 following study drug 
administration. 
Number of Subjects (planned):  Approximately 60 subjects (20 subjects per treatment arm). 
Inclusion Criteria: 
1. Men or women ≥18 years of age with type 1 or 2 diabetes mellitus.  Participants must have a 
hemoglobin A1c (HbA1c) ≤12% (as confirmed by laboratory assessments obtained at the 
Screening Visit or by a documented laboratory report dated within 60 days prior to the 
Screening Visit). 


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 6 of 65 
 
 
 
2. Study eye with moderately severe to severe NPDR (based on the Diabetic Retinopathy 
Severity Scale [DRSS] levels 47 or 53), using standard 4-widefield digital stereoscopic fundus 
photographs confirmed by the central reading center (CRC), in whom pan-retinal 
photocoagulation (PRP) and anti-vascular endothelial growth factor (anti-VEGF) injections 
can be safely deferred for at least 6 months per the Investigator. 
3. Best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study 
(ETDRS) letter score in the study eye of ≥69 letters (approximate Snellen equivalent of 20/40 
or better). 
4. Able to understand, and willingness to sign, the informed consent and to provide access to 
personal health information via Health Insurance Portability and Accountability Act (HIPAA) 
authorization. 
5. Willingness and ability to comply with all scheduled visits, restrictions, and assessments. 
6. For women of childbearing potential, or men with female partners of childbearing potential, 
agreement to the use of an appropriate form of contraception for the duration of the study. 
Exclusion Criteria: 
1. Presence of any active center involved-diabetic macular edema (CI-DME) in the study eye as 
determined by the Investigator on clinical examination, or within the central subfield thickness 
(CST) of the study eye as determined by spectral-domain – optical coherence tomography 
(SD-OCT) evaluated by the CRC, with a CST threshold greater than 320 microns. 
2. Evidence of retinal neovascularization on clinical examination or wide-field fluorescein 
angiography (FA). 
3. Any evidence or documented history of prior focal or grid laser photocoagulation or any PRP 
in the study eye in the last 12 months. 
4. Any evidence of optic nerve pallor on clinical examination in the study eye as determined by 
the Investigator. 
5. Any evidence of high-risk characteristics typically associated with vision loss in the study eye 
as determined by the Investigator. 
6. Any evidence of new vascularization anywhere (neovascularization of the iris [NVI], 
neovascularization of the angle [NVA], neovascularization everywhere [NVE], 
neovascularization of the disc [NVD]) on clinical examination as per the Investigator, or 
imaging evaluated by the CRC, in the study eye. 
7. Any prior systemic anti-VEGF treatment in the past 12 months. 
8. Any prior IVT anti-VEGF treatment in the past 12 months.  
9. Any documentation of more than 4 prior anti-VEGF IVT injections in the study eye. 
10. Any concurrent intraocular condition in the study eye (eg, cataract or glaucoma) that, in the 
opinion of the Investigator, would either require surgical intervention during the study to 
prevent or treat visual loss that might result from that condition or affect interpretation of the 
study results. 
11. History of prior vitrectomy surgery in study eye. 
12. Historical or active intraocular inflammation (grade trace or above) in the study eye, other than 
expected findings from routine cataract surgery. 
13. History of vitreous hemorrhage in the study eye within 12 weeks prior to the Screening Visit. 


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 7 of 65 
 
 
 
14. History of rhegmatogenous retinal detachment or treatment for retinal detachment or macular 
hole (stage 3 or 4) in the study eye. 
15. Aphakia or pseudophakia with the absence of the posterior capsule in the study eye (YAG 
capsulotomy is permitted). 
16. Spherical equivalent of the refractive error in the study eye demonstrating >8 diopters of 
myopia.  For subjects who have undergone prior refractive or cataract surgery in the study eye, 
preoperative refractive error in the study eye exceeding 8 diopters of myopia. 
17. Intraocular surgery (including cataract surgery) in the study eye within 12 weeks prior to the 
Screening Visit. 
18. Uncontrolled ocular hypertension or glaucoma in the study eye (defined as intraocular pressure 
[IOP] >25 mmHg or a cup to disc ratio ≥0.8, despite treatment with two or more classes of 
antiglaucoma medication) and any such condition which the Investigator feels may require a 
glaucoma filtering surgery while in the study. 
19. History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery in the 
study eye. 
20. History of corneal transplant in the study eye. 
21. Any prior intraocular corticosteroid injection in the study eye in the past 12 months. 
22. Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional 
retinal detachment visible at the screening assessments in the study eye. 
23. Prior participation in a clinical trial involving investigational anti-angiogenic drugs 
administered in either eye or systemically within 8 weeks prior to the Screening Visit. 
24. Prior participation in a clinical trial involving investigational ocular gene therapy for either 
eye. 
25. History of idiopathic or autoimmune-associated uveitis in either eye. 
26. Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye. 
27. Presence of any other systemic or ocular condition which, in the judgment of the Investigator, 
could make the subject inappropriate for entry into this study. 
28. Uncontrolled blood pressure (defined as systolic >180 mmHg and/or diastolic >100 mmHg), 
based on the average of three readings taken with the subject in a resting state. 
29. Myocardial infarction within 6 months prior to screening or New York Hospital Association 
(NYHA) Class III or IV heart failure, uncontrolled atrial fibrillation, uncontrolled angina, 
cardiomyopathy, ventricular arrhythmias, or other cardiac conditions which, in the judgment of 
the Investigator, could make the subject inappropriate for entry into this study. 
30. Serious non-healing wound, ulcer, or bone fracture. 
31. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the 
use of EYP-1901. 
32. Current treatment for any active systemic infection. 
33. Use of oral corticosteroids (prednisone >10 mg/day or equivalent) within 30 days prior to the 
Screening Visit. 


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 8 of 65 
 
 
 
34. History or presence of bleeding disorders, including platelet disorders, hemorrhage, acquired or 
hereditary coagulation disorders (including deep vein thrombosis and pulmonary embolisms), 
acquired or hereditary vascular disorders, stroke, or transient ischemic attack in the past 
2 years. 
35. Excluding certain skin cancers (specifically, basal cell carcinoma and squamous cell 
carcinoma), any malignancy receiving treatment, or in remission less than 5 years prior to 
study entry. 
36. History of allergy to fluorescein, not amenable to treatment. 
37. Inability to obtain fundus photographs, wide-field FA, fundus autofluorescence, or SD-OCT 
images of sufficient quality to be analyzed and graded by the CRC. 
38. Historical or active diagnosis of any medical or psychological condition that could interfere 
with the ability of the subject to give informed consent, or to comply with study or follow-up 
procedures. 
39. Previous participation in any ocular or non-ocular (systemic) disease studies of investigational 
drugs within 30 days prior to the Screening Visit (excluding vitamins and minerals). 
40. Use of anti-mitotic or anti-metabolite therapy within 30 days or 5 elimination half-lives of the 
Screening Visit, whichever is longer. 
41. Intolerance, contraindication, or hypersensitivity to topical anesthetics, dyes, povidone iodine, 
mydriatic medications, or any of the ingredients of the EYP-1901 insert. 
42. Requirement for continuous use of any protocol-prohibited medications or treatments. 
43. Pregnant or nursing females; females of childbearing potential who are unwilling to use an 
acceptable method of contraception during the study as outlined in this protocol. 
Treatment Assignment:  Subjects will receive the EYP-1901 intravitreal insert (the test article) in the 
designated study eye.  
Control:  Sham IVT injection 
Duration of Treatment:  Duration of release of the EYP-1901 active ingredient (vorolanib) is 
expected to be at least 9 months. 
Test Article Therapy:  Each EYP-1901 intravitreal insert is 8 mm long and is designed to deliver 
vorolanib into the vitreous humor at two different doses for at least 9 months.  Single or multiple 
inserts will be administered to the study eye at Day 1 by injection through the pars plana using a pre-
loaded applicator with a 22-gauge needle.  Two of the following doses will be selected based upon 
ongoing Phase 1 studies: 
• 
2060 µg dose, 2 inserts, 22-gauge needle 
• 
3090 µg dose; 3 inserts, 22-gauge needle 
Designation of Study Eye:  For subjects with unilateral NPDR, the affected eye will be designated as 
the study eye; for subjects with bilateral NPDR, the study eye will be the more severely affected eye 
meeting the inclusion/exclusion criteria, ie, the eye having the worse DRSS or if equal, the eye 
clinically judged to be the more severely affected eye as determined by the Investigator.  If the eyes are 
symmetrically affected, the study eye will be the right eye.  The fellow eye will receive treatment as 
needed and according to the Investigator’s judgment. 
Study Procedures:  Assessments will include the ETDRS-DRSS score on 4-widefield digital 
stereoscopic fundus photography, BCVA by ETDRS, anterior/posterior segment ocular examination, 
intraocular pressure (IOP), wide-field FA, color fundus photography (CFP), ocular and non-ocular 


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 9 of 65 
 
 
 
treatment-emergent adverse events (TEAEs), clinical laboratory evaluations (HbA1c, hematology, 
serum chemistry, coagulation, and urinalysis), bioanalytical testing for plasma levels of vorolanib and 
X-297, its main metabolite, heart rate and blood pressure measurements, SD-OCT, and, at study sites 
where equipment is available, OCT-angiography (OCT-A).  Photographs will be sent to the CRC for 
analysis. 
Follow-up Visits:  Following injection on Study Day 1, subjects will return at Weeks 4, 12, 24, 36, and 
48 (see details in attached Schedule of Study Procedures and Assessments). 
Masking:  Except for the Investigators administering the study treatments, masking will be maintained 
for both subjects and the Investigators conducting the study assessments.  Sham IVT injections will be 
used during the study to maintain masking of investigational EYP-1901 therapy for study subjects. 
Only the Sponsor/CRO will be unmasked after the last subject completes the Week 36 visit to conduct 
endpoint analysis. 
Criteria for Evaluation in the Study Eye: 
Primary Endpoint:  
• 
Percentage of subjects improving ≥2 steps from baseline in the DRSS score at Week 36 in each 
dose level vs. sham. 
The DRSS may be used to describe overall retinopathy severity as well as the change in severity over 
time.  Severity ranges from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior 
fundus obscured, or center of macula detached).  Here, DRSS describes severity level 47 (moderately 
severe NPDR) and level 53 (severe NPDR) at Week 36 from baseline. 
Secondary Endpoints: 
• 
Percentage of subjects improving ≥2 steps from baseline in the DRSS score at Weeks 24 and 
48 in each dose level vs. sham. 
• 
Percentage of subjects improving ≥2-steps or ≥3-steps over time in DRSS from baseline. 
• 
Percentage of subjects worsening ≥2-steps or ≥3-steps over time in DRSS from baseline. 
• 
Percentage of subjects who developed a vision-threatening complication due to diabetic 
retinopathy at Weeks 24, 36, and 48. 
• 
Percentage of subjects who developed CI-DME at Weeks 24, 36, and 48. 
• 
Time to develop any neovascular vision threatening complication (PDR/ASNV) through 
Weeks 24, 36, and 48. 
• 
Time to develop CI-DME through Weeks 24, 36, and 48. 
• 
Percentage of subjects who received anti-VEGF or additional standard of care intervention due 
to ocular diabetic complications at Weeks 24, 36 and 48. 
• 
Percentage of subjects who received PRP, inclusive of subjects undergoing vitrectomy with 
endolaser, at Weeks 24, 36, and 48. 
• 
Area Under the Curve (AUC) for change from baseline in BCVA at Weeks 24, 36, and 48. 
• 
Systemic exposures to vorolanib and X-297, its main metabolite, measured through plasma 
levels up to Weeks 24, 36, and 48. 
• 
Rates of ocular (study eye and fellow eye) and non-ocular TEAEs at Weeks 24, 36, and 48. 


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 10 of 65 
 
 
 
Statistical Methods: 
Sample Size: 
The objectives of the study are to provide efficacy and safety data in a prospective, randomized, 
double-masked, controlled trial.  However, the study is not formally powered to perform statistical 
hypothesis testing between each EYP-1901 arm versus sham IVT injection.  Approximately 60 subjects 
will be randomized at 1:1:1 ratio to each of three treatment arms (20 per treatment arm). 
Efficacy and Safety Analyses: 
Descriptive statistics by treatment arm will be provided for all TEAEs, DRSS scores, BCVA and 
imaging endpoints, and plasma pharmacokinetic data.  Frequency counts and percentage of subjects 
will be provided by MedDRA system organ class (SOC) and preferred term (PT) by dose cohort.  
Concomitant medications will be presented after coding with WHO-Drug Dictionary terms.  Clinical 
laboratory assessments will be presented using descriptive statistics by treatment arm. 
 
 
 
 
 
 


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 11 of 65 
 
 
 
Table of Contents 
PROTOCOL APPROVAL PAGE ................................................................................................................. 2 
INVESTIGATOR’S AGREEMENT .............................................................................................................. 3 
PERSONNEL CONTACT INFORMATION ................................................................................................ 4 
SYNOPSIS ...................................................................................................................................................... 5 
TABLE OF CONTENTS ............................................................................................................................. 11 
LIST OF TABLES........................................................................................................................................ 13 
LIST OF ABBREVIATIONS ....................................................................................................................... 14 
1 
INTRODUCTION ............................................................................................................................. 16 
1.1 
BACKGROUND ........................................................................................................................... 16 
1.2 
OVERVIEW OF NPDR ................................................................................................................. 16 
1.3 
STUDY RATIONALE .................................................................................................................... 17 
1.4 
NONCLINICAL EXPERIENCE WITH EYP-1901 .............................................................................. 17 
1.5 
CLINICAL EXPERIENCE WITH EYP-1901 ..................................................................................... 17 
2 
STUDY OBJECTIVES ...................................................................................................................... 17 
3 
INVESTIGATIONAL PLAN ............................................................................................................ 18 
3.1 
OVERALL STUDY DESIGN .......................................................................................................... 18 
3.1.1 
General Study Methods ............................................................................................. 18 
3.2 
MASKING AND RANDOMIZATION ................................................................................................ 19 
3.2.1 
Emergency Unmasking ............................................................................................. 19 
3.3 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS ........................... 19 
3.4 
DURATION OF STUDY................................................................................................................. 19 
3.5 
RECORDING OF INJECTION PROCEDURE ...................................................................................... 20 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ..................................................................... 20 
4.1 
INCLUSION CRITERIA ................................................................................................................. 20 
4.2 
EXCLUSION CRITERIA ................................................................................................................ 21 
4.3 
PREGNANCY AND CONTRACEPTION ............................................................................................ 23 
4.4 
STUDY TERMINATION CRITERIA ................................................................................................. 24 
5 
STUDY PROCEDURES .................................................................................................................... 25 
5.1 
MEASUREMENTS AND EVALUATIONS BY VISIT ........................................................................... 26 
5.1.1 
Day -30 to Day -5 (Screening Visit) .......................................................................... 29 
5.1.2 
Day 1 (Study Treatment) ........................................................................................... 29 
5.1.3 
Week 4 (±7 days) ...................................................................................................... 30 
5.1.4 
Week 12 (±7 days) .................................................................................................... 31 
5.1.5 
Week 24 (±7 days) .................................................................................................... 31 
5.1.6 
Week 36 (±7 days) .................................................................................................... 32 
5.1.7 
Week 48 (±7 days, End of Study) and Early Termination Visit .................................. 32 
5.2 
APPROPRIATENESS OF MEASUREMENTS ...................................................................................... 33 
6 
STUDY INTERVENTIONS .............................................................................................................. 33 
6.1 
STUDY INTERVENTION IDENTIFICATION AND DESCRIPTION ......................................................... 33 
6.1.1 
EYP-1901 Composition ............................................................................................ 33 
6.1.2 
EYP-1901/Sham Applicator Packaging ..................................................................... 34 
6.2 
STUDY DRUG ADMINISTRATION ................................................................................................. 34 
6.2.1 
EYP-1901 Intravitreal Insert ..................................................................................... 34 
6.2.2 
EYP-1901 Injection Procedure .................................................................................. 34 
6.3 
STORAGE AND DISPENSING OF STUDY DRUGS ............................................................................. 34 
6.4 
DRUG ACCOUNTABILITY ............................................................................................................ 34 


EYP-1901 (Vorolanib Intravitreal Insert) 
EyePoint Pharmaceuticals, Inc. 
Protocol EYP-1901-204 (Version 3.0) 
 
31 March 2023 
CONFIDENTIAL 
Page 12 of 65 
 
 
 
6.5 
ANAPHYLAXIS, OVERDOSE, AND DOSE MODIFICATION ............................................................... 35 
6.6 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................................. 36 
6.6.1 
Prior Medications ..................................................................................................... 36 
6.6.2 
Concomitant Medications ......................................................................................... 36 
6.6.3 
Prohibited Concomitant Medications ......................................................................... 36 
6.6.4 
Permitted Medication and Procedures........................................................................ 36 
7 
ASSESSMENT OF SAFETY ............................................................................................................ 37 
7.1 
ADVERSE EVENTS ..................................................................................................................... 37 
7.1.1 
Ocular Adverse Events.............................................................................................. 38 
7.1.2 
Serious Adverse Events ............................................................................................ 38 
7.1.3 
Sight-Threatening Ocular Events Defined as SAEs in This Study .............................. 40 
7.1.4 
Clinical Laboratory Adverse Events .......................................................................... 40 
7.1.5 
Adverse Event Severity and Relationship .................................................................. 41 
7.1.6 
Recording of Adverse Events .................................................................................... 42 
7.1.7 
Adverse Event Reporting .......................................................................................... 42 
7.1.7.1 
Reporting of Serious Adverse Events ........................................................ 42 
7.2 
CLINICAL LABORATORY EVALUATIONS ...................................................................................... 44 
7.3 
VITAL SIGNS ............................................................................................................................. 45 
7.4 
ELECTROCARDIOGRAMS ............................................................................................................ 45 
7.5 
CONCOMITANT MEDICATION USE .............................................................................................. 45 
8 
REPORTING OF TECHNICAL PRODUCT COMPLAINTS ........................................................ 45 
9 
PHARMACOKINETICS .................................................................................................................. 46 
10 
ASSESSMENT OF EFFICACY ........................................................................................................ 46 
11 
STATISTICAL METHODS AND DATA ANALYSIS ..................................................................... 47 
11.1 
DETERMINATION OF SAMPLE SIZE .............................................................................................. 47 
11.2 
ANALYSIS POPULATION ............................................................................................................. 47 
11.3 
GENERAL STATISTICAL CONSIDERATIONS .................................................................................. 48 
11.3.1 
Data Summarization ................................................................................................. 48 
11.3.2 
Definition of Baseline ............................................................................................... 48 
11.3.3 
Handling of Missing Data ......................................................................................... 48 
11.3.4 
Multicenter Considerations ....................................................................................... 48 
11.3.5 
Adjustment for Covariates ........................................................................................ 48 
11.3.6 
Interim Analyses ....................................................................................................... 48 
11.3.7 
Multiple Comparisons and Multiplicity ..................................................................... 48 
11.3.8 
Examination of Subgroups ........................................................................................ 48 
11.3.9 
Statistical Software ................................................................................................... 48 
11.4 
ANALYSES ................................................................................................................................ 49 
11.4.1 
Subject Disposition ................................................................................................... 49 
11.4.2 
Demographic and Baseline Characteristics ................................................................ 49 
11.4.3 
Medical History ........................................................................................................ 49 
11.4.4 
Efficacy Analysis ...................................................................................................... 49 
11.4.5 
Pharmacokinetic Analysis ......................................................................................... 49 
11.4.6 
Use of Prohibited Medications .................................................................................. 49 
11.4.7 
Adverse Events ......................................................................................................... 49 
11.4.8 
Clinical Laboratory Evaluations ................................................................................ 50 
11.4.9 
Vital Signs ................................................................................................................ 50 
11.4.10 
Prior and Concomitant Medications .......................................................................... 50 
12 
ADMINISTRATIVE AND REGULATORY CONSIDERATIONS ................................................. 50 
12.1 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................................................... 50 
12.2 
INSTITUTIONAL REVIEW BOARDS/INDEPENDENT ETHICS COMMITTEE ......................................... 51 
12.3 
INFORMED CONSENT PROCESS ................................................................................................... 51 
12.4 
SOURCE DOCUMENTATION......................................................................................................... 51 
12.5 
ELECTRONIC CASE REPORT FORMS ............................................................................................ 52 


EYP-1901 (Vorolanib Intravitreal Insert) 
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Protocol EYP-1901-204 (Version 3.0) 
 
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12.6 
RETENTION OF STUDY RECORDS ................................................................................................ 53 
12.7 
MONITORING THE STUDY AND DATA QUALITY ASSURANCE........................................................ 53 
12.8 
DISCONTINUATION OF THE STUDY .............................................................................................. 54 
12.9 
POLICY FOR PUBLICATIONS ........................................................................................................ 54 
13 
ETHICS ............................................................................................................................................. 54 
13.1 
ETHICS REVIEW ......................................................................................................................... 54 
13.2 
ETHICAL CONDUCT OF THE STUDY ............................................................................................. 54 
13.3 
WRITTEN INFORMED CONSENT .................................................................................................. 54 
14 
REFERENCES .................................................................................................................................. 56 
APPENDIX 1: 
MEASUREMENT OF BCVA BY ETDRS ..................................................................... 57 
APPENDIX 2: 
SLIT LAMP BIOMICROSCOPY, OPHTHALMOSCOPY, AND INTRAOCULAR 
PRESSURE ........................................................................................................................................ 58 
APPENDIX 3: 
PHARMACOKINETIC PROCEDURES AND ANALYSIS ......................................... 61 
APPENDIX 4: 
NCI CTCAE V5.0 ........................................................................................................... 62 
APPENDIX 5: 
SUMMARY OF CHANGES ........................................................................................... 63 
 
 
 
List of Tables 
Table 1–1: 
Abbreviations and Specialist Terms ........................................................................... 14 
Table 5–1: 
Schedule of Study Procedures and Assessments, Study EYP-1901-204 ....................... 27 
Table 6–1: 
Characteristics of the Two Intravitreal Doses of EYP-1901, Study EYP-1901-204 ...... 34 
 
 
 


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List of Abbreviations 
Table 1–1: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
ASNV 
Anterior segment neovascularization 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
BCVA 
Best corrected visual acuity 
CFP 
Color fundus photography 
CFR 
(US) Code of Federal Regulations 
CI-DME 
Center involved-diabetic macular edema 
CPR 
Cardiopulmonary resuscitation 
CRA 
Clinical Research Associate 
CRC 
Central reading center 
CRO 
Contract Research Organization 
CST 
Central subfield thickness 
CTCAE 
(National Cancer Institute’s) Common Toxicity Criteria for Adverse Events 
DME 
Diabetic macular edema 
DRSS 
Diabetic Retinopathy Severity Scale 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice (guidelines) 
HbA1c 
Hemoglobin A1c (reported in %) 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFU 
Instructions for Use 
IND 
Investigational New Drug application 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVT 
Intravitreal 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
NPDR 
Nonproliferative Diabetic Retinopathy 
NVA 
Neovascularization of the angle 
NVD 
Neovascularization of the disc 
NVE 
Neovascularization everywhere 
NVI 
Neovascularization of the iris 
NYHA 
New York Hospital Association 
OCT-A 
Optical coherence tomography - angiography 


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Abbreviation or Specialist Term 
Explanation 
OTC 
Over-the-counter 
PDGF 
Platelet-derived growth factor 
PK 
Pharmacokinetic 
PRP 
Pan-retinal photocoagulation 
PT 
Preferred term 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD-OCT 
Spectral-domain – optical coherence tomography 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected, unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitor 
US/USA 
United States of America 
VEGF 
Vascular endothelial growth factor 
wAMD 
Wet age-related macular degeneration 
WHO 
World Health Organization 
 
 
 


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1 INTRODUCTION 
1.1 Background 
Vorolanib is a multi-kinase inhibitor of both vascular endothelial growth factor (VEGF) and 
platelet-derived growth factor (PDGF), which is a potent inhibitor of angiogenesis.  This drug 
was originally developed as an oral pharmaceutical formulation to treat patients with pathologic 
angiogenesis found in certain solid tumors, in von Hippel-Lindau disease, and in exudative age-
related macular degeneration (AMD).  As a small molecule, vorolanib has more recently been 
developed as an intravitreal formulation utilizing the Durasert® platform, a proprietary sustained 
delivery technology used in FDA-approved intraocular products indicated for the treatment of 
posterior segment uveitis, such as Retisert® (Bausch & Lomb, Inc., USA) and Yutiq® (EyePoint 
Pharmaceuticals, Inc., USA), and for the treatment of diabetic macular edema (DME), such as 
Iluvien® (Alimera Sciences, USA).  EYP-1901 Intravitreal Insert is a bioerodible, sterile, 
sustained-release drug delivery system formulated in Durasert® and designed to release 
microgram levels of vorolanib daily into the ocular vitreous chamber for the treatment of wet 
age-related macular degeneration (wAMD) and nonproliferative diabetic retinopathy (NPDR). 
1.2 Overview of NPDR 
Diabetic retinopathy is the leading cause of new blindness in the US, with a prevalence rate in 
adults with diabetes of approximately 28.5% (https://emedicine.medscape.com/article/1225122-
overview).  The global impact of DR-related vision complications is expected to rise given the 
increasing rates of diabetes across the US and other developed countries.  As ocular 
manifestations often precede other systemic complications of diabetes mellitus, eye care 
specialists play a critical role in the prevention, diagnosis, and management of diabetic eye 
disease. 
There are several stages of DR, ranging from mild nonproliferative disease to severe proliferative 
disease.  While the most common early clinically manifestations of NPDR include formation of 
microaneurysms and intraretinal hemorrhages, these patients do not present with any symptoms.  
Progressing in stage, further damage can be observed such as intraretinal microvascular 
abnormalities, cotton wool spots, increased numbers of hemorrhages, and venous caliber 
abnormalities.  At any stage in the course of the disease, increased vasopermeability results in 
retinal thickening (edema) and/or exudates that may lead to a loss in central vision.  The 
proliferative diabetic retinopathy (PDR) stage results from closure of arterioles and venules with 
secondary proliferation of new vessels on the retina, optic disc, or anterior segment.  Common 
complications of DR that puts the patient’s vision at risk and requires either urgent medical or 
surgical intervention include center involved-diabetic macular edema (CI-DME), tractional 
retinal detachments, epiretinal membranes, and vitreous hemorrhage.  The risk of these 
complications usually increases as the severity of DR increases, although DME can be present at 
any stage of DR (Aiello et al. 1994).  The link between diabetic ischemia and subsequent 
proliferation of angiogenic factors including VEGF has been established. 
Preventing the conversion to PDR and the associated vision threatening complications has the 
potential to improve the quality of a patient lives for decades.  The ability to minimize sight-
threatening diabetic complications in the working-age population could have significant impact 
on public health. 


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While both ranibizumab (LUCENTIS®) and aflibercept (EYLEA®) have demonstrated that 
intravitreal (IVT) anti-VEGF therapy can effectively regress the severity of DR, the use of these 
agents in clinical practice remains limited due to the need for regular treatment and visits to 
achieve the desired outcomes (LUCENTIS® and EYLEA® prescribing information).  EYP-1901 
could potentially provide long-term treatment to patients. 
For this Phase 2 clinical study, participants with moderately severe to severe NPDR without 
CI-DME at baseline will be enrolled.  This represents a population that is often observed without 
treatment in clinical practice until signs of high-risk proliferative disease are present.  These 
patients are at significant risk of progressing to more serious vision threatening stages of DR.  
Therefore, this population of patients has the potential to benefit from EYP-1901 long lasting 
treatment. 
1.3 Study Rationale 
Despite the introduction of a number of improved anti-VEGF biologic agents in recent years, 
there remains a need for new therapies that will provide equivalent efficacy and anatomic disease 
control while reducing the need for frequent injections to prevent the progression to more serious 
vision threatening stages of DR.  EyePoint Pharmaceuticals, the Sponsor of this study, has 
developed EYP-1901 Intravitreal Insert, a sustained and controlled delivery formulation of 
vorolanib over a period of at least 9 months as a therapy to address this unmet medical need. 
1.4 Nonclinical Experience with EYP-1901 
X-82, an oral vorolanib formulation, and EYP-1901(Vorolanib Intravitreal Insert) were both 
investigated in nonclinical efficacy models and in nonclinical safety and pharmacokinetic 
studies.  For a summary of the nonclinical experience with these drug formulations please refer 
to the current EYP-1901 Investigator’s Brochure (IB). 
1.5 Clinical Experience with EYP-1901 
This is the third clinical investigational study of EYP-1901 (vorolanib intravitreal insert); a 
previous Phase 1 dose-escalation study (ie, the DAVIO trial) in patients with wAMD was 
initiated in Jan 2021 and a Phase 2 trial in patients with wAMD will be initiated in mid-2022.  
Interim safety and efficacy analyses conducted upon completion of Week 24 in the DAVIO study 
provided support for initiation of the present Phase 2 study. 
For X-82 (oral vorolanib), two previous studies were conducted in wAMD (Jackson et al. 2017; 
Cohen et al. 2021).  For additional details on the clinical experience from previous EYP-1901 
and X-82 studies please refer to the current EYP-1901 IB. 
2 STUDY OBJECTIVES 
The primary objective is to assess the efficacy of EYP-1901 compared to sham treatment in the 
improvement of moderately severe to severe NPDR. 
The secondary objectives are: 
• To characterize the safety of EYP-1901 in subjects with moderately severe to severe 
NPDR. 


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• To determine if EYP-1901 will prevent the worsening of diabetic retinopathy and reduce 
the incidence of DME. 
• To evaluate the need for additional standard of care intervention due to ocular diabetic 
complications. 
• To determine the anatomic effects of EYP-1901 in subjects with moderately severe to 
severe NPDR. 
• To determine the systemic exposure to vorolanib and X-297, its main metabolite, 
measured through plasma levels up to Week 48. 
3 INVESTIGATIONAL PLAN 
3.1 Overall Study Design 
This is a prospective, randomized, double-masked, multicenter study evaluating the ocular 
efficacy and safety of two doses of the EYP-1901 intravitreal insert compared to sham in adult 
subjects with NPDR.  Up to 60 subjects will be randomized on a 1:1:1 basis to three different 
treatment arms (2060 µg EYP-1901, 3090 µg EYP-1901, or sham IVT injection) across 
approximately 30 sites in the US, such that each treatment arm will include up to 20 subjects.  
All subjects, irrespective of treatment arm, will receive an IVT injection on Day 1 in the 
designated study eye. 
Following injection on Day 1, subjects will return at Weeks 4, 12, 24, and 48 following study 
drug administration.  The Schedule of Assessments is presented in Table 5–1. 
3.1.1 
General Study Methods 
For subjects with unilateral NPDR, the affected eye will be designated as the study eye; for 
subjects with bilateral NPDR, the study eye will be the more severely affected eye meeting the 
inclusion/exclusion criteria, ie, the eye having the worse Diabetic Retinopathy Severity Scale 
(DRSS) score or if equal, the eye clinically judged to be the more severely affected eye as 
determined by the Investigator.  If the eyes are symmetrically affected, the study eye will be the 
right eye.  The fellow eye will receive treatment as needed and according to the Investigator’s 
judgment. 
Subjects ≥18 years of age with type 1 or 2 diabetes mellitus (documented hemoglobin A1c 
[HbA1c] ≤12%) and an active diagnosis of moderately severe to severe NPDR (based on DRSS 
levels 47 or 53) in whom pan-retinal photocoagulation (PRP) and anti-VEGF injections can be 
safely deferred for at least 6 months as per the Investigator, and who satisfy all other protocol 
eligibility criteria up until dosing on Day 1, will be enrolled and receive the assigned study 
treatment. 
Study procedures will include:  ETDRS-DRSS score on 4-widefield digital stereoscopic fundus 
photography, best corrected visual acuity (BCVA) by ETDRS, anterior/posterior segment ocular 
examination, intraocular pressure (IOP), wide-field fluorescein angiography (FA), color fundus 
photography (CFP), ocular and non-ocular treatment-emergent adverse events (TEAEs), clinical 
laboratory evaluations (HbA1c, hematology, serum chemistry, coagulation, and urinalysis), 
bioanalytical testing for plasma  levels of vorolanib and X-297, its main metabolite, heart rate 
and blood pressure measurements, spectral-domain – optical coherence tomography (SD-OCT), 


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and, at study sites where equipment is available, OCT-angiography (OCT-A).  Photographs will 
be sent to the central reading center (CRC) for analysis. 
3.2 Masking and Randomization 
Except for the Investigators administering the study treatments, masking will be maintained for 
both subjects and the Investigators conducting the study assessments.  Sham injections will be 
used during the study to maintain masking of investigational EYP-1901 therapy for study 
subjects. Only the Sponsor/CRO will be unmasked after the last subject completes the Week 36 
visit to conduct endpoint analysis. 
The randomization code will be generated with a computer program according to the study 
design, the number of subjects, and the number of treatments.  The random allocation of each 
treatment to each subject will be done in such a way that the study is balanced.  Randomization 
will occur on Day 1. 
3.2.1 
Emergency Unmasking 
Unmasking a subject’s treatment to the assessing Investigator should only be done in emergency 
situations for reasons of subject safety. 
At the initiation of the study, the clinical sites will receive instructions for unmasking a subject. 
In the event that an emergency unmasking is required, the assessing Investigator/medically 
qualified designee has the authority to unmask a subject’s treatment using IXRS, or its back-up 
system if IXRS is not functioning.  If possible, the assessing Investigator/medically qualified 
designee should contact the Medical Monitor or designee before breaking the mask. 
When the masked treatment code is broken, the date and time of unmasking, name of person 
doing the unmasking, and the reason for unmasking must be fully documented in the source 
documentation. 
3.3 Discussion of Study Design, Including the Choice of Control Groups 
The prospective, randomized, double-masked study with a sham IVT injection control group is 
an acceptable design for the evaluation of comparative efficacy and safety of two doses of 
EYP-1901. 
The two doses (2060 µg and 3090 µg) chosen for EYP-1901 were based on the safety profile 
through Week 36 in the ongoing Phase 1 DAVIO study (see details in Section 1.5). 
3.4 Duration of Study 
Total study participation will be approximately 52 weeks (including the Screening period).  After 
the initial Screening Visit, subjects may have between 5 and 30 days to be enrolled, at which 
point the study treatments/control will be administered on Day 1, if the eligibility criteria are still 
met.  Subjects who require a longer period between initial screening and Day 1 will be 
re-screened prior to entry into the study.  After Day 1 study treatment dosing, the follow-up 
period will be through 48 weeks (with visit windows of ±7 days starting at Week 4).  Eligible 
subjects who are enrolled in this study will be seen for the scheduled study visits over 
approximately 12 months depending on the time between Day 1 and the final study visit.  Screen 


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failures will be recorded along with the reason(s) for not meeting the eligibility criteria.  Study 
completion is achieved at the Week 48 visit (End of Study Visit). 
3.5 Recording of Injection Procedure 
The injection procedure of EYP-1901 or sham may be photographed or video-recorded 
according to the site’s standard procedures.  Images and/or video will be provided to the Sponsor 
who may distribute them to other participating sites or other appropriate parties.  Subject 
identifying information must be redacted from all images and video prior to distribution. 
4 SELECTION AND WITHDRAWAL OF SUBJECTS 
Three treatment groups of up to 20 subjects each will be enrolled to assess the efficacy and safety 
of 2060 µg or 3090 µg EYP-1901 intravitreal insert compared to sham IVT injection. 
Subjects will be enrolled in the study only if they meet all the following eligibility criteria; 
continued eligibility will be assessed again at treatment randomization on Day 1. The 
Investigator will exercise medical and scientific judgement in deciding whether a laboratory 
finding, or other assessment should be reassessed within the Screening Period. Subjects that do 
not meet all the requirements as outlined in the eligibility criteria (screen failures), may be 
rescreened at the discretion of the Investigator.  
4.1 Inclusion Criteria 
Subjects will be considered eligible for participation in the study if all of the following inclusion 
criteria are satisfied: 
1. Men or women ≥18 years of age with type 1 or 2 diabetes mellitus.  Participants must 
have a HbA1c ≤12% (as confirmed by laboratory assessments obtained at the Screening 
Visit or by a documented laboratory report dated within 60 days prior to the Screening 
Visit). 
2. Study eye with moderately severe to severe NPDR (based on the DRSS levels 47 or 53), 
using standard 4-widefield digital stereoscopic fundus photographs confirmed by the 
CRC, in whom PRP and anti-VEGF injections can be safely deferred for at least 
6 months per the Investigator. 
3. Best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study 
(ETDRS) letter score in the study eye of ≥69 letters (approximate Snellen equivalent of 
20/40 or better). 
4. Able to understand, and willingness to sign, the informed consent and to provide access 
to personal health information via Health Insurance Portability and Accountability Act 
(HIPAA) authorization. 
5. Willingness and ability to comply with all scheduled visits, restrictions, and assessments. 
6. For women of childbearing potential, or men with female partners of childbearing 
potential, agreement to the use of an appropriate form of contraception for the duration of 
the study. 


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4.2 Exclusion Criteria 
1. Presence of any active CI-DME in the study eye as determined by the Investigator on 
clinical examination, or within the central subfield thickness (CST) of the study eye as 
determined by SD-OCT evaluated by the CRC, with a CST threshold greater than 
320 microns. 
2. Evidence of retinal neovascularization on clinical examination or wide-field FA. 
3. Any evidence or documented history of prior focal or grid laser photocoagulation or any 
PRP in the study eye in the last 12 months. 
4. Any evidence of optic nerve pallor on clinical examination in the study eye as determined 
by the Investigator. 
5. Any evidence of high-risk characteristics typically associated with vision loss in the study 
eye as determined by the Investigator. 
6. Any evidence of new vascularization anywhere (neovascularization of the iris [NVI], 
neovascularization of the angle [NVA], neovascularization everywhere [NVE], 
neovascularization of the disc [NVD]) on clinical examination as per the Investigator, or 
imaging evaluated by the CRC, in the study eye. 
7. Any prior systemic anti-VEGF treatment in the past 12 months. 
8. Any prior IVT anti-VEGF treatment in the past 12 months. 
9. Any documentation of more than 4 prior anti-VEGF IVT injections in the study eye. 
10. Any concurrent intraocular condition in the study eye (eg, cataract or glaucoma) that, in 
the opinion of the Investigator, would either require surgical intervention during the study 
to prevent or treat visual loss that might result from that condition or affect interpretation 
of the study results. 
11. History of prior vitrectomy surgery in study eye. 
12. Historical or active intraocular inflammation (grade trace or above) in the study eye, 
other than expected findings from routine cataract surgery. 
13. History of vitreous hemorrhage in the study eye within 12 weeks prior to the Screening 
Visit. 
14. History of rhegmatogenous retinal detachment or treatment for retinal detachment or 
macular hole (stage 3 or 4) in the study eye. 
15. Aphakia or pseudophakia with the absence of the posterior capsule in the study eye (YAG 
capsulotomy is permitted). 
16. Spherical equivalent of the refractive error in the study eye demonstrating >8 diopters of 
myopia. For subjects who have undergone prior refractive or cataract surgery in the study 
eye, preoperative refractive error in the study eye exceeding 8 diopters of myopia. 
17. Intraocular surgery (including cataract surgery) in the study eye within 12 weeks prior to 
the Screening Visit. 


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18. Uncontrolled ocular hypertension or glaucoma in the study eye (defined as IOP 
>25 mmHg or a cup to disc ratio ≥0.8, despite treatment with two or more classes of 
antiglaucoma medication) and any such condition which the Investigator feels may 
require a glaucoma filtering surgery while in the study. 
19. History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery in 
the study eye. 
20. History of corneal transplant in the study eye. 
21. Any prior intraocular corticosteroid injection in the study eye in the past 12 months. 
22. Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional 
retinal detachment visible at the screening assessments in the study eye. 
23. Prior participation in a clinical trial involving investigational anti-angiogenic drugs 
administered in either eye or systemically within 8 weeks prior to the Screening Visit. 
24. Prior participation in a clinical trial involving investigational ocular gene therapy for 
either eye. 
25. History of idiopathic or autoimmune-associated uveitis in either eye. 
26. Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye. 
27. Presence of any other systemic or ocular condition which, in the judgment of the 
Investigator, could make the subject inappropriate for entry into this study. 
28. Uncontrolled blood pressure (defined as systolic >180 mmHg and/or diastolic 
>100 mmHg), based on the average of three readings taken with the subject in a resting 
state. 
29. Myocardial infarction within 6 months prior to screening or New York Hospital 
Association (NYHA) Class III or IV heart failure, uncontrolled atrial fibrillation, 
uncontrolled angina, cardiomyopathy, ventricular arrhythmias, or other cardiac conditions 
which, in the judgment of the Investigator, could make the subject inappropriate for entry 
into this study. 
30. Serious non-healing wound, ulcer, or bone fracture. 
31. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of EYP-1901. 
32. Current treatment for any active systemic infection. 
33. Use of oral corticosteroids (prednisone >10 mg/day or equivalent) within 30 days prior to 
the Screening Visit. 
34. History or presence of bleeding disorders, including platelet disorders, hemorrhage, 
acquired or hereditary coagulation disorders (including deep vein thrombosis and 
pulmonary embolisms), acquired or hereditary vascular disorders, stroke, or transient 
ischemic attack in the past 2 years. 


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35. Excluding certain skin cancers (specifically, basal cell carcinoma and squamous cell 
carcinoma), any malignancy receiving treatment, or in remission less than 5 years prior to 
study entry. 
36. History of allergy to fluorescein, not amenable to treatment. 
37. Inability to obtain fundus photographs, wide-field FA, fundus autofluorescence, or 
SD-OCT images of sufficient quality to be analyzed and graded by the CRC. 
38. Historical or active diagnosis of any medical or psychological condition that could 
interfere with the ability of the subject to give informed consent, or to comply with study 
or follow-up procedures. 
39. Previous participation in any ocular or non-ocular (systemic) disease studies of 
investigational drugs within 30 days prior to the Screening Visit (excluding vitamins and 
minerals). 
40. Use of anti-mitotic or anti-metabolite therapy within 30 days or 5 elimination half-lives 
of the Screening Visit, whichever is longer. 
41. Intolerance, contraindication, or hypersensitivity to topical anesthetics, dyes, povidone 
iodine, mydriatic medications, or any of the ingredients of the EYP-1901 insert. 
42. Requirement for continuous use of any protocol-prohibited medications or treatments. 
43. Pregnant or nursing females; females of childbearing potential who are unwilling to use 
an acceptable method of contraception during the study as outlined in this protocol. 
4.3 Pregnancy and Contraception 
Women of childbearing potential must be practicing and willing to continue using a highly 
effective method of birth control during the course of the study, such as:  oral contraceptive pill 
(eg, Ortho Tri-Cyclen®); injection (eg, Depo Provera®); implant (eg, Norplant®); patch 
(eg, Ortho Evra Patch®); vaginal ring (eg, NuvaRing®); intrauterine coil (eg, Mirena® coil); 
intrauterine device (IUD) with or without hormones; a barrier method (eg, latex condom, 
diaphragm, or cap) used with an additional form of contraception (ie, two methods [eg, 
sponge, spermicide, hormonal contraceptive pill, or injection]); or complete abstinence.  A 
female is considered to be of childbearing potential UNLESS she is post-menopausal (no menses 
for two consecutive years) or without a uterus and/or both ovaries. 
Before enrolling a woman of childbearing potential, Investigators must review with the subject 
the following: 
• Pregnancy prevention information 
• Risks to unborn child(ren) 
• Risks if currently nursing 
• Any drug interactions with hormonal contraceptives 
• Contraceptives in current use (or if complete abstinence is being followed) 
• Guidelines for the follow-up of a reported pregnancy 


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For subjects who become pregnant during the study positive urine pregnancy results will be 
confirmed by a serum pregnancy test.  Based on the anti-VEGF mechanism of action of 
EYP-1901, the study treatments may pose a risk to human embryofetal development.  Subjects 
should continue participation in the study at the discretion of the Investigator and only if the 
potential benefit justifies the potential risk to the fetus.  Subjects should be instructed to notify 
the Investigator if it is determined after completion of the study that they became pregnant while 
participating in the study.  However, it is the Investigator’s responsibility to pursue the follow-
up.  Whenever possible, a pregnancy should be followed to term, any premature terminations of 
pregnancy should be reported, and the status of the mother and the child should be reported to 
the Medical Monitor after delivery. 
Subjects who are not of childbearing potential meeting one or both of the following criteria will 
not be required to be tested for pregnancy or use contraception: 
• Amenorrheic for >2 years without a hysterectomy and bilateral oophorectomy and a FSH 
value in the postmenopausal range upon pre-trial (screening) evaluation. 
• Post-hysterectomy, bilateral oophorectomy, or tubal ligation.  Tubal ligation must be 
confirmed with medical records of the actual procedure. 
4.4 Study Termination Criteria 
Each subject will be informed that they are free to 
 
 Monitor, or the Medical Monitor 
may exercise his or her medical judgment to terminate a subject’s participation in the study if it 
is in the best interest of the subject. 
If a subject withdraws from the study during the follow-up period, the Investigator should make 
every effort to have the subject return to the clinic for the end of study safety evaluations. 
Medical Monitoring for this study will be conducted by: 
, MD 
 and 
 
EyePoint Pharmaceuticals, Inc. 
480 Pleasant Street, Suite B300 
Watertown, MA 02472 USA 
Cell:  
 
 
The Sponsor reserves the right to terminate the study at any time.  Every effort should be made to 
collect all data required by the protocol during or following the subject’s Early Termination Visit. 
In cases of early termination, every effort should be made to complete the case report forms and 
report the results as thoroughly as possible.  A termination electronic case report form (eCRF) 
page should be completed for every subject who received study treatment whether or not the 
subject completed the study.  The reason for any early termination from the study should be 
indicated on this form.  The primary reason for a subject’s early termination should be selected 
from the following standard categories: 
PPD
PPD
PPD
PPD
PPD


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Adverse Event (AE):  Clinical or laboratory events occurred that in the medical judgment of the 
Investigator for the best interest of the subject are grounds for discontinuation.  This includes 
serious AEs (SAEs) and non-serious AEs regardless of the relationship to study drugs. 
Subjects who are withdrawn due to AEs must be followed until there is either: 
• Resolution 
• Stabilization or severity to the National Cancer Institute’s Common Toxicity Criteria for 
Adverse Events (CTCAE) Grade 1/mild 
• Returned to baseline status 
• Subject is lost to follow-up 
• The event is otherwise explained by the Investigator 
Death:  The subject died during the study. 
Withdrawal of Consent:  The subject desired to withdraw from further participation in the study 
in the absence of a medical need to withdraw as determined by the Investigator.  If the subject 
gave a reason for this desire, this should be recorded. 
Major Protocol Violation:  There was failure to meet the protocol entry criteria or the subject 
failed to adhere to the protocol requirements or received prohibited medication (eg, subject 
failure to follow instructions, or inability to complete study assessments).  The violation 
necessitated premature termination from the study. 
Other:  The subject was terminated for a reason other than those listed above, such as termination 
of study by the Sponsor or a regulatory authority.  The Investigator must specify the reason. 
5 STUDY PROCEDURES 
To ensure the health of both eyes, observations of both the study eye and non-study (fellow) eye 
should be made at all visits as described in the Schedule of Study Procedures and Assessments 
(Table 5–1) unless otherwise indicated. 
BCVA by ETDRS:  The equipment and procedures necessary for testing BCVA are presented in 
Appendix 1.  Visual acuity is always tested with the subject’s best correction and should be 
measured prior to pupil dilation and slit lamp biomicroscopy examination or any drops or 
ointments are used.  BCVA by ETDRS will be measured at every study visit (Table 5–1).  Visual 
acuity testing in this study is required at a distance of 4 meters, and for subjects with reduced 
vision at 1 meter.  Each site should have at least one certified refractionist available for the use of 
ETDRS charts.  An ETDRS-certified refractionist should perform all protocol refraction and 
BCVA measurements required by the protocol. 
Slit lamp Biomicroscopy:  Anterior chamber evaluation will be conducted using a slit beam of 
1 mm height and 1 mm width with maximum luminance through the highest powered lens using 
the Investigator’s standard slit lamp equipment and procedure.  This procedure will be the same 
for all subjects observed at the Investigator’s site.  Ocular signs assessments, including vitreous 
haze, the presence of anterior chamber cells, and will be scored according to the scales and 
conventions presented in Appendix 2.  Ocular examinations will be done at the study visits noted 
in (Table 5–1). 


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Dilated Ophthalmoscopy:  Will be performed according to the Investigator’s preferred 
procedure.  This procedure will be the same for all subjects observed at the Investigator’s site 
(Appendix 2).  Ocular examinations will be done at the study visits noted in (Table 5–1). 
Intraocular Pressure/Tonometry:  IOP will be measured as described in Appendix 2 at the 
study visits noted in (Table 5–1). 
Wide-Field Fluorescein Angiography and Color Fundus Photography:  A study-certified 
photographer will take mydriatic stereoscopic color photographs and a fluorescein angiogram of 
both eyes according to the standardized procedures described in the Study Manual.  Photography 
must be performed after testing visual acuity if these procedures are performed on the same day.  
FA/CFP will be done at the study visits noted in (Table 5–1). 
ETDRS-DRSS:  The CFP images will be assessed by the CRC to determine the ETDRS-DRSS 
score on 4-widefield digital stereoscopic fundus photography for study eligibility (specifically 
Inclusion Criterion #2) and for the primary efficacy endpoint (ie, percentage of subjects 
improving ≥2 steps from baseline in the DRSS score at Week 36 in each dose level vs. sham).  
The DRSS may be used to describe overall retinopathy severity as well as the change in severity 
over time.  Severity ranges from level 10 (DR absent) to level 85 (advanced proliferative DR: 
posterior fundus obscured, or center of macula detached).  Here, DRSS describes severity level 
47 (moderately severe NPDR) and level 53 (severe NPDR) at Week 36 from baseline. 
SD-OCT and SD-OCTA Assessments:  Spectral-domain – optical coherence tomography 
assessments of both eyes will be taken by a study-certified OCT technician according to the 
standardized procedures described in the Study Manual.  Because the eye must be dilated for 
OCT, it must be performed after testing visual acuity if these procedures are performed on the 
same day.  SD-OCT and SD-OCTA (at pre-specified study sites where equipment is available) 
testing will be done at the study visits noted in (Table 5–1).  Please note that either SD-OCTA or 
swept-source – optical coherence tomography angiography (SS-OCTA) imaging could be 
collected in this study. 
Ocular and Non-ocular TEAEs:  Subjects will be queried regarding ocular and nonocular AEs, 
SAEs, and changes in their general health, concomitant medications or concurrent procedures. 
Both elicited and volunteered reports will be recorded.  
5.1 Measurements and Evaluations by Visit 
The schedule of study procedures and assessments by visit is presented in Table 5–1.  Starting at 
Week 4, study visits should be conducted within ±7 days for all scheduled visits. 
 
 
 


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Table 5–1: 
Schedule of Study Procedures and Assessments, Study EYP-1901-204 
 
Screening 
Study Treatment and Follow-Up 
Days 
-30 to -5 
Day 1 
Week 4 
Week 12 
Week 24 
Week 36 
Week 48 
ETa 
Time Window (in days) 
 
 
±7 
±7 
±7 
±7 
±7 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Vital Signsb 
X 
X 
X 
X 
X 
X 
X 
X 
Standard 12-lead ECG 
X 
 
 
 
 
 
X 
X 
Medical and Medication History 
X 
 
 
 
 
 
 
 
Pre-Injection IOP (bilateral) 
 
X 
 
 
 
 
 
 
Ocular Examination (bilateral)c 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug/Sham Dosingd 
(study eye only) 
 
X 
 
 
 
 
 
 
Post-Injection/Sham injection IOPe 
 
X 
 
 
 
 
 
 
ETDRS BCVA (bilateral) 
X 
X 
X 
X 
X 
X 
X 
X 
Color Fundus Photography (bilateral)f  
X 
X 
X 
X 
X 
X 
X 
X 
Wide-Field FA (bilateral) 
X 
 
 
 
X 
X 
X 
X 
SD-OCT Assessment (bilateral) 
X 
X 
X 
X 
X 
X 
X 
X 
SD-OCTA Assessment (bilateral)g 
X 
 
 
 
X 
 
X 
X 
Clinical Laboratory Evaluationsh 
Xi 
 
 
X 
X 
X 
X 
X 
Urine Pregnancy Testj 
X 
 
 
 
 
 
X 
X 
Blood sampling for PKk 
 
X 
 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsl 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA = best corrected visual acuity; CFP = color fundus photography; DRSS = Diabetic Retinopathy Severity Scale; ECG = electrocardiogram; ETDRS = Early Treatment Diabetic 
Retinopathy Study; ET = early termination; FA = fluorescein angiography; HbA1c = hemoglobin A1c; IOP = intraocular pressure; PK = pharmacokinetic; SD-OCT = spectral domain – 
optical coherence tomography; SD-OCTA = spectral-domain – optical coherence tomography angiography 
Note  During any unscheduled visit or if posterior inflammation is present in the study eye, CFP, SD-OCT, and wide field FA of the study eye should be collected at a minimum. 
(table footnotes on next page) 


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Footnotes for Table 5-1: 
a. 
Subjects who terminate the study prior to the Week 48 (end of study) visit should undergo all procedures noted for the early termination visit. 
b. 
Vital signs will include pulse rate, respiratory rate, body temperature, and systolic and diastolic blood pressure (average of 3 readings will be taken in a resting state). 
c. 
Anterior and posterior segments ocular examination, including dilated ophthalmoscopy, IOP, and slit lamp biomicroscopy (see Appendix 2). 
d. 
Check central retinal artery perfusion following study injection.  
e. 
At Day 1: measure IOP at 10 (+/- 5) and 60 (+/- 10) minutes following the EYP-1901 dose/sham injection.  If IOP measurements at any study time points are 30 mmHg 
or higher, two additional measurements should be performed and IOP recorded as a mean of three measurements. 
f. 
All CFP images will be assessed by the CRC to determine the ETDRS-DRSS scores. 
g. 
Spectral-domain – optical coherence tomography angiography (SD-OCTA) or swept-source – optical coherence tomography angiography (SS-OCTA) imaging to be 
collected at these time points at pre-specified study sites where SD-OCTA equipment is available. 
h. 
Clinical laboratory testing will include HbA1c, hematology, serum chemistry, coagulation, and urinalysis evaluations (refer to the study Laboratory Manual). 
i. 
Documented HbA1c test results dated 60 days prior to the Screening Visit will be accepted. 
j. 
Females of childbearing potential only.  Positive urine pregnancy results will be confirmed by a serum pregnancy test. 
k. 
Pharmacokinetic analyses of vorolanib and X-297, its main metabolite, will be performed on blood plasma samples. 
l. 
Adverse events, ocular and non-ocular, will be collected from the time the informed consent is signed.  However, for safety analysis, only treatment-emergent adverse 
events (TEAEs) will be summarized. 
 
 
 


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5.1.1 
Day -30 to Day -5 (Screening Visit) 
The following procedures must be completed during the initial Screening Visit (Table 5–1): 
Informed Consent:  Properly executed informed consent (written and verbal) is to be obtained 
prior to completion of any trial related procedures.  A subject may take as long as needed to 
review the informed consent form (ICF) and consider trial participation; they may take the 
document with them and return at a later date (provided the study is still open for enrollment).  
The subject must review, sign and date the document, and receive a copy. 
Inclusion/Exclusion Criteria:  Inclusion/exclusion criteria (Section 4.1 and Section 4.2, 
respectively) will be reviewed to determine the subject's eligibility to participate in the trial with 
the Investigator verifying enrollment eligibility. 
Demography, Medical History, and Medication History:  Demography, complete medical history, 
and recent (previous 30 days) medications (Section 6.6.1) are to be recorded.  Current contact 
lens use or ocular trauma in the study eye must be documented. 
Ocular procedures to be performed with data collected for both eyes: 
• ETDRS BCVA (Appendix 1) 
• Ocular examination – dilated ophthalmoscopy, IOP, and slit lamp biomicroscopy 
(Appendix 2) 
• CFP 
• Wide-field FA 
• SD-OCT assessment 
• SD-OCTA assessment (at pre-specified study sites where equipment is available) 
Non-ocular procedures to be performed: 
• Vital sign measurements (Section 7.3) 
• ECG (Section 7.4) 
• Collect blood and urine samples for clinical laboratory evaluations (Section 7.2) 
• Documented HbA1c ≤12% for Inclusion Criterion #1 (confirmed by laboratory 
evaluation at the Screening Visit or by a documented laboratory report dated within 
60 days prior to the Screening Visit). 
• Urine pregnancy test (females of childbearing potential only) 
• Use of concomitant medications (Section 7.5) 
• Adverse events, which will be collected from the time the ICF is signed (Section 7.1) 
5.1.2 
Day 1 (Study Treatment) 
The following procedures will be completed during the Day 1 visit (Table 5–1). 


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Inclusion/exclusion criteria (Section 4.1 and Section 4.2, respectively) will be reviewed again to 
confirm the subject’s eligibility to keep participating in the trial, with the Investigator verifying 
eligibility. 
If meeting the eligibility criteria, study subjects will be randomized to study treatments and all 
subjects will receive EYP-1901 or sham IVT injection in the designated study eye on Day 1. 
For subjects with unilateral NPDR, the affected eye will be designated as the study eye; for 
subjects with bilateral NPDR, the study eye will be the more severely affected eye meeting the 
inclusion/exclusion criteria, ie, the eye having the worse DRSS or if equal, the eye clinically 
judged to be the more severely affected eye as determined by the Investigator.  If the eyes are 
symmetrically affected, the study eye will be the right eye.  The fellow eye will receive treatment 
as needed and according to the Investigator’s judgment. 
Ocular procedures to be performed with data collected for both eyes (unless otherwise specified): 
• ETDRS BCVA (Appendix 1) 
• IOP, pre- and post-injection (Appendix 2) 
• Ocular examination – dilated ophthalmoscopy, IOP, and slit lamp biomicroscopy 
(Appendix 2); check central retinal artery perfusion following study injection 
• CFP 
• SD-OCT assessment 
Non-ocular procedures to be performed: 
• Vital sign measurements (Section 7.3) 
• Blood sampling for PK analysis (Section 9) 
• Use of concomitant medications (Section 7.5) 
• Adverse events (Section 7.1) 
Throughout the study, unscheduled visit assessments may be performed as necessary at the 
discretion of the Investigator and following Sponsor approval.  During an unscheduled visit or if 
posterior inflammation is present in study eye, CFP, SD-OCT, and wide-field FA of the study eye 
should be collected at a minimum. 
5.1.3 
Week 4 (±7 days) 
The following procedures will be completed during the Week 4 visit (Table 5–1). 
Ocular procedures to be performed with data collected for both eyes (unless otherwise specified): 
• ETDRS BCVA (Appendix 1) 
• Ocular examination – dilated ophthalmoscopy, IOP, and slit lamp biomicroscopy 
(Appendix 2) 
• CFP 
• SD-OCT assessment 


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Non-ocular procedures to be performed: 
• Vital sign measurements (Section 7.3) 
• Use of concomitant medications (Section 7.5) 
• Adverse events (Section 7.1) 
5.1.4 
Week 12 (±7 days) 
The following procedures will be completed during the Week 12 visit (Table 5–1). 
Ocular procedures to be performed with data collected for both eyes (unless otherwise specified): 
• ETDRS BCVA (Appendix 1) 
• Ocular examination – dilated ophthalmoscopy, IOP, and slit lamp biomicroscopy 
(Appendix 2) 
• CFP 
• SD-OCT assessment 
Non-ocular procedures to be performed: 
• Vital sign measurements (Section 7.3) 
• Collect blood and urine samples for clinical laboratory evaluations (including HbA1c) 
(Section 7.2) 
• Blood sampling for PK analysis (Section 9) 
• Use of concomitant medications (Section 7.5) 
• Adverse events (Section 7.1) 
5.1.5 
Week 24 (±7 days) 
The following procedures will be completed during the Week 24 visit (Table 5–1). 
Ocular procedures to be performed with data collected for both eyes (unless otherwise specified): 
• ETDRS BCVA (Appendix 1) 
• Ocular examination – dilated ophthalmoscopy, IOP, and slit lamp biomicroscopy 
(Appendix 2) 
• CFP 
• Wide-field FA 
• SD-OCT assessment 
• SD-OCTA assessment (at pre-specified study sites where equipment is available) 


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Non-ocular procedures to be performed: 
• Vital sign measurements (Section 7.3) 
• Collect blood and urine samples for clinical laboratory evaluations (including HbA1c) 
(Section 7.2) 
• Blood sampling for PK analysis (Section 9) 
• Use of concomitant medications (Section 7.5) 
• Adverse events (Section 7.1) 
5.1.6 
Week 36 (±7 days) 
The following procedures will be completed during the Week 36 visit (Table 5–1). 
Ocular procedures to be performed with data collected for both eyes (unless otherwise specified): 
• ETDRS BCVA (Appendix 1) 
• Ocular examination – dilated ophthalmoscopy, IOP, and slit lamp biomicroscopy 
(Appendix 2) 
• CFP 
• Wide-field FA 
• SD-OCT assessment 
Non-ocular procedures to be performed: 
• Vital sign measurements (Section 7.3) 
• Collect blood and urine samples for clinical laboratory evaluations (including HbA1c) 
(Section 7.2) 
• Blood sampling for PK analysis (Section 9) 
• Use of concomitant medications (Section 7.5) 
• Adverse events (Section 7.1) 
5.1.7 
Week 48 (±7 days, End of Study) and Early Termination Visit 
Subjects who terminate the study prior to the Week 48 visit should undergo all procedures noted 
for the Early Termination Visit in Table 5–1. 
The following procedures will be completed during the Week 48 or ET visits (Table 5–1). 
Ocular procedures to be performed with data collected for both eyes (unless otherwise specified): 
• ETDRS BCVA (Appendix 1) 
• Ocular examination – dilated ophthalmoscopy, IOP, and slit lamp biomicroscopy 
(Appendix 2) 
• CFP 
• Wide-field FA 


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• SD-OCT assessment 
• SD-OCTA assessment (at pre-specified study sites where equipment is available) 
Non-ocular procedures to be performed: 
• Vital sign measurements (Section 7.3) 
• ECG (Section 7.4) 
• Collect blood and urine samples for clinical laboratory evaluations (including HbA1c) 
(Section 7.2) 
• Urine pregnancy test (females of childbearing potential only) 
• Blood sampling for PK analysis (Section 9) 
• Use of concomitant medications (Section 7.5) 
• Adverse events (Section 7.1) 
5.2 Appropriateness of Measurements 
The efficacy and safety assessments to be utilized in this study (eg, ETDRS-DRSS, BCVA by 
ETDRS, slit lamp biomicroscopy, dilated ophthalmoscopy, IOP measurements, wide-field FA, 
CFP, SD-OCT, SD-OCTA [where equipment is available], collection of ocular and non-ocular 
AEs, clinical laboratory evaluations, vital signs, ECGs, use of concomitant medications) are 
standard measures in studies evaluating intravitreal investigational products like EYP-1901. 
6 STUDY INTERVENTIONS 
6.1 Study Intervention Identification and Description 
EYP-1901 intravitreal insert is a bioerodible, sterile, sustained-release drug delivery system that 
is designed to release microgram levels of vorolanib into the ocular vitreous chamber for the 
treatment of NPDR.  The intravitreal insert formulation design is based on the Durasert® 
technology that allows EYP-1901 to exhibit the following characteristics: 
• Bioerodible properties 
• Sustained-release kinetics 
• Prolonged duration of release (not less than 9 months) 
• High drug loading 
• Administration in an office setting through an intravitreal needle injection 
6.1.1 
EYP-1901 Composition 
EYP-1901 intravitreal insert contains vorolanib as the active ingredient and polyvinyl alcohol as 
an excipient. 
The drug delivery system is placed into a one-time-use siliconized needle attached to an 
applicator delivery system.  The drug product is sterilized after packaging and prior to 


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distribution.  In subject, the needle is inserted through the pars plana and the insert is injected 
into the vitreous. 
Two different doses will be administered by delivering multiple inserts on Day 1 (Table 5–1).  
Table 6–1 summarizes the characteristics of the two intravitreal doses of EYP-1901. 
Table 6–1: 
Characteristics of the Two Intravitreal Doses of EYP-1901, 
Study EYP-1901-204 
 
Dose (µg) 
Number of Inserts 
per Single 
Applicator 
Needle 
Gauge 
Insert Length 
(mm) 
2060 
2 
22 
8 
3090 
3 
22 
8 
 
6.1.2 
EYP-1901/Sham Applicator Packaging 
EYP-1901 is packaged at EyePoint Pharmaceuticals.  EYP-1901 loaded applicators (and sham 
applicators) are placed inside a foil chevron pouch and sealed.  The sealed foil pouch is then 
placed inside a Tyvek® chevron pouch.  The final pouch is sent for terminal sterilization.  Upon 
completion of sterilization, each pouch is labeled with a “Sterile” label, and then placed into a 
labeled box. 
6.2 Study Drug Administration 
6.2.1 
EYP-1901 Intravitreal Insert 
Each EYP-1901 insert has been designed to deliver vorolanib into the vitreous humor for at least 
9 months.  EYP-1901 will be administered to the study eye by a single injection through the pars 
plana using a pre-loaded applicator with a 22-gauge needle. 
6.2.2 
EYP-1901 Injection Procedure 
For a detailed description of the EYP-1901 injection procedure, please refer to the EYP-1901 
Instructions for Use (IFU) document. 
6.3 Storage and Dispensing of Study Drugs 
EYP-1901 must be stored in a secure place and at controlled room temperature (20°C to 
25°C/68°F to 77°F) and in the original container to protect the product from light.  Temperature 
excursions between 15°C to 30°C/59°F to 86°F are acceptable. 
The Investigator has the overall responsibility of ensuring that EYP-1901 is stored in a safe 
location with limited-access under the specified storage conditions.  Limited responsibility may 
be delegated to a pharmacy representative; however, this delegation must be documented. 
6.4 Drug Accountability 
The Investigator is responsible for ensuring adequate accountability of all used and unused 
EYP-1901.  While the Investigator may delegate components of drug accountability tasks to 


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documented designee(s) (eg, pharmacist or staff designee), the ultimate responsibility for drug 
control and accountability resides with the Investigator.  This includes acknowledgment of 
receipt of each shipment (quantity and condition), maintenance of subject dispensing records and 
returned (as required) documentation.  Dispensing records will document quantities received 
from the Sponsor (or designee) and quantities dispensed to subjects, including treatment 
kit/package number, date dispensed, subject identification number, subject initials, and the 
initials of the person dispensing drug will be recorded on the drug accountability log. 
During study initiation, the study monitor (Clinical Research Associate, CRA) will evaluate and 
obtain a copy of each site’s written standard operating procedure for study drug 
disposal/destruction or return to ensure that it complies with Sponsor requirements if supplies 
will not be returned. 
An inspection for inventory and accounting purposes, and the assurance of proper storage, will 
also be conducted during monitoring visits.  Any significant accounting or storage discrepancy 
will be recorded and reported to the Sponsor and a plan for resolution will be documented.  After 
the monitor has checked and verified drug accountability during interim site visits and at the end 
of the study, any expired, partially-used, and used product should be handled according to the 
Sponsor’s instructions (ie, returned or destroyed). 
6.5 Anaphylaxis, Overdose, and Dose Modification 
Vorolanib and the inactive ingredients of EYP-1901 are not known to cause hypersensitivity 
reactions. 
Since EYP-1901 is delivered through a pre-loaded applicator, the risk of accidental overdose is 
minimal.  Refer to the current IB for information on potential risks associated with EYP-1901.  
Dose modification is not applicable since EYP-1901 is for single-delivery only. 
Note:  Hypersensitivity reactions to iodine and/or fluorescein used during ocular assessments are 
also possible. 
Signs and symptoms of hypersensitivity include: 
• Localized or generalized itching 
• Facial flushing, generalized flushing 
• Shortness of breath, wheezing 
• Uneasiness and agitation 
• Local edema followed by facial edema 
• Light-headedness/dizziness 
• Chest tightness 
• Tachycardia 
• Hypotension 
• Rigors (chills) 


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If anaphylaxis occurs, the subject should be managed according to standard cardiopulmonary 
resuscitation (CPR) procedures, as necessary.  The subject may require the following treatment: 
• Epinephrine (adrenaline) to reduce the allergic response 
• Oxygen 
• Intravenous antihistamines and cortisone to reduce airway inflammation and improve 
breathing 
• A beta-agonist (such as albuterol) to relieve breathing symptoms 
6.6 Prior and Concomitant Medications 
6.6.1 
Prior Medications 
Prior medications are defined as all prescription, vaccinations, supplements, herbal therapies, any 
prohibited medications, and over-the-counter (OTC) medications taken within the 30 days 
(whether continuing or not) prior to Day 1 with the exception of previous treatments for NPDR, 
both approved and investigational products.  Previous treatments for NPDR are to be captured 
for the 12 months prior to Screening, and any historical anti-VEGF injections. 
All prior medications must be documented on the concomitant medications eCRF. 
6.6.2 
Concomitant Medications 
All prescription and OTC concomitant medications used concurrently (from the Screening Visit 
to Week 48 or Early Termination) must be documented on the concomitant medication eCRF. 
Information on the concomitant medication eCRF includes the name of the medication/therapy, 
dose, frequency, route, dates of use, and indication for use.  Subjects should be instructed not to 
take any medication including OTC products, without first consulting with the Investigator.  Any 
AE(s) that result(s) from taking a concomitant medication following the first study dose should 
be recorded on the AE eCRF. 
6.6.3 
Prohibited Concomitant Medications 
Any medications or therapies that the subject is using during the study period and that would 
preclude eligibility as indicated in the Exclusion Criteria (Section 4.2), are prohibited 
concomitant medications.  In addition, any medication or therapies initiated during the study 
period that, in the Investigator’s judgment, could potentially confound the safety and preliminary 
efficacy of EYP-1901 would also be considered prohibited concomitant medications. 
All prohibited concomitant medications used concurrently (from Day 1 to Week 48 or Early 
Termination) must be documented on the concomitant medication eCRF 
6.6.4 
Permitted Medication and Procedures 
Following the intravitreal injections of either dose of the EYP-1901 insert (2060 µg or 3090 µg) 
on Day 1, treatment of the fellow eye will be at the discretion of the Investigator.  Any fellow eye 
therapy should be documented in concomitant meds during the study if required. 
After Day 1, all subjects, regardless of treatment assignment, may receive approved anti-VEGF 
supplemental therapy or other standard of care therapy if they have ocular diabetic complications 


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warranting intervention.  All ocular diabetic complications in the study eye will be managed in 
accordance with each study center’s standard of care and must be documented as an AE. 
During the study, participants who develop ocular diabetic complications in the study eye 
requiring anti-VEGF treatment per standard of care may be administered therapy as required.  If 
needed, the study centers will provide their own supply of FDA-approved anti-VEGF therapy 
and submit the associated costs for reimbursement.  The number of anti-VEGF injections 
received, the name of the product being injected, and the timing of all injections must be 
recorded in the source documents and eCRF. 
Participants who develop ocular diabetic complications requiring PRP or retinal laser standard of 
care must have the time of laser treatment recorded in the source documents and eCRF. 
Participants who develop ocular diabetic complications requiring surgical intervention standard 
of care (eg, pneumatic retinopexy, cryopexy, scleral buckle) must have the type of intervention 
and the time of intervention recorded in the source documents and eCRF. 
In this case, the Investigator is required to contact the Medical Monitor prior to administering 
treatment if feasible. 
7 ASSESSMENT OF SAFETY 
Safety assessments will include the incidence and severity of TEAEs reported after Screening, 
clinical laboratory evaluations (hematology, serum chemistry, coagulation, and urinalysis), safety 
data collected from ocular examinations and IOP measurements, vital sign measurements, ECGs, 
and the use of concomitant medications. 
Medical safety reviews will be conducted by the Sponsor for all TEAEs and other relevant 
information related to safety on an ongoing basis and throughout the duration of the study 
according to the study Safety Management Plan. 
7.1 Adverse Events 
The following are specific definitions of terms guided by the International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH E2), 
Guidelines for Good Clinical Practice (GCP), and the US Code of Federal Regulations (CFR) 
that apply to the following sections.  The severity of AEs will be graded by CTCAE version 5 or 
higher (Appendix 4). 
Definition of Adverse Event: 
An AE is defined as any new untoward medical occurrence or worsening of a pre-existing 
medical condition in a patient or clinical investigation subject administered an investigational or 
marketed (medicinal) product and that does not necessarily have a causal relationship with the 
product.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the product. 
AEs may also include pre- or post-treatment complications that occur as a result of 
protocol-specified procedures (eg, invasive procedures such as venipuncture, delivery procedure, 
etc.).  Pre-existing conditions that increase in severity or change in nature during (or as a 
consequence of use of a medicinal product) the study will also be considered AEs. 


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An AE Will Not Include: 
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion) for 
events that led to the procedure 
• Pre-existing diseases, conditions, or laboratory abnormalities present or detected prior to 
the Screening Visit, unless they worsen during the study 
• Situations where an AE or untoward medical occurrence has not occurred (eg, 
hospitalization for elective surgery, social and/or convenience admissions) 
Associated with the Use of the Drug (Causality): 
There is a reasonable possibility that the event may have been caused by the study medicinal 
product (and/or the administration procedures). 
Unexpected Adverse Event: 
Any event that is not identified in nature, severity, or frequency in the current version of the IB; 
or in the product labeling for marketed products.  For example, if the IB or product labeling 
referred to elevated hepatic enzymes or hepatitis, then an event of hepatic necrosis would be 
considered unexpected by the virtue of the greater severity.  The Sponsor or designee will 
determine AE expectedness. 
7.1.1 
Ocular Adverse Events 
The following ocular events will be considered AEs for the purposes of this study: 
• Decrease in BCVA of ≥15 letters or ≥3 lines from the previous BCVA measurement 
• Moderate or severe (Grade 2 or 3) ocular findings compared to the last ocular 
examination 
• Worsening of >2 steps in anterior chamber cell count or vitreous haze compared to the 
last ocular examination 
• Increase in IOP of >10 mmHg at two visits at least 1 week apart or an increase in IOP to 
>25 mmHg 
7.1.2 
Serious Adverse Events 
An SAE is any AE that results in one of the following outcomes: 
• Death. 
• Is life-threatening (the term “life-threatening” refers to an event in which the subject was 
at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more intense). 
• Requires in-patient hospitalization (formal admission to a hospital for medical reasons for 
any length of time), or prolongs existing hospitalization. 
• Results in a persistent or significant disability/incapacity, or substantial disruption of the 
ability to conduct normal life functions. 


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• Congenital anomaly/birth defect (in the child of a subject who was exposed to the study 
treatment). 
• Other important medical event.  Medical and scientific judgment should be exercised in 
determining whether an event is an important medical event.  An important medical event 
may not be immediately life-threatening and/or result in death or hospitalization but 
required medical intervention in order to prevent a SAE outcome.  However, if it is 
determined that the event may jeopardize the subject and/or may require intervention to 
prevent one of the other SAE outcomes, the important medical event should be reported 
as serious.  Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
The following hospitalizations will not be considered SAEs: 
• A visit to the emergency room or other hospital department for <24 hours that does not 
result in in-patient admission (unless considered an “important medical event” or a 
“life -threatening event”). 
• Elective surgery or planned surgery prior to signing the ICF. 
• Admissions as per protocol for a planned medical/surgical procedure. 
• Routine health assessments requiring admission for Baseline/trending of health status (eg, 
routine colonoscopy). 
• Medical/surgical admission for a purpose other than healthcare purposes and was planned 
prior to entry into the study (appropriate documentation is required in these cases). 
• Admission encountered for another life circumstance that carries no bearing on health 
status and/or requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
• Progressive disease (NPDR) is expected and will not be considered an SAE. 
Clarification of SAEs: 
• Death is an outcome of an AE, and not an AE in itself. 
• All deaths, regardless of cause or relationship, must be reported. 
• Complications that occur during hospitalizations are AEs.  If a complication prolongs 
hospitalization, it is an SAE. 
• “In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons for any length of time.  This may or may not be overnight.  It does not 
include presentation to, and/or care within, an emergency department. 
• The Investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. 
Note:  Progressive disease should be recorded on the AE eCRF.  However, because it is expected 
in the study population, it will not be considered as an SAE. 


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7.1.3 
Sight-Threatening Ocular Events Defined as SAEs in This Study 
In addition to the standard SAE categories described above, this study defines these additional 
ocular events as SAEs: 
• An AE that causes a decrease in visual acuity of ≥30 letters or ≥6 lines from the most 
recent previous measurement of visual acuity, lasting more than 1 hour. 
• An AE that causes a decrease in visual acuity to light perception or worse, lasting more 
than 1 hour. 
• An AE that requires surgical intervention (eg, conventional surgery, vitreous tap, or 
biopsy with intravitreal injection of anti-infectives, or laser or retinal cryopexy with gas) 
to prevent permanent loss of sight. 
• An AE that is associated with severe intraocular inflammation (ie, 4+ anterior chamber 
cell score or 4+ vitreous haze score). 
• Two consecutive IOP measurements of ≥30 mmHg taken at least 72 hours apart when a 
subject is already being treated with two IOP-lowering medications. 
• An IOP <6 mmHg requiring medical intervention. 
• An AE that in the opinion of the Investigator requires medical or surgical intervention to 
prevent permanent loss of sight. 
The Investigator must employ all necessary therapeutic measures to resolve the SAE.  Any 
medications or therapies used to treat the SAE must be recorded in the concomitant medication 
eCRF. 
7.1.4 
Clinical Laboratory Adverse Events 
An abnormal laboratory result should be considered an AE if it: 
• Results in the initiation or change of an intervention (eg, increased dose of medication), 
based on medical evaluation (eg, packed red cells for low hemoglobin). 
• Results in any out of range laboratory value that in the Investigator’s judgment fulfills the 
definitions of an AE. 
• Increases in severity compared to baseline. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE.  Any laboratory abnormality considered 
to constitute an AE should be reported on the AE eCRF.  It is the responsibility of the 
Investigator to review all laboratory findings in all subjects and determine if they constitute an 
AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE. 
All laboratory AEs should be repeated and reassessed by the Investigator to track resolution and 
especially to confirm if they meet the definition of serious.  If serious, they will be reported as 
SAEs. 
The Investigator or a licensed designee must review all laboratory results in a timely manner as 
demonstrated by signature/date. 


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7.1.5 
Adverse Event Severity and Relationship 
Adverse event severity is defined as a qualitative assessment of the intensity of an AE as 
determined by the Investigator.  The assessment of severity is made irrespective of the 
relationship or seriousness of the event to EYP-1901, sham, or the injection device. 
In the absence of an assigned severity per the CTCAE version 5.0 or higher (Appendix 4) 
grading criteria, the Investigator will grade AEs according to the following severity criteria:  
Mild/Grade 1: 
The event may be noticeable to subject; does not influence daily 
activities; usually does not require intervention. 
Moderate/Grade 2: 
The event may be of sufficient severity to make subject 
uncomfortable; performance of daily activities may be influenced; 
intervention may be needed. 
Severe/Grade 3: 
The event may cause severe discomfort; usually interferes with 
daily activities; subject may not be able to continue in the study; 
treatment or other intervention usually required. 
Life- or Sight-Threatening/Grade 4: 
The event requires urgent intervention to preserve life and/or 
permanent loss of vision. 
Death/Grade 5: 
The event resulted in the subject’s death. 
Causality/Relationship to Study Treatment 
The relationship of study treatment (ie, EYP-1901 or sham), the applicator, or the injection 
procedure, to each AE must be determined by the Investigator according to the following: 
Not Related: 
Evidence indicates no plausible direct relationship to the study 
treatment, device, or procedure, or there is a reasonable causal 
relationship between non-study product, concurrent disease, or 
circumstance and the AE; and/or a causal relationship is considered 
biologically implausible. 
Possibly Related: 
There is a reasonable causal relationship between the study 
treatment, device, or procedure and the AE.  There may or may not 
be a clinically-plausible temporal sequence between the onset of the 
AE and study treatment, device, or procedure; the AE is not 
reasonably supported by other conditions. 
Probably Related: 
The study treatment, device, or procedure and AE occurrence are 
reasonably related in time; a clinically-plausible temporal sequence 
between the onset of the AE and study treatment, device, or 
procedure is likely; based upon the Investigator’s clinical 
experience, the association of the AE with study treatment, device, 
or procedure is likely; all other potential causes have been ruled 
out. 
If the relationship between the AE/SAE and the sequence study treatment, device, or procedure is 
determined to be “possible” or “probable”, the event will be considered related for the purposes 
of expedited regulatory reporting. 


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7.1.6 
Recording of Adverse Events 
Medical conditions or diseases present before a subject starts study treatment are only considered 
AEs if they worsen after the start of the study treatment. 
Adverse events may be spontaneously reported or elicited at each study visit through open-ended 
questioning, examination, or evaluation of a subject.  To prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more AEs. 
The Investigator will record all AEs in the eCRF.  Where a diagnosis is possible, it is preferable 
to report the diagnosis rather than a series of terms (signs/symptoms) relating to the diagnosis.  If 
a definitive diagnosis is not possible, the individual symptoms and signs should be recorded. 
The following information must be captured for all AEs: 
• Onset and end date 
• Severity 
• Seriousness  
• Relationship to EYP-1901, sham, the injection device, or the procedure 
• Action taken 
• Any treatment required 
• Outcome 
If treatment for the AE was administered, it should be recorded on the appropriate concomitant 
medication/procedure eCRF page.  Each distinct AE should be recorded separately. 
7.1.7 
Adverse Event Reporting 
All subjects enrolled in the study will be evaluated for AEs, which will be collected from the 
time the ICF is signed until study completion (Table 5–1). 
All AEs will be evaluated from onset until resolution or stabilization, whichever is first.  Adverse 
events that continue after the subject’s discontinuation or completion of the study will be 
followed until their medical outcomes are determined or until no further change in the condition 
is expected.  The event and outcome will be reported in writing by the Investigator to the 
Sponsor.  The Investigator shall supply the Sponsor and Institutional Review Board (IRB)/Ethics 
Committee (EC) with any additional requested information, notably for reported deaths. 
7.1.7.1 
Reporting of Serious Adverse Events 
All SAEs, regardless of cause(s) or relationship to study drugs, must be recorded on the 
appropriate eCRF page and reported to the Sponsor within 24 hours of the Investigator’s first 
awareness using the study’s designated SAE/SADR (Serious Adverse Drug Reaction) Report 
Form. 
Minimal information to be provided on the SAE/SADR Report Form includes: 
• Protocol number 
• Site and Investigator identifiers 


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• Subject number 
• Brief description of the event(s) 
• Onset date of the event 
• Outcome of the event as of the date of report, if known 
• Resolution date and time, if the event(s) resolved 
• Any medication administered to treat the event 
• Investigator’s assessment of the causal relationship of the SAE to the study medicinal 
product 
• Additional and follow-up information as requested by Sponsor or its designee 
SAEs must be reported using the study’s designated SAE/SADR Report Form and sent to: 
 
  
 
 
The Investigator will also compile other relevant documentation with urgent priority (eg, copies 
of test results, hospital discharge summary, autopsy report, etc.), and send this information to the 
Sponsor (or Sponsor’s designee). 
The FDA and all participating Investigators shall be notified by a written Investigational New 
Drug Application (IND) safety report of any AE associated with the use of the investigational 
product that is both serious and unexpected no later than 15 calendar days from the Sponsor’s 
awareness date of the event.  An SAE is considered to be associated with the use of the 
investigational product if the relationship between the SAE and the investigational product is 
classified by the Investigator as “possibly related” or “probably related” (ie, suspected, 
unexpected serious adverse reaction [SUSAR]).  Any unexpected fatal or life-threatening SAE 
associated with the use of the investigational product will be reported to the FDA by the Sponsor 
within 7 calendar days. 
The IRB/EC should be notified of SAEs as required in accordance with the local institutional 
policy. 
All Investigators participating in the study will be notified of unexpected SAEs determined to be 
related to study treatment/injection procedure. 
Pregnancy 
Pregnancy that occurs during the study must be immediately reported to the Investigator who 
will immediately notify the Sponsor or designee within 24 hours of first awareness using the 
study’s designated Pregnancy Report Form.  This includes any pregnancy following maternal or 
paternal exposure to the study treatments. 
The pregnancy should be followed to term.  The outcome, including premature termination must 
also be reported to the Sponsor or designee within 24 hours of the Investigator’s awareness using 
the Pregnancy Report Form.  All live births must be followed for a minimum of 4 weeks or to the 
first well-baby visit.  All reports of congenital abnormalities/birth defects and spontaneous 
abortions/miscarriages should be reported as SAEs.  Elective abortion procedures without 
complications should not be considered as AEs. 
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If the Investigator becomes aware of a pregnancy occurring in any male subject’s partner during 
the male subject’s treatment with the assigned study medicinal product, the Investigator must 
submit this information to the Sponsor on the Pregnancy Report Form. 
The Pregnancy Report Form should be sent to: 
 
  
 
 
Special Situations 
Notification must be made to the Sponsor or designee of any special situation which includes the 
following, regardless of any associated AE: 
• A medication error, defined as any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the health care provider or 
subject. 
• Abuse, defined as persistent or sporadic intentional excessive use of a medicinal or other 
product. 
• Misuse, defined as any intentional or inappropriate use of a medicinal product that is not 
in accordance with the protocol instructions or local prescribing information. 
• An overdose, defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose per protocol or in the product labeling.  In cases of a discrepancy in 
drug accountability, overdose will be determined only when it is clear that the subject 
received an excess dose(s). 
Special situations should be reported on the study’s designated SAE/SADR Report Form except 
pregnancies for which there is a dedicated form.  If any special situation results in clinical 
sequela(ae)/AE(s), the event(s) must be recorded on the AE eCRF.  If the AE is serious, the SAE 
eCRF must be completed and a SAE/SADR Report Form must be completed and submitted to 
the Sponsor or designee within 24 hours of first awareness. 
Special situations involving concomitant medication do not need to be reported on the 
SAE/SADR Report Form.  However, special situations involving concomitant medication that 
result in clinical sequelae/AEs should be reported on the AE eCRF.  In addition, any 
inappropriate use of prohibited concomitant medications should not be reported as “misuse” but 
may be more appropriately documented as a protocol deviation. 
Using the SAE/SADR Report Form, reports of special situations should be sent to: 
 
  
 
 
7.2 Clinical Laboratory Evaluations 
The clinical laboratory tests listed in the Study Laboratory Manual, including hematology, 
HbA1c, serum chemistry, coagulation, and urinalysis, will be done at the study visits indicated in 
Table 5–1. 
PPD
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A central laboratory will be used to measure laboratory parameters.  The Investigator will use 
these results for clinical purposes and the laboratory data will be used for safety analyses. 
Normal value ranges and laboratory certification will be collected prior to study initiation. 
Investigators must review and document laboratory test results, as well as address the clinical 
significance and causality (for significant abnormalities).  Clinically significant abnormal 
laboratory results should be repeated as soon as possible.  Section 7.1.4 provides further 
guidance as to when abnormal laboratory results are to be reported as AEs. 
7.3 Vital Signs 
Vital signs will include pulse rate, respiratory rate, body temperature, and systolic and diastolic 
blood pressure (average of 3 readings will be taken in a resting state) at the visits indicated in 
Table 5–1. 
7.4 Electrocardiograms 
Standard 12-lead ECG assessments will be performed at visits indicated in Table 5–1. 
7.5 Concomitant Medication Use 
During the study, treatment for the progression of NPDR may be required in the study eye for 
some subjects as a result of AEs or lack of efficacy of the study treatment.  Intervention per the 
clinical sites standard of care are permitted (Section 6.6.4).  Prohibited medications 
(Section 6.6.3), although discouraged, can be used if necessary (eg, no other alternative) but will 
be considered protocol deviations.  Information regarding concomitant medication use will be 
collected at the visits specified in Table 5–1. 
8 REPORTING OF TECHNICAL PRODUCT COMPLAINTS 
A Product Complaint (PC) is defined as any written, electronic, or verbal expression of 
dissatisfaction regarding the identity, quality, reliability, safety, purity, potency, effectiveness, or 
performance of an investigational or commercial product after it is released for distribution (eg, 
any failure of the applicator to deliver the intravitreal insert), or dissatisfaction with any other 
characteristic(s) of the drug product (eg, labeling, packaging, etc.). 
Any/all PCs should be reported to EyePoint within 24 hours using the designated PC Report 
Form.  The complaint report should include the following information: 
• Product identification number 
• Investigator name, study site name, and contact phone number 
• Date the complaint occurred 
• Brief description of the complaint 
• Subject involved? (yes or no); if yes, were any AEs associated with the complaint? (yes 
or no).  If (yes) an AE is associated with the complaint, please refer to Section 7.1 


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Once all information is collected please report to: 
 
 
 
 
The drug container (applicator, foil pouch, and carton) for which the complaint was initiated 
should be retained for return to EyePoint for analysis. 
 
 
 
 
 
Any complaint about an investigational product must be reported regardless of whether the 
defect or deficiency had any effect on a subject or on study personnel. 
9 PHARMACOKINETICS 
Secondary endpoints in this study include the evaluation of the systemic exposure to vorolanib 
and X-297, its main metabolite, as measured through plasma.  Blood samples will be collected at 
the visits noted in Table 5–1 for PK analysis of vorolanib and its main metabolite concentrations.  
Collection, handling, storage, and shipment of samples to the designated analytical testing 
laboratory will be conducted according to the procedures described in Appendix 3. 
In the event the subject requires vitrectomy during the study, the unmasked Investigator or 
designee will collect a vitreous sample and EYP-1901 implants (if applicable) to be sent to 
sponsor as described in Appendix 3. 
10 ASSESSMENT OF EFFICACY 
The primary objective of this study is to assess the efficacy of EYP-1901 compared to sham 
treatment in the improvement of moderately severe to severe NPDR.  The primary endpoint of 
this study will be the percentage of subjects improving ≥2 steps from baseline in the DRSS score 
at Week 36 in each EYP-1901 dose level versus the sham IVT injection group in the study eye. 
The DRSS may be used to describe overall retinopathy severity as well as the change in severity 
over time.  Severity ranges from level 10 (DR absent) to level 85 (advanced proliferative DR: 
posterior fundus obscured, or center of macula detached).  Here, DRSS describes severity level 
47 (moderately severe NPDR) and level 53 (severe NPDR) at Week 36 from baseline. 
Additional secondary endpoints include the following in the study eye (unless otherwise 
specified): 
• Percentage of subjects improving ≥2 steps from baseline in the DRSS score at 
Weeks 24 and 48 in each dose level vs. sham. 
• Percentage of subjects improving ≥2-steps or ≥3-steps over time in DRSS from 
baseline. 
• Percentage of subjects worsening ≥2-steps or ≥3-steps over time in DRSS from 
baseline. 
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• Percentage of subjects who developed a vision-threatening complication due to diabetic 
retinopathy at Weeks 24, 36, and 48. 
• Percentage of subjects who developed CI-DME at Weeks 24, 36, and 48. 
• Time to develop of any neovascular vision threatening complication (PDR/ASNV) 
through Weeks 24, 36 and 48. 
• Time to develop CI-DME through Weeks 24, 36, and 48. 
• Percentage of subjects who received anti-VEGF or additional standard of care 
intervention due to ocular diabetic complications at Weeks 24, 36, and 48. 
• Percentage of subjects who received PRP, inclusive of subjects undergoing vitrectomy 
with endolaser, at Weeks 24, 36. and 48. 
• Area under the curve (AUC) for change from baseline in BCVA at Weeks 24, 36, and 
48. 
• Systemic exposures to vorolanib and X-297, its main metabolite, measured through 
plasma levels up to Weeks 24 and 48. 
• Rates of ocular (study eye and fellow eye) and non-ocular TEAEs at Weeks 24 and 48. 
11 
STATISTICAL METHODS AND DATA ANALYSIS 
Detailed methodology for statistical analyses of the data collected in this study will be 
documented in a Statistical Analysis Plan (SAP), which will be developed and maintained by the 
Sponsor. 
The SAP may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol amendment. 
All study data will be presented in by-subject listings. 
11.1 Determination of Sample Size 
The objectives of the study are to provide efficacy and safety data in a prospective, randomized, 
double-masked, controlled trial.  However, the study is not formally powered to perform 
statistical hypothesis testing between each EYP-1901 arm versus sham IVT injection.  
Approximately 60 subjects will be randomized at 1:1:1 ratio to each of three treatment arms 
(20 per treatment arm). 
11.2 Analysis Population 
The intent-to-treat (ITT) population will include all subjects who received at least one dose of 
study treatment (EYP-1901 or sham).  The safety summaries will be based on the ITT 
population.  The subjects will be summarized based on the treatments that they actually receive. 
The efficacy population will include all subjects who received at least one dose of study 
treatment (EYP-1901 or sham) and continue until at least Week 36 (ie, have had the primary 
endpoint assessed). 


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11.3 General Statistical Considerations 
11.3.1 Data Summarization 
Data summaries for variables measured on a continuous scale will include descriptive statistics 
(n, mean, median, standard deviation, minimum, and maximum) by treatment arm.  Data will be 
pooled for all study sites for data analysis, unless otherwise specified. 
For variables evaluated on a categorical scale, data summaries will include the number and 
percentage of subjects who provide each possible category, by treatment arm.  The 95% 
confidence interval (CI) of the proportions will be constructed, as appropriate. 
11.3.2 Definition of Baseline 
Baseline measurements are those taken at Screening or prior to receiving study drug on Day 1, 
whichever is the latest. 
11.3.3 Handling of Missing Data 
In general, missing data will not be imputed, unless otherwise specified.  Every effort will be 
made to ensure completeness of data collection. 
11.3.4 Multicenter Considerations 
Approximately 30 investigative study sites in the US will participate in the study.  Due to the 
limited sample size, a site effect will not be analyzed, unless otherwise specified. 
11.3.5 Adjustment for Covariates 
Not applicable. 
11.3.6 Interim Analyses 
No interim analyses are planned for this study prior to the primary endpoint readout at Week 36. 
11.3.7 Multiple Comparisons and Multiplicity 
Not applicable.  This study is not powered for statistical significance hypothesis testing.  All 
analysis will be descriptive. 
11.3.8 Examination of Subgroups 
Data will be summarized by treatment arm.  Subgroup analyses could be performed upon 
completion of study follow-up and data collection as described in the SAP. 
11.3.9 Statistical Software 
All statistical summaries and analyses will be produced using SAS, Release 9.4 or higher. 


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11.4 Analyses 
11.4.1 Subject Disposition 
A summary table will be prepared indicating the number and percentage of subjects in each 
treatment arm and overall who were included in the ITT population.  Within the ITT population, 
the number and percentage of subjects who did/did not complete the study will be presented.  
Screen failures, including reasons for failing to satisfy eligibility criteria will also be 
summarized.  
Subjects who discontinue any time during the study will be categorized by reason for 
termination, and the percentage within each category will be provided. 
11.4.2 Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment arm and overall 
using descriptive statistics for the ITT population. 
11.4.3 Medical History 
Medical history will be coded and listed by treatment arm. 
11.4.4 Efficacy Analysis 
Primary Endpoint: 
The percentage of subjects improving ≥2 steps from baseline in the DRSS score at Week 36 in 
each dose level vs. sham will be descriptively summarized by treatment arm for the efficacy 
population.  Further details will be described in the SAP. 
Secondary Endpoints: 
Descriptive statistics will be provided for the secondary endpoints by treatment arm for the 
efficacy population.  Further details will be described in the SAP. 
11.4.5 Pharmacokinetic Analysis 
Descriptive statistics will be provided for plasma PK data by treatment arm for the ITT 
population. 
11.4.6 Use of Prohibited Medications 
Prior to database lock, the Sponsor will conduct a blinded data review of concomitant treatments 
to determine if any fall under prohibited medications (Section 6.6.3).  The proportion of subjects 
receiving these medications will be summarized by treatment arm and time point. 
11.4.7 Adverse Events 
Both ocular and non-ocular TEAEs are defined as events that start after the first study drug 
administration, and occur before termination of the study, or were present before first study drug 
administration and worsened after administration.  Descriptive statistics will be provided for all 
TEAEs by treatment arm and overall for the ITT population. 


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Adverse events will be coded by System Organ Class (SOC) and preferred term (PT) using the 
current version of the Medical Dictionary for Regulatory Activities (MedDRA).  Ocular and 
non-ocular TEAEs will be summarized separately.  The number and percentage of subjects who 
experience an AE will be presented.  Within each level of summarization (SOC, PT), subjects 
who experience more than one occurrence will only be counted once.  Adverse events will also 
be presented by severity (mild, moderate, severe, life-threatening, fatal), and by relationship to 
study drug (not related, possibly related, probably related).  Listings of deaths, SAEs, and 
withdrawals due to AEs will be presented. 
11.4.8 Clinical Laboratory Evaluations 
Clinical laboratory evaluations (hematology, HbA1c, serum chemistry, coagulation, and 
urinalysis) will be presented using descriptive statistics by treatment arm for the ITT population.  
Laboratory values will be listed by subject, and values outside of a normal reference range will 
be flagged.  Pregnancy test results will be listed separately. 
11.4.9 Vital Signs 
Vital signs (pulse rate, respiratory rate, body temperature, and systolic and diastolic blood 
pressure) will be presented using descriptive statistics by treatment for the ITT population.  
Averages of replicate readings will be used in analysis.  Listing of vital signs data will be 
provided. 
11.4.10 Prior and Concomitant Medications 
Medications for both ocular and non-ocular indications will be coded using the World Health 
Organization (WHO) Drug Dictionary.  These medications (prescription, OTC, and nutritional 
supplements) will be summarized by anatomical therapeutic chemical (ATC) classification 
levels, WHO generic name, and treatment arm.  Subjects will only be counted once at each level 
of the generic name or ATC level. Listing of prior and concomitant meds will be provided. 
12 
ADMINISTRATIVE AND REGULATORY CONSIDERATIONS 
12.1 Quality Control and Quality Assurance 
The Sponsor’s employees and/or their contracted representatives utilize standard operating 
procedures (SOPs) designed to ensure that research procedures and documentation are 
consistently conducted/prepared to the highest quality standards.  These SOPs also require 
compliance with Health Authority regulations and GCP guidance. 
A Quality Assurance audit may be conducted by the Sponsor or a designee at any time during or 
after completion of this study.  The Investigator will be given adequate notice if he/she is 
selected for an audit.  The audit will include, but is not limited to, a review of all ICFs, a review 
of eCRFs, associated source documents and medical records, a review of regulatory 
documentation, an assessment of study conduct and protocol compliance, and a review of the 
investigational drug accountability.  At the conclusion of an audit, the auditor will conduct a brief 
meeting with the Investigator to review the audit findings. 


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12.2 Institutional Review Boards/Independent Ethics Committee 
Prior to the study initiation, the protocol and ICF will be submitted to the IRB/EC for approval. 
The IB may also be submitted as supplemental information.  By signing the “Statement of 
Investigator” form (FDA form 1572), the Investigator is assuring that an IRB/EC that complies 
with the requirements set forth in 21 CFR Part 56 will be responsible for the initial and 
continuing review of the clinical study.  A copy of the IRB/EC approval letter for the protocol, 
and the informed consent, as well as the protocol signature page must be submitted to the 
Sponsor or its designee prior to release of investigational supplies to the study site.  The approval 
letter must refer to the specific protocol and informed consent form.  The study site must 
maintain an accurate and complete record of all reports, documents, and other submissions made 
to the IRB/EC concerning this protocol.  A list of the IRB/EC members, their titles or 
occupations, and their institutional affiliation, or an IRB/EC assurance number must be provided 
to the Sponsor or its designee prior to release of study supplies. 
FDA/relevant health authority regulations require that all advertisements for subject recruitment 
be approved by an IRB/EC prior to implementation.  The complete text and format must be 
submitted to the Sponsor or designee for approval prior to IRB/EC submission. 
The Investigator is responsible for notifying the IRB/EC of any SAEs.  A copy of the notification 
must be forwarded to the Sponsor or its designee. 
Status reports must be submitted to the IRB/EC at least once a year (or more frequently as 
required by the IRB/EC) and the IRB/EC must be notified of study completion or termination.  
A final report must be provided to the IRB/EC and the Sponsor within 6 months of study 
completion or termination.  This report should include:  any protocol deviations, the number of 
subjects evaluated, the number of subjects who withdrew or were withdrawn and the reasons for 
withdrawal, any significant AEs, and the Investigator’s summation of the study. 
12.3 Informed Consent Process 
It is the responsibility of the Investigator to inform each subject, prior to the screening 
evaluation, of the purpose of this clinical trial, including possible risks and benefits and 
document the informed consent process in the subject’s chart.  Prior to entry into the study or 
initiation of any study-related procedures, the subject must read, sign and date the IRB/EC 
approved ICF.  The person executing the consent must also sign and date the final consent form 
page.  One or two signed originals of the ICF will be prepared, in accordance with applicable 
local requirements.  A signed original copy will be retained with the subject records, and either a 
copy of the signed original or the other signed original of the ICF will be given to the subject, in 
accordance with applicable local requirements. 
12.4 Source Documentation 
The Investigator must maintain adequate and accurate source documents upon which eCRFs for 
each subject are based.  These documents are to be separate and distinct from eCRFs, except for 
cases in which the Sponsor has predetermined that direct data entry into specified pages of the 
subject’s eCRF is appropriate.  The Investigator must allow access to the source documents by 
representatives of the Sponsor and regulatory authorities as needed.  These records should 
include detailed notes on: 


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• The date the subject entered the study, study protocol number, and name of the Sponsor. 
• The oral and written communication with the subject regarding the study treatment 
(including the risks and benefits of the study).  The date of informed consent must be 
recorded in the source documentation. 
• The subject’s medical history prior to participation in the study and evidence that the 
subject meets study eligibility requirements. 
• The subject’s basic identifying information, such as demographics, that link the subject’s 
source documents with the eCRFs. 
• The dates of all study-related subject visits. 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject. 
• The subject’s exposure to study treatment, and documentation of study treatment 
accountability. 
• All AEs. 
• The subject’s exposure to any concomitant therapy (including start and stop dates, route 
of administration, and dosage). 
• All relevant observations and data on the condition of the subject throughout the study. 
• The date when subject exited the study and a notation as whether the subject completed 
the study or was discontinued, including the reason for discontinuation. 
Upon request, the Investigator will provide the Sponsor with any required background data from 
the study documentation or clinic records.  This is particularly important when source documents 
are illegible or when errors in data transcription are suspected.  In case there are issues or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 
12.5 Electronic Case Report Forms 
All study data must be incorporated in the corresponding eCRFs which are designed for 
computer processing and analysis.  The Investigator will be responsible for recording all data in 
the eCRFs and must ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the Sponsor in the eCRF and in all required reports. 
Data from clinical laboratory reports, etc., will be incorporated into the eCRFs either by direct 
transcription into appropriate eCRF pages or by inclusion of photocopies of these reports with 
printouts of the appropriate eCRF pages and stored in the site’s Study Binder. 
If corrections are made following official final review and sign-off by the Investigator, the 
Investigator must be made aware of the changes and provide written acknowledgement. 
This study will be conducted in compliance with the regulations contained within 21 CFR 
Part 11, electronic records/electronic signatures regulations. 


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12.6 Retention of Study Records 
GCP regulations require that the Investigator retain all documentation related to this clinical trial 
for a period of 2 years after the approval of the NDA in the US (or Product License outside the 
US) for this drug or 2 years after the withdrawal of the IND.  These records include the protocol 
and copies of all documents submitted to the Sponsor or to government authorities, subject 
records (including signed ICFs, subject charts, eCRFs, and other source documents), IRB/EC 
approvals and correspondence, records of drug accountability, and all study communications, 
whether written, telephonic, or electronic.  None of the required documents will be destroyed or 
transferred to the control of another party without the written approval of the Sponsor.  
If the Investigator cannot guarantee the archiving requirement at the site for any or all of the 
documents, special arrangements must be made between the Investigator and the Sponsor to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the subject, appropriate copies will be made for storing outside of the study site. 
12.7 Monitoring the Study and Data Quality Assurance 
Representatives of the Sponsor (or designees) will contact the Investigator and his/her staff prior 
to the start of the trial to review the procedures to be followed in conducting the study and 
recording the findings, and to confirm the facility’s readiness to conduct the trial. 
It will be the monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study, to verify the adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them.  The monitor must have access to all study related reports and 
records needed to verify the entries on the eCRF.  The Investigator (or designee) must agree to 
cooperate with the monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved and agree to provide missing information and grant access to all 
study documentation. 
Every attempt must be made to follow the protocol, obtain and record all data requested for each 
subject at the specified times.  However, ethical reasons may warrant the failure to obtain and 
record certain data or to record data at the times specified.  If data is not recorded per protocol, 
the reasons must be clearly documented on the eCRF/records. 
Accurate and reliable data collection will be ensured by the verification of the eCRFs against the 
Investigator’s records by the monitor (source documentation verification).  Collected data will be 
entered into a computer database and subject to electronic and manual quality assurance 
procedures. 
The study data must be verifiable with the source data, which requires access to all original 
recordings, laboratory reports, product accountability records, including access to the subject 
electronic medical record, and source data must be made available for all study data.  Subjects 
must also allow access to their medical records.  They will be informed of this and must consent 
to permission by providing their signature on the ICF prior to enrollment. 
Representatives of the Sponsor (or designees) may audit the study periodically to ensure that all 
records are correct and complete.  The verification of the eCRF data must be by direct inspection 
of source documents. 


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12.8 Discontinuation of the Study 
The Sponsor reserves the right to discontinue this study for administrative reasons at any time. 
The trial may also be terminated prematurely if unexpected AEs occur or if the Investigator does 
not adhere to the protocol. 
12.9 Policy for Publications 
The detailed procedures for the review of publications are set out in the clinical trial agreement 
entered into with the Sponsor in connection with this study.  Results from the study shall not be 
made available to any third party by the Investigator or staff outside of the publication policy. 
13 
ETHICS 
13.1 Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB/EC as appropriate.  The IB may also be provided as 
required.  The Investigator must submit written approval from an IRB/EC to the Sponsor or a 
designee such as a Contract Research Organization (CRO) before the Investigator may initiate 
this study. 
The Principal Investigator is responsible for informing the IRB/EC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB/EC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the 
IRB/EC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  The Sponsor or the CRO will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/EC according to local regulations and guidelines. 
13.2 Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and applicable 
regulatory requirements. 
13.3 Written Informed Consent 
A properly executed, written informed consent document, in compliance with 21 CFR 50, the 
ICH guidelines, and relevant local regulatory requirements, will be obtained from each subject 
before the subject is enrolled into the study and before any study-related procedure is performed.  
Attention will be directed to the basic elements required for incorporation into the informed 
consent under US Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a]) and 
(21 CFR 50.25[b]). 
The informed consent document will be reviewed by the Sponsor or designee for inclusion of all 
required elements prior to submission to the IRB/EC.  The Sponsor must also review any 


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revisions to the approved informed consent document prior to submission to the IRB/EC.  The 
final IRB/EC-approved document must be provided to the Sponsor for regulatory purposes.  It is 
the responsibility of the Investigator, or a person designated by the Investigator, to obtain written 
informed consent from each subject (or the subject’s legally authorized representative) 
participating in the study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study.  In the case where the subject is unable to read the form, an 
impartial witness will be present during the entire informed consent discussion.  After the subject 
has orally consented to participate in the study, the witness’ signature on the form will attest that 
the information in the consent form was accurately explained and understood. 
A copy of the fully executed informed consent document must be provided to the subject or the 
subject’s legally authorized representative.  If applicable, it will be provided in a certified 
translation of the local language by the site under the guidance of the Investigator.  Signed 
informed consent documents must remain in each subject’s medical record and be made 
available for verification by the monitor at any time. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form will be reviewed and updated as necessary.  All subjects (including those who have 
already been treated with EYP-1901 during the study) will be informed of the new information 
and given a copy of the revised form to provide their consent in order to continue participation in 
the study. 


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14 
REFERENCES 
Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of 
patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):1480-
1487. 
Cohen MN, O’Shaughnessy D, Fisher K, et al. APEX: a phase II randomised clinical trial 
evaluating the safety and preliminary efficacy of oral X-82 to treat exudative age-related macular 
degeneration. Br J Ophthalmol. 2021;105(5):716-722. 
EYLEA® (aflibercept) prescribing information. Regeneron Pharmaceuticals, Inc. Tarrytown, NY. 
June 2021. 
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. 
Jackson TL, Boyer D, Brown DM, Chaudhry N, Elman M, et al. Oral tyrosine kinase inhibitor 
for neovascular age-related macular degeneration: a phase 1 dose-escalation study. JAMA 
Ophthalmol. 2017;135(7):761-767. 
LUCENTIS® (ranibizumab injection) prescribing information. Genentech, Inc. South San 
Francisco, CA. March 2018. 
Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmol. 1985;92:467-471. 
 
 
 


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APPENDIX 1: MEASUREMENT OF BCVA BY ETDRS 
Please refer to the BCVA Assessment Manual for the study. 






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Intraocular Pressure 
Intraocular pressure will be assessed by applanation tonometry (preferably, Goldmann) and 
should be measured before the slit lamp examination has been completed at all study visits and at 
the Day 1 visit , it should be measured at 10 (+/- 5) and 60 (+/- 10) minutes following the 
intravitreal injection (EYP-1901 or sham IVT injection).  If IOP measurements at any study time 
points are ≥30 mmHg, two additional measurements should be performed and IOP recorded as a 
mean of three measurements per eye.  All reasonable efforts should be made to have the same 
examiner obtain all IOP measurement for a given subject.  Measurement should be performed 
before dilated ophthalmoscopy. 


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APPENDIX 3: Pharmacokinetic Procedures and Analysis 
Please refer to the Laboratory Manual for the study. 


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APPENDIX 4: NCI CTCAE v5.0 
Adapted from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf  
 
 
 
 
 


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APPENDIX 5: Summary of Changes 
The following changes were made to Protocol EYP-1901-204 as Amendment 1: 
SECTION(S) 
CHANGE/RATIONALE 
Synopsis 
Section 2 
Section 3.1 
Section 3.4 
Section 5.1.7 
Table 5–1 Schedule of Assessments 
• 
End of study visit was changed from Week 96 to Week 48, which 
allows for a 48-week follow-up from EYP-1901 administration. 
• 
Removed aqueous humor testing  
 
Synopsis 
Section 2 
Section 10 
• 
The secondary endpoints were updated to reflect the new end of 
study at Week 48 instead of Week 96. 
Synopsis 
Section 3.2 
Section 5 
Section 10 
Section 11.3.6 
Section 11.4.4 
• 
Changed the unmasking of study data from Week 24 to Week 36. 
• 
Clarified only sponsor/CRO will be unmasked at Week 36 
Section 3.2.1 
• 
Renamed subsection as “Emergency Unmasking” for clarity. 
Section 4.3 
• 
Added “complete abstinence” as a highly effective method of birth 
control. 
Table 5–1 Schedule of Assessments 
• 
The Schedule of Assessments table was completely revised to 
reflect the change from Week 96 to Week 48 end of study visit. 
• 
The footnotes for Table 5-1 were also revised accordingly. 
• 
Removed aqueous humor testing 
Appendix 5:  Summary of Changes 
• 
Added Appendix 5 due to Amendment 1 changes. 
Throughout 
• 
Changed study week numbers accordingly to reflect the change in 
end of study visit week. 
• 
Miscellaneous typographical, abbreviations, and formatting issues 
were corrected, and some hyperlinks were fixed and/or added. 
 
 


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The following changes were made to Protocol EYP-1901-204 as Amendment 2 (Version 3.0) 
SECTION(S) 
CHANGE/RATIONALE 
Personnel contact information 
• 
Changed the drug safety physician name to current Director of 
Pharmacovigilance. 
Synopsis 
Section 3.1 
Section 4 
Section 11.1 
• 
Adjusted the sample size to 60 subjects (20 subjects per treatment 
arm) 
Section 1.5 
Section 14 
• 
Updated reference to Cohen et al. 2021. 
Section 4 
• 
Clarified the details regarding subject eligibility to assist 
Investigators when making decisions to reassess and rescreen 
subjects during the Screening Period 
Section 3.4 
Table 5–1 
Section 5.1.1 
• 
Increased the time of the Screening Visit to Day -30 to Day -5. 
Section 5.1 
Table 5–1 
Section 5.1.3 to 5.1.7 
• 
Increased the study visit window starting at Week 4 to Week 48 
from 5 to 7 days. 
Synopsis 
Section 10 
• 
Clarified that the primary and secondary endpoint assessments 
were specifically for the study eye (unless otherwise specified). 
Section 4.2 
• 
As summarized in Administrative Letter#1 (25May2022), 
corrected the inconsistency in the Exclusion Criteria numbering 
between the Synopsis section of the protocol and the body of the 
protocol in Section 4.2. The method of numbering the Exclusion 
Criteria for both sections of the protocol were numbered 
sequentially. 
Table 5–1 
Section 5.1.1 to Section 5.1.7 
• 
As summarized in Administrative Letter #2 (23June2022), updated 
the Schedule Procedures and Assessments to indicate that the 
intraocular pressure (IOP) measurements will be performed at all 
study visits. 
Section 7.1.1 
• 
As summarized in Administrative Letter #3 (10August2022), 
ocular adverse events was updated to define moderate or severe as 
Grade 2 and 3. Clarified the grading of ocular adverse events to 
provide consistency within the body protocol.  
Table 5–1, footnote “e” 
Appendix 2 
• 
As summarized in Administrative Letter #4 (04October2022), 
clarified the timing window for post-injection IOP at 10- and 
60-minutes. 
Section 6.6.4 
• 
As summarized in Administrative Letter #4 (04October2022), 
clarified that after Day 1, a subject may be administered standard 
of care treatment at the Principal Investigators discretion.  
Section 6.6.4 
• 
Removed the statement “treatment for the fellow eye is not 
covered by the Sponsor”. 
Synopsis 
Section 4.2 
• 
As summarized in Administrative Letter #4 (04October202), 
Exclusion Criteria #8 was split into two separate exclusion criteria. 
An additional Exclusion Criteria #9 was created to state “any 
documentation of more than 4 prior anti-VEGF intravitreal 
injections in the study eye”. 


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SECTION(S) 
CHANGE/RATIONALE 
Section 7 
• 
As summarized in Administrative Letter #5 (10January2023), 
removed the reference to safety review by a Drug Safety 
Committee (DSC). All safety reviews will be conducted by the 
Sponsor. 
Synopsis 
Section 4.2 
• 
Combined previous Exclusion Criteria #16 with #15 to provide 
clarity for those subjects who have undergone prior refractive or 
cataract surgery to create a new Exclusion Criteria #16. 
Synopsis 
Section 4.2 
• 
For Exclusion Criteria #33, added that subjects were excluded if 
any history of the stroke events within the past 2 years.  
Throughout 
• 
Miscellaneous typographical, abbreviations, and formatting issues 
were corrected, and some hyperlinks were fixed and/or added. 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 






Statistical Analysis Plan for Interventional Studies 
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204 
 
 
This document is confidential. 
SAP Text and Shells Version: 1.0, 12-Apr-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 4 of 53 
Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................. 3 
 
Glossary of Abbreviations ................................................................................................... 7 
 
Introduction ........................................................................................................................ 9 
 
Study Objectives .............................................................................................................. 10 
 
Study Details/Design ........................................................................................................ 11 
 
Endpoints ......................................................................................................................... 18 
 
Analysis Sets .................................................................................................................... 19 
 
Estimands ........................................................................................................................ 20 
 
General Aspects for Statistical Analysis ........................................................................... 21 


Statistical Analysis Plan for Interventional Studies 
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204 
 
 
This document is confidential. 
SAP Text and Shells Version: 1.0, 12-Apr-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 5 of 53 
 
Demographic, Other Baseline Characteristics and Medication ......................................... 25 
 
Efficacy ............................................................................................................................ 28 
 
Safety ............................................................................................................................... 33 
 
Pharmacokinetics ............................................................................................................. 37 


Statistical Analysis Plan for Interventional Studies 
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204 
 
 
This document is confidential. 
SAP Text and Shells Version: 1.0, 12-Apr-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 6 of 53 
 
Interim Analyses ............................................................................................................... 38 
 
Changes from Analyses Planned in Protocol .................................................................... 39 
 
Reference List .................................................................................................................. 40 
 
Programming Considerations ........................................................................................... 41 
 
Quality Control ................................................................................................................. 45 
 
Index of Tables ................................................................................................................. 46 
 
Index of Figures................................................................................................................ 51 
 
Index of Listings ............................................................................................................... 52 
 




 
Statistical Analysis Plan for Interventional Studies
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204
Abbreviation
n
Description
Number of subjects
NPDR
NVA
Nonproliferative Diabetic Retinopathy
Neovascularization of the angle
Neovascularization of the disc
Neovascularization everywhere
Neovascularization of the iris
New York Hospital Association
Oculus dexter (right eye)
NVD
NVE
NVI
NYHA
OD
OS
Oculus sinister (left eye)
OU
Oculus uterque (both eyes)
Potentially clinically significant
Potentially clinically significant change
Pharmacokinetic(s)
PCS
PCSC
PK
PP
Per Protocol Set
PRP
Pan-retinal photocoagulation
Preferred term
PT
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SD-OCT
SD-OCTA
SOC
TEAE
TFL
Spectral-domain – optical coherence tomography
Spectral-domain – optical coherence tomography angiography
System Organ Class
Treatment-emergent adverse event
Tables, figures, and listings
Vascular endothelial growth factor
Wet age-related macular degeneration
World Health Organization
Main metabolite of vorolanib
VEGF
wAMD
WHO
X-297
This document is confidential.
SAP Text and Shells Version: 1.0, 12-Apr-2024
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 8 of 53


Statistical Analysis Plan for Interventional Studies 
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204 
 
 
This document is confidential. 
SAP Text and Shells Version: 1.0, 12-Apr-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 9 of 53 
 
Introduction 
This document describes the planned analyses that will be used for the Study EYP-1901-204 clinical 
study report. This randomized, double-masked, parallel study is designed to assess the safety, efficacy, 
and pharmacokinetics (PK) of vorolanib intravitreal insert (EYP-1901) compared to sham for the 
improvement in subjects diagnosed with moderately severe to severe non-proliferative diabetic 
retinopathy (NPDR). The purpose of this statistical analysis plan (SAP) is to ensure that the tables, 
figures, and listings (TFLs) which will be produced, and that the statistical methodologies which will be 
used, are complete and appropriate to allow valid conclusions regarding the study objectives. This SAP is 
based on EYP-1901-204 Protocol Version 3 dated 31-Mar-2023. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and is responsible for the production and quality 
control of all TFLs. 
 
Timing of Final Analyses 
The final analysis of safety, efficacy, and/or PK is planned after all subjects complete the final study visit 
(Week 48) or terminate early from the study, and all data is entered, cleaned, and locked.  An unmasked, 
final, primary endpoint readout will take place after associated Week 36 data are entered and cleaned; 
only key individuals from sponsor and a specifically designated contract research organization team will 
be unmasked after the last subject completes the Week 36 visit. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204 
 
 
This document is confidential. 
SAP Text and Shells Version: 1.0, 12-Apr-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 10 of 53 
 
Study Objectives 
 
Primary Objective 
The primary objective is to assess the efficacy of EYP-1901 (vorolanib intravitreal [IVT] insert) compared to 
sham treatment in the improvement of moderately severe to severe NPDR.  
 
Secondary Objectives 
The secondary objectives are:  
 
To characterize the safety of EYP-1901 in subjects with moderately severe to severe NPDR. 
 
To determine if EYP-1901 will prevent the worsening of diabetic retinopathy and reduce the 
incidence of diabetic macular edema (DME). 
 
To evaluate the need for additional standard of care intervention due to ocular diabetic 
complications. 
 
To determine the anatomic effects of EYP-1901 in subjects with moderately severe to severe 
NPDR. 
 
To determine the systemic exposure to vorolanib and X-297, its main metabolite, measured 
through plasma levels up to Week 48. 


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Study Details/Design 
 
Brief Description 
This is a prospective, randomized, double-masked, multicenter study evaluating the ocular efficacy and 
safety of 2 different doses of the EYP-1901 IVT insert compared to sham in adult subjects with NPDR. 
Approximately 60 subjects will be randomized in a 1:1:1 ratio to each of three treatment arms (2060 μg 
EYP-1901, 3090 μg EYP-1901, or sham IVT injection) across approximately 30 sites in the United States, 
such that each treatment arm will include approximately 20 subjects.  
All subjects, irrespective of treatment arm, will receive an IVT injection on Day 1 in the designated study 
eye. Subjects in the EYP-1901 treatment arms will receive study treatment which is expected to deliver 
vorolanib into the vitreous humor for at least 9 months, while subjects in the sham treatment arm will 
receive a sham injection to maintain masking. Following study drug IVT injection on Day 1, subjects will 
return at Weeks 4, 12, 24, 36 and 48.  
For subjects with unilateral NPDR, the affected eye will be designated as the study eye; for subjects with 
bilateral NPDR, the study eye will be the more severely affected eye meeting the inclusion/exclusion 
criteria, ie, the eye having the worse Diabetic Retinopathy Severity Scale (DRSS) score or if equal, the 
eye clinically judged to be the more severely affected eye as determined by the Investigator. If the eyes 
are symmetrically affected, the study eye will be the right eye. The fellow eye will receive treatment as 
needed and according to the Investigator’s judgment.  
The study design including treatment and visit schedules is shown in Figure 1. 
Figure 1: Study Design 
 
 
Subject Selection 
Subjects will be enrolled in the study only if they meet all the following eligibility criteria; continued 
eligibility will be assessed again at treatment randomization on Day 1.   


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Inclusion Criteria 
Subjects will be considered eligible for participation in the study if all of the following inclusion criteria are 
satisfied: 
1. Men or women ≥18 years of age with type 1 or 2 diabetes mellitus. Participants must have a 
hemoglobin A1c (HbA1c) ≤12% (as confirmed by laboratory assessments obtained at the 
Screening Visit or by a documented laboratory report dated within 60 days prior to the Screening 
Visit).  
2. Study eye with moderately severe to severe NPDR (based on the DRSS levels 47 or 53), using 
standard 4-widefield digital stereoscopic fundus photographs confirmed by the central reading 
center (CRC), in whom pan-retinal photocoagulation (PRP) and anti-vascular endothelial growth 
factor (anti-VEGF) injections can be safely deferred for at least 6 months per the Investigator.   
3. Best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) 
letter score in the study eye of ≥69 letters (approximate Snellen equivalent of 20/40 or better).   
4. Able to understand, and willingness to sign, the informed consent and to provide access to 
personal health information via Health Insurance Portability and Accountability Act (HIPAA) 
authorization.  
5. Willingness and ability to comply with all scheduled visits, restrictions, and assessments.  
6. For women of childbearing potential, or men with female partners of childbearing potential, 
agreement to the use of an appropriate form of contraception for the duration of the study.  
   
 
Exclusion Criteria 
Subjects will be considered ineligible for participation in the study if any or all of the following exclusion 
criteria are satisfied: 
1. Presence of any active center involved-diabetic macular edema (CI-DME) in the study eye as 
determined by the Investigator on clinical examination, or within the central subfield thickness 
(CST) of the study eye as determined by spectral-domain – optical coherence tomography 
(SD-OCT) evaluated by the CRC, with a CST threshold greater than 320 microns. 
2. Evidence of retinal neovascularization on clinical examination or wide-field fluorescein 
angiography (FA).  
3. Any evidence or documented history of prior focal or grid laser photocoagulation or any PRP in 
the study eye in the last 12 months.  
4. Any evidence of optic nerve pallor on clinical examination in the study eye as determined by the 
Investigator.  
5. Any evidence of high-risk characteristics typically associated with vision loss in the study eye as 
determined by the Investigator.  
6. Any evidence of new vascularization anywhere (neovascularization of the iris [NVI], 
neovascularization of the angle [NVA], neovascularization everywhere [NVE], neovascularization 
of the disc [NVD]) on clinical examination as per the Investigator, or imaging evaluated by the 
CRC, in the study eye.  
7. Any prior systemic anti-VEGF treatment in the past 12 months.  
8. Any prior IVT anti-VEGF treatment in the past 12 months. 
9. Any documentation of more than 4 prior anti-VEGF IVT injections in the study eye.  
10. Any concurrent intraocular condition in the study eye (eg, cataract or glaucoma) that, in the 
opinion of the Investigator, would either require surgical intervention during the study to prevent 
or treat visual loss that might result from that condition or affect interpretation of the study results.  


 
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11. History of prior vitrectomy surgery in study eye.
12. Historical or active intraocular inflammation (grade trace or above) in the study eye, other than
expected findings from routine cataract surgery.
13. History of vitreous hemorrhage in the study eye within 12 weeks prior to the Screening Visit.
14. History of rhegmatogenous retinal detachment or treatment for retinal detachment or macular
hole (stage 3 or 4) in the study eye.
15. Aphakia or pseudophakia with the absence of the posterior capsule in the study eye (YAG
capsulotomy is permitted).
16. Spherical equivalent of the refractive error in the study eye demonstrating >8 diopters of myopia.
For subjects who have undergone prior refractive or cataract surgery in the study eye,
preoperative refractive error in the study eye exceeding 8 diopters of myopia.
17. Intraocular surgery (including cataract surgery) in the study eye within 12 weeks prior to the
Screening Visit.
18. Uncontrolled ocular hypertension or glaucoma in the study eye (defined as intraocular pressure
[IOP] >25 mmHg or a cup to disc ratio ≥0.8, despite treatment with 2 or more classes of
antiglaucoma medication) and any such condition which the Investigator feels may require a
glaucoma filtering surgery while in the study.
19. History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery in the study
eye.
20. History of corneal transplant in the study eye.
21. Any prior intraocular corticosteroid injection in the study eye in the past 12 months.
22. Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional retinal
detachment visible at the screening assessments in the study eye.
23. Prior participation in a clinical trial involving investigational anti-angiogenic drugs administered in
either eye or systemically within 8 weeks prior to the Screening Visit.
24. Prior participation in a clinical trial involving investigational ocular gene therapy for either eye.
25. History of idiopathic or autoimmune-associated uveitis in either eye.
26. Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye.
27. Presence of any other systemic or ocular condition which, in the judgment of the Investigator,
could make the subject inappropriate for entry into this study.
28. Uncontrolled blood pressure (defined as systolic >180 mmHg and/or diastolic >100 mmHg),
based on the average of 3 readings taken with the subject in a resting state.
29. Myocardial infarction within 6 months prior to screening or New York Hospital Association (NYHA)
Class III or IV heart failure, uncontrolled atrial fibrillation, uncontrolled angina, cardiomyopathy,
ventricular arrhythmias, or other cardiac conditions which, in the judgment of the Investigator,
could make the subject inappropriate for entry into this study.
30. Serious non-healing wound, ulcer, or bone fracture.
31. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory
finding giving reasonable suspicion of a disease or condition that contraindicates the use of EYP-
1901.
32. Current treatment for any active systemic infection.
33. Use of oral corticosteroids (prednisone >10 mg/day or equivalent) within 30 days prior to the
Screening Visit.
34. History or presence of bleeding disorders, including platelet disorders, hemorrhage, acquired or
hereditary coagulation disorders (including deep vein thrombosis and pulmonary embolisms),
acquired or hereditary vascular disorders, stroke, or transient ischemic attack in the past 2 years.
35. Excluding certain skin cancers (specifically, basal cell carcinoma and squamous cell carcinoma),
any malignancy receiving treatment, or in remission less than 5 years prior to study entry.
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36. History of allergy to fluorescein, not amenable to treatment.  
37. Inability to obtain fundus photographs, wide-field FA, fundus autofluorescence, or SD-OCT 
images of sufficient quality to be analyzed and graded by the CRC.  
38. Historical or active diagnosis of any medical or psychological condition that could interfere with 
the ability of the subject to give informed consent, or to comply with study or follow-up 
procedures.  
39. Previous participation in any ocular or non-ocular (systemic) disease studies of investigational 
drugs within 30 days prior to the Screening Visit (excluding vitamins and minerals).  
40. Use of anti-mitotic or anti-metabolite therapy within 30 days or 5 elimination half-lives of the 
Screening Visit, whichever is longer.  
41. Intolerance, contraindication, or hypersensitivity to topical anesthetics, dyes, povidone iodine, 
mydriatic medications, or any of the ingredients of the EYP-1901 insert.  
42. Requirement for continuous use of any protocol-prohibited medications or treatments.  
43. Pregnant or nursing females; females of childbearing potential who are unwilling to use an 
acceptable method of contraception during the study as outlined in this protocol.   
 
Determination of Sample Size 
The objectives of the study are to provide efficacy and safety data in a prospective, randomized, 
double-masked, controlled trial. However, the study is not formally powered to perform statistical 
hypothesis testing between each EYP-1901 arm versus sham IVT injection. Approximately 60 subjects 
will be randomized in a 1:1:1 ratio to each of 3 treatment arms (approximately 20 per treatment arm).   
 
Treatment Assignment and Masking 
This is a randomized, double-masked, parallel study. Subjects will be randomized to the 3 different 
treatment arms (2060 μg EYP-1901, 3090 μg EYP-1901, or sham IVT injection) in a 1:1:1 ratio. The 
randomization code will be generated with a computer program according to the study design, the 
number of subjects, and the number of treatment arms. The random allocation of each treatment to each 
subject will be done in such a way that the study is balanced. Randomization will occur on Day 1. 
Subjects, site staff, and the study team will be masked to treatment allocation during the study. The 
randomization code will be kept strictly confidential, accessible only to authorized personnel until the time 
of unmasking. 
Except for the Investigators administering the study treatments, masking will be maintained for both 
subjects and the Investigators conducting the study assessments. Sham IVT injections will be used 
during the study to maintain masking of investigational EYP-1901 therapy for study subjects. Only key 
individuals from sponsor/contract research organization team otherwise uninvolved in the study will be 
unmasked after the last subject completes the Week 36 visit to conduct endpoint analysis. 
In the event that an emergency unmasking is required, the assessing Investigator/medically qualified 
designee has the authority to unmask a subject’s treatment arm using the interactive voice/web response 
system (IXRS), or its back-up system if IXRS is not functioning. If possible, the assessing 
Investigator/medically qualified designee should contact the Medical Monitor or designee before breaking 
the mask. When the masked treatment code is broken, the date and time of unmasking, name of person 
doing the unmasking, and the reason for unmasking must be fully documented in the source 
documentation. 
The masking of the study will be broken after the database has been locked. 


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Administration of Study Medication 
EYP-1901 will be administered to the study eye by a single injection through the pars plana using a pre-
loaded applicator with a 22-gauge needle. Each EYP-1901 IVT insert has been designed to deliver 
vorolanib into the vitreous humor for at least 9 months. Sham injections will be used to maintain masking 
of investigational EYP-1901 therapy for study subjects. 
 
Study Procedures and Flowchart 
An overview of the scheduled visits and measurements to be conducted during the study and their timing 
is presented in Table 1. Further details of the assessments are available in the protocol. 
 
 
 
 
 






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Endpoints   
 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percentage of subjects improving ≥2 steps from baseline in the 
DRSS score in the study eye at Week 36 in each EYP-1901 dose level versus the sham IVT injection 
group.  
 
Secondary Efficacy Endpoints 
The secondary objectives will be assessed with the following secondary endpoints in each EYP-1901 
dose level versus the sham IVT injection group: 
 
Percentage of subjects improving ≥2 steps from baseline in the DRSS score in the study eye at 
Weeks 24 and 48 in each EYP-1901 dose level versus the sham IVT injection group.  
 
Percentage of subjects improving ≥2 steps or ≥3 steps over time in DRSS score in the study eye 
from baseline. 
 
Percentage of subjects worsening ≥2 steps or ≥3 steps over time in DRSS score in the study eye 
from baseline. 
 
Percentage of subjects who developed a vision-threatening complication due to diabetic 
retinopathy in the study eye at Weeks 24, 36, and 48. 
 
Percentage of subjects who developed CI-DME in the study eye at Weeks 24, 36, and 48. 
 
Time to develop any neovascular vision threatening complication (PDR/ASNV) in the study eye 
through Weeks 24, 36, and 48.  
 
Time to develop CI-DME in the study eye through Weeks 24, 36, and 48. 
 
Percentage of subjects who received anti-VEGF or additional standard of care intervention due to 
ocular diabetic complications in the study eye at Weeks 24, 36, and 48.  
 
Percentage of subjects who received PRP in the study eye, inclusive of subjects undergoing 
vitrectomy with endolaser, at Weeks 24, 36, and 48.  
 
Area under the curve (AUC) for change from baseline in BCVA in the study eye at Weeks 24, 36, 
and 48.  
 
Pharmacokinetic Endpoints 
The PK endpoints are systemic exposure to vorolanib and X-297, its main metabolite, measured through 
plasma levels up to Weeks 24, 36, and 48.  
 
Safety Endpoints 
The safety endpoints are the rates of ocular (study eye and non-study eye) and non-ocular TEAEs at 
Weeks 24, 36, and 48. 


Statistical Analysis Plan for Interventional Studies 
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Analysis Sets 
 
Screened Set 
The Screened Set will include all subjects screened (who have signed informed consent). 
 
Full Analysis Set 
The Full Analysis Set (FAS) will include all subjects who received study treatment (EYP-1901 or sham).  
Subjects will be assigned according to the treatment to which they were randomized. FAS will be used to 
summarize efficacy, demographic, and baseline data.   
 
Per Protocol Set 
The Per-protocol (PP) Set will include all subjects who received study treatment (EYP-1901 or sham), 
continue until at least Week 36 (i.e., have had the primary endpoint assessed), and have no major 
protocol deviation(s) that would significantly impact the primary endpoint. Subjects will be assigned 
according to the treatment actually received. PP will be used to summarize the primary efficacy endpoint 
as sensitivity analysis.  
 
Safety Set 
The Safety Set will include all subjects who received study treatment (EYP-1901 or sham). Subjects will 
be assigned according to treatment actually received. The Safety Set will be used to summarize 
treatment exposure and safety data. 
 
Pharmacokinetic Set  
The PK Set will include all subjects in the Safety Set for whom at least 1 evaluable PK sample is 
available. 
 
 


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Estimands 
No estimands were defined within the protocol of this study. 


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General Aspects for Statistical Analysis 
 
General Methods 
 All analysis and summary outputs will be generated using SAS® version 9.4 or higher. 
 Ocular data for both eyes are collected for each subject, but only 1 eye is identified as the study 
eye. Details regarding the presentation of individual analyses, that is, for study eye, non-study eye, 
or non-ocular, will be described in the relevant sections of this SAP as applicable. 
 Continuous variables will be summarized using the number of subjects (n), mean, median, 
standard deviation (SD), minimum (min), and maximum (max). 
 Categorical variables will be summarized using n and percentages of subjects. 
 Time to event variables will be summarized using number and percentage of subjects with the 
event and censored and estimates of percentiles. 
 All screened subjects will be included in subject data listings. Listings will be sorted by treatment 
arm, site, subject number, and date and time of assessment. 
 Unscheduled visit data will be listed but not included in the by-visit summary tables, unless 
otherwise selected for analysis after application of visit windows (see Section 8.4). 
 
Key Definitions 
Baseline measurements are defined as the last non-missing measure prior to the initiation of study 
treatment, likely assessed at Screening or Day 1, but available unscheduled assessments will also be 
considered.  
Study Day 1 will be the date on which study treatment is administered. Positive study days will be 
counted forward from Study Day 1, and negative study days will be counted backward from Study Day 1, 
beginning with Study Day -1.  There will be no Study Day 0.  
 
Missing Data 
In general, missing data will not be imputed, unless otherwise specified. Every effort will be made to 
ensure completeness of data collection. 
 
Medication Dates 
A partial/missing start date recorded on the Prior and Concomitant Medications case report form (CRF) 
will be handled as follows: 
 
If only the day is missing, and the month and year match the month and year of study drug 
administration date, then the day of the study drug administration date will be imputed. Otherwise, 
the first of the month will be used. 
 
If both the day and month are missing, and the year matches the year of the study drug 
administration date, then the month and the day of the study drug administration date will be 
imputed. Otherwise, 01 January will be used. 
 
If the start date is completely missing, the study drug administration date will be imputed, unless 
the stop date is prior to the study drug administration date, then the stop date of the medication will 
be imputed and the medication will be considered to be a prior medication. 




 
Statistical Analysis Plan for Interventional Studies
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Visit windows to be used for endpoints not collected at every visit are presented in Table 3, Table 4, and
Table 5.
Table 3: Visit Windows for Wide-field Fluorescein Angiography
Target
Study Day
-21 to -5
168
Time
Window
NA
± 5 days
± 5 days
± 5 days
Visit
Visit Windows for Analysis
Screening
Week 24
Week 36
Week 48
Study Days 2 to 210
Study Days 211 to 294
Study Days 295 to 350
252
336
Table 4: Visit Windows for Spectral-Domain – Optical Coherence Tomography Angiography (SD-
OCTA)
Target
Study Day
-21 to -5
168
Time
Window
NA
± 5 days
± 5 days
Visit
Visit Windows for Analysis
Screening
Week 24
Week 48
Study Days 2 to 252
Study Days 253 to 350
336
Table 5: Visit Windows for Clinical Laboratory Evaluations and PK
Target
Study Day
-21 to -5
1
Time
Window
NA
Visit
Visit Windows for Analysis
Screening (labs only)
Day 1 (PK only)
Week 12
Week 24
Week 36
NA
84
168
252
336
± 5 days
± 5 days
± 5 days
± 5 days
Study Days 2 to 126
Study Days 127 to 210
Study Days 211 to 294
Study Days 295 to 350
Week 48
Unscheduled and early termination visits will be associated with a visit according to the visit windows for
analysis. Once visits are assigned for analysis, records will be flagged for analysis according to the
following rules (in order):


If a record is available for the scheduled visit, it will be used for analysis.
If no record is available for the scheduled visit, the available windowed record will be used for
analysis.
o
If more than 1 windowed record is available, the record closest to the target study day will
be used for analysis.
o
If 2 windowed records are equidistant from the target study day, the windowed record
after the target study day will be used.
Electrocardiogram (12-lead) and urine pregnancy data will be summarized at baseline and Week 48 / end
of treatment using only nominal visit designators (no visit windows defined).
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Statistical Analysis Plan for Interventional Studies 
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Pooling of Centers 
No by-center analyses are planned. 
 
Subgroups 
Planned subgroup analyses are detailed in Section 10.1.  
 
Multiple Comparisons and Multiplicity 
Not applicable. 
 
Adjustment for Covariates 
Secondary efficacy endpoints will include baseline value as a covariate, when applicable. 
 


Statistical Analysis Plan for Interventional Studies 
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Demographic, Other Baseline Characteristics and Medication 
 
Subject Disposition and Withdrawals 
Subject disposition and withdrawals from the study will be summarized for all subjects in the Screened 
Set and by treatment arm (for treated subjects) and overall to include the following: 
 
Number of subjects screened 
 
Number of screen failure subjects and primary reason for screen failure  
 
Number of subjects randomized  
 
Number (%) of randomized subjects in the FAS, PP Set, Safety Set, and PK Set 
 
Number (%) of subjects completing Week 36 
 
Number (%) of subjects who discontinued the study at or prior to Week 36 and primary reason for 
study discontinuation 
 
Number (%) of subjects completing the study 
 
Number (%) of subjects who discontinued the study early and primary reason for study 
discontinuation 
A subject is considered to have completed the study if on the eCRF they have a date of completion and 
have no reason for study discontinuation reported. 
 
Protocol Deviations 
Protocol deviations may be identified during visits (via source data verification, for example) or after the 
fact, such as the site’s reply to a data query that confirms that the protocol was not followed. For this 
project, collection of protocol deviations will be managed in the Medidata Clinical Trial Management 
System (CTMS) by the Site Monitor or Central Monitor during site visits or contacts. Protocol deviations 
will be reviewed by the Syneos Health team and the Sponsor, classified as major or minor deviations, and 
a list generated of subjects with significant deviations who are to be excluded from the Per-protocol 
Analysis Set; this list will be finalized and approved prior to database lock. 
All protocol deviations, including COVID-19 related, will be listed by subject for the Safety Set.  
Major protocol deviations will be summarized by treatment arm and overall for the FAS using counts and 
percentages of subjects.   
 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the FAS by treatment arm and overall. 
The following demographic variables will be listed and summarized: 
 
Age in years at screening  
o 
<40 years; 40 to <65 years; ≥65 years 
Age in years at screening will be computed using SAS code similar to the following: 
floor(YRDIF(<date of birth variable>, screen date, "AGE")) 
 
Sex (Male, Female) 


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 
Child-bearing potential (Yes, No). If child bearing potential is ”No”, then reason will be 
summarized (surgically sterile, post-menopausal, other) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)   
 
Race (Asian, Black, White, American Indian or Alaska Native, Native Hawaiian or Other Pacific 
Islander, Other, Unknown) 
 
Study Eye (OD, OS) 
The following baseline characteristics will be listed and summarized: 
 
Baseline DRSS score in the study eye (43, moderate NPDR; 47, moderately severe NPDR; 53, 
severe NPDR)  
 
Baseline DRSS score in the study eye, categorical (≤47, ≥53) 
 
Baseline HbA1c 
o 
≤8%; >8% 
 
Diabetes diagnosis to randomization (years) 
 
Baseline BCVA ETDRS letter score in the study eye 
o 
≤55 letters; 56 – 70 letters; ≥71 letters  
 
Baseline CST in the study eye 
o 
≤300 µm; >300 µm 
 
Number of anti-VEGF injections in the study eye prior to screening 
o 
0 injections; 1 to 4 injections   
 
Time since diagnosis of NPDR in years at Screening in the study eye 
o 
Medical history terms, mapped and/or reported verbatim terms, will be examined by masked 
team members to identify those indicating NPDR, and the identified list will be logged in the 
programming specifications. The start date of earliest occurrence from amongst the identified 
events will be the NPDR diagnosis date and the time since diagnosis at screening will be 
calculated as screening date minus NPDR diagnosis date, plus 1. If the NPDR diagnosis date 
is missing only the day, the day will be set to 1, and if the NPDR diagnosis date is missing 
month and day (but not year), the month and day will be set to January 1. 
Summaries will be using both categorical and continuous descriptive statistics, as detailed in Section 8.1. 
Unless otherwise specified, percentages will be calculated based on the n in the respective population. 
 
Medical History 
Medical history (inclusive of medical, surgical, and ophthalmic history) will be coded using the most recent 
version of Medical Dictionary for Regulatory Activities (MedDRA) version 25.0 or higher. Incidence of 
ocular medical history for the study eye, ocular medical history for the non-study eye, and non-ocular 
medical history will be separately summarized by system organ class (SOC) and preferred term (PT) for 
the Safety Set by treatment arm and overall. Incidence of medical conditions will be presented 
alphabetically by SOC and then within each SOC, alphabetically by PT for the overall column.  


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Prior and Concomitant Medications 
Medications will be coded using the most recent version of the World Health Organization Drug Dictionary 
(Global B3 September 2021 Version). Missing medication dates will be handled as described in Section 
8.3.1. Anti-VEGF medications will be identified via review of standardized medication terms and flagged 
in the data. 
Start date and stop date for medications, in conjunction with the ongoing indicator, from the eCRF will be 
used to determine whether medication is prior or concomitant.  
Prior medication will be defined as all medications recorded on the “Concomitant Medication” CRF taken 
prior to study drug administration, whether continuing or not.  
Concomitant medications will be defined as medications that are ongoing at study treatment 
administration or started on or after study treatment administration. 
The number and percentage of subjects by treatment arm and overall in the Safety Set for prior 
medication (ocular study-eye, ocular non-study eye, and non-ocular summarized separately) and 
concomitant medication (ocular study eye, ocular non-study eye, and non-ocular summarized separately) 
will be summarized by Anatomical Therapeutic Chemical (ATC) level 2 and PT. They will be presented by 
descending overall count of ATC and within each ATC, by descending overall count of PT. Subjects will 
be counted only once for each ATC and PT if they have multiple records of the same ATC or PT in the 
database. 
Prior to database lock, the sponsor will conduct a masked data review of medications to determine if any 
are classified as prohibited medications per the protocol; prohibited medications (if any) will be flagged in 
the prior and concomitant medication listings.    
 
Study Drug Exposure 
The number and percentage of randomized subjects who had study drug administered and who did not 
have study drug administered (overall and broken out by adverse event and other reason) will be 
summarized by treatment group and overall.  The number and percentage of subjects to whom study 
drug was administered who had and did not have clinically significant signs/symptoms observed following 
injection will also be summarized by treatment group and overall. 
Study drug exposure data will be presented in a data listing, including information as to whether the study 
drug IVT was administered, the date and time of the administration, and any clinically significant 
signs/symptoms observed. 


Statistical Analysis Plan for Interventional Studies 
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Efficacy 
All efficacy endpoints will be summarized descriptively by treatment arm and for EYP-1901 overall for the 
FAS; summarization and analyses will be repeated for the PP Set as sensitivity analyses. For continuous 
endpoints, n, mean, SD, median, min, and max will be presented. For categorical endpoints, numbers 
and percentages will be presented. The 95% confidence interval (CI) of the proportions will be 
constructed, as appropriate. 
 
 
 
 
 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is the percentage of subjects improving ≥2 steps from baseline in the 
DRSS score at Week 36 in the study eye.  The percentage of subjects improving ≥2 steps from baseline 
in the DRSS score will be summarized descriptively using counts and percentages of subjects by 
randomized treatment arm at each scheduled visit (Weeks 4, 12, 24, 36, and 48) and the corresponding 
95% Clopper-Pearson CI will be presented for each treatment group.  
 
 
 
 
Subgroup Analysis 
The summarization and analyses (not plots) of the primary efficacy endpoint will be repeated for FAS for 
the following subgroups: 
 
Age at screening (<40 years; 40 to <65 years; ≥65 years) 
 
Sex (male, female) 
 
Baseline DRSS score in the study eye of 43 (moderate NPDR), 47 (moderately severe NPDR), 
and 53 (severe NPDR) 
 
Baseline DRSS score in the study eye, categorical (≤47, ≥53) 
 
Baseline BCVA ETDRS letter score in the study eye  
o 
≤ median; > median 
o 
≤55 letters; 56 to 70 letters; ≥71 letters 
 
Baseline CST in the study eye 
o 
≤300 microns 
o 
>300 microns 
 
Number of anti-VEGF injections in the study eye prior to screening 
o 
0 injections 
o 
1-4 injections 
 
Baseline HbA1c (≤8%; >8%) 
PPD
PPD


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 
Years from NPDR diagnosis to screening 
o 
≤ median; > median 
o 
≤2 years; >2 to 4 years; >4 years 
 
Secondary Efficacy Endpoint Analyses 
Response Endpoints 
The analysis and summarization performed for the primary endpoint (Section 10.1) will be repeated for 
the following secondary efficacy endpoints.  
 
Percentage of subjects improving ≥2 steps from baseline in the DRSS score in the study eye at 
Weeks 24 and 48.  
 
Percentage of subjects improving ≥2 steps from baseline in the DRSS score in the study eye at 
each timepoint (remaining timepoints apart from Weeks 24, 36, and 48) 
 
Percentage of subjects worsening ≥2 steps from baseline in the DRSS score in the study eye at 
each timepoint 
 
Percentage of subjects improving ≥3 steps from baseline in the DRSS score in the study eye at 
each timepoint 
 
Percentage of subjects worsening ≥3 steps from baseline in the DRSS score in the study eye at 
each timepoint 
 
Percentage of subjects who developed a vision-threatening complication due to diabetic 
retinopathy in the study eye through Week 24, through Week 36, and through Week 48. 
Vision threatening complications due to diabetic retinopathy will be indicated by the presence of 
“Vitreous hemorrhage” or the presence of “Tractional retinal detachment” reported on the Ocular 
Examination – Dilated Ophthalmoscopy CRF (proliferative diabetic retinopathy [PDR] events, and 
“Neovascularization for the Iris” answered as “Yes” or “Neovascularization for the Angle” 
answered as “Yes” per the Ocular Examination - Slit Lamp Biomicroscopy CRF (anterior segment 
neovascularization [ASNV] events).  
Summarization and analyses will be repeated for the following subgroups – baseline DRSS in the 
study eye of 43 (moderate NPDR), 47 (moderately severe NPDR), and 53 (severe NPDR), and 
baseline DRSS score in the study eye, categorical (≤47, ≥53). 
PPD


 
Statistical Analysis Plan for Interventional Studies
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
Percentage of subjects who developed CI-DME in the study eye through Week 24, through Week
36, and through Week 48.
The occurrence of a CI-DME event in the study eye will be identified via examination of centrally
read custom algorithm CST data and adverse events. For the CST data at any given time point, if
results are available for no more than 2 raters, the average value will be used, and if results are
available for three raters, the median value will be used. CI-DME will have occurred when an
adverse event occurs which has a mapped preferred term of ‘Cystoid macular oedema', 'Diabetic
retinal oedema', or 'Macular oedema', for which the temporally closest CST measurement is
greater than or equal to 320 microns.
Two additional endpoints will also be summarized.
o
o
Macular edema (Definition 1) will have occurred when an adverse event occurs which
has a mapped preferred term of ‘Cystoid macular oedema', 'Diabetic retinal oedema', or
'Macular oedema'.
Macular edema (Definition 2) will have occurred when an adverse event occurs which
has a mapped preferred term of ‘Cystoid macular oedema', 'Diabetic retinal oedema', or
'Macular oedema', and which has treatment with a concomitant medication with a
mapped preferred term of ‘aflibercept’, ‘ranibizumab’, ‘bevacizumab’, or ‘faricimab’.

Percentage of subjects who received anti-VEGF or additional standard of care intervention due to
ocular diabetic complications in the study eye through Week 24, through Week 36, and through
Week 48.
Anti-VEGF use is identified in reported concomitant medication data as those medications with
ATC code ‘S01LA’.
Unique mapped concomitant medication and procedure terms and associated information will be
reviewed by masked ophthalmology team members to identify those mapped concomitant
medication and procedure terms that indicate the use of additional standard of care intervention
due to ocular diabetic complications.

Percentage of subjects who received PRP in the study eye, inclusive of subjects undergoing
vitrectomy with endo-laser, through Week 24, through Week 36, and through Week 48.
Unique mapped procedure terms and associated information will be reviewed by masked
ophthalmology team members to identify those mapped procedure terms that indicate receipt of
PRP.
Time to Event Endpoints
Time (in weeks) to develop any vision threatening complication (PDR/ASNV) in the study eye through a
particular time point (Week 24, Week 36, or Week 48) will be computed as the earliest date of a vision
threatening complication in the study eye prior to the particular time point minus the date of study drug
administration, plus 1 day, divided by 7 days per week. For subjects not experiencing a vision
threatening complication in the study eye prior to the particular time point of interest, the subject will be
censored at their date of discontinuation from the study (if prior to the time point of interest) or at the time
point of interest.
Time (in weeks) to develop a CI-DME in the study eye, macular edema in the study eye per Definition 1,
and macular edema in the study eye per Definition 2 will be computed in a similar manner.
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Statistical Analysis Plan for Interventional Studies
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204
Each time to event endpoint will be summarized with the number and percentage of subjects who
experienced the endpoint, number and percentage of subjects who were censored, and Kaplan-Meier
estimates of median and first and third quartiles. The EYP-1901 treatment arms will be compared to the
sham IVT group using a log-rank test. A corresponding Kaplan-Meier plot will be prepared for the FAS
only.
Area Under the Curve Endpoint
Observed BCVA values, change from baseline to each follow-up visit, and area under the curve (AUC) for
change from baseline in BCVA through Week 24, Week 36, and Week 48 will be summarized
descriptively. AUC through each time point of interest will be computed using the trapezoidal rule
normalized to months, with a final unit of letters. Mean AUC for change from baseline in BCVA through
Week 24, Week 36, and Week 48 will be compared between each active treatment arm and sham IVT
using analysis of covariance (ANCOVA) with treatment arm as the main effect and baseline BCVA as a
covariate. A plot of mean change from baseline in BCVA score over time will be prepared for the FAS.
Change from Baseline in DRSS Step
DRSS scores (not including indeterminate results) will be coded to numeric values for change in step
analysis as indicated in Table 6.
Table 6: Mapping of DRSS Scores to Numeric Steps
Coded
DRSS
Score
10
Numeric
Step
0
20
1
35
2
43
3
47
4
53
5
61
6
65
7
71
8
75
9
85
10
The coded numeric values represent whole steps on the DRSS, where Step 0 is no diabetic retinopathy
and Step 10 is advanced proliferative diabetic retinopathy. Baseline is defined as the last non-missing
DRSS measurement prior to the initiation of study treatment. Change from baseline is computed as
follow-up step minus baseline step; a negative change indicates improvement in disease and a positive
change indicates worsening of disease.
Observed values and change from baseline will be summarized descriptively by treatment group for the
full analysis set.
The SAS MIXED procedure (MMRM) will be used with the REPEATED statement for visits with an
unstructured covariance structure and a RANDOM statement set at the subject level. The model will
include change from baseline at each visit as the dependent variable and fixed effects for treatment and
visit and the interaction between treatment and visit, and baseline DRSS step as a covariate. The
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. If there is a
convergence issue (lack of convergence in general, or convergence with a non-positive definite estimated
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Statistical Analysis Plan for Interventional Studies
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204
G-matrix or non-positive definite Hessian matrix) with the unstructured covariance structure, a Toeplitz or
Autoregressive (1) [AR(1)] covariance structure will be used, following this sequence, until convergence is
achieved. If the model still does not converge, no results will be reported. Model-based point estimates
(i.e., least squares means and least squares mean differences, 80%, 85%, 90%, 95%, and 97.5% CI, and
p-values) will be reported at each visit.
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Statistical Analysis Plan for Interventional Studies 
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Safety 
Safety assessments will include the incidence and severity of TEAEs, clinical laboratory evaluations 
(hematology, chemistry, coagulation, and urinalysis), vital sign measurements, ECGs, IOP 
measurements, and safety data collected from ocular examinations. Safety analyses will be based on the 
Safety Set. 
 
Adverse Events 
All AEs will be coded using the most recent version of MedDRA, version 25.0 or higher, and will be 
presented in the following data listings by SOC and PT for each subject. 
 
All AEs 
 
Ocular AEs 
 
AEs related to study treatment 
 
Serious adverse events (SAEs) 
 
SAEs related to study treatment  
 
AEs with an outcome of death 
 
AEs leading to study treatment discontinuation 
 
AEs leading to study withdrawal 
Treatment-emergent adverse events (TEAEs) are AEs that began on or after the date of study treatment 
administration. Missing/incomplete start or stop dates associated with an adverse event (AE) will be 
handled as per Section 8.3.2 to determine whether an AE is a TEAE. The following categories of TEAEs 
will be summarized by treatment arm and overall for the Safety Set using count and percentage of unique 
subjects experiencing a TEAE and number of events for each TEAE by SOC and PT. An overall summary 
table will also be produced to summarize the following categories of TEAEs. 
 
All TEAEs 
 
TEAEs related to study treatment 
 
Serious TEAEs 
 
Serious TEAEs related to study treatment 
 
TEAEs by maximum severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life/sight-
threatening [Grade 4], death [Grade 5]), total number of events at each severity summarized  
 
TEAEs by worst relationship (not related, possibly related, probably related), total number of 
events at each relationship summarized 
 
TEAEs leading to study treatment discontinuation 
 
TEAEs leading to study withdrawal 
Summaries will be presented separately by location of the TEAEs (ocular in study eye, ocular in non-
study eye, and non-ocular), and will be sorted by overall descending count of SOC and then, within a 
SOC, by overall descending count of PT. Subjects will only be counted once if they experience multiple 
events under the same SOC or PT, and at the maximum severity or worst relationship, as applicable.  


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Summaries by SOC and PT (not by maximum severity or worst relationship) will also include a 
summarization of the number and percentage of subjects with more than 1 TEAE. 
Summaries of TEAEs (ocular in study eye, ocular in non-study eye, and non-ocular) by PT only will be 
presented by treatment arm and overall, sorted by overall descending count of PT. Subjects will only be 
counted once if they experience multiple events under the same PT.   
 
 Laboratory Evaluations 
All statistical analyses of laboratory values will be performed using SI units.  
Some numeric lab values may be reported as ‘<n.n’ or ‘>n.n’; these will be analyzed in the summary 
statistics as n.n/2 and n.n, respectively. For example, triglycerides recorded as <0.50 mmol/L would be 
summarized as 0.25 mmol/L and potassium recorded as >6.0 mmol/L would be summarized as 
6.0 mmol/L. 
Continuous hematology including coagulation, HbA1c, chemistry, and urinalysis results (raw and change 
from baseline) will be summarized by actual treatment arm and overall at each scheduled visit for the 
Safety Set. Categorical urinalysis results will be summarized by frequencies and percentages at each 
scheduled visit for the Safety Set. The number and percentage of subjects with shift changes from 
baseline based on the laboratory normal ranges provided by the laboratory will be tabulated at each 
scheduled visit. 
Hematology including coagulation, chemistry, and urinalysis data will be listed with the values outside the 
normal ranges flagged. Pregnancy test results will be listed but not summarized. 
 
Vital Signs  
Vital signs will include pulse rate, respiration rate, body temperature, and systolic and diastolic blood 
pressure; the average of 3 readings will be taken in a resting state and reported on the eCRF. Vital sign 
results (systolic and diastolic blood pressure [mmHg], pulse rate [beats/min], body temperature [C], and 
respiration rate [breaths/min]) and changes from baseline will be summarized by scheduled visit and by 
treatment arm and overall for the Safety Set.  
Potentially clinically significant (PCS) values will be identified for vital sign parameters as outlined in 
Table 6; these values will be summarized by scheduled visit and by treatment arm and overall for the 
Safety Set. Any vital sign results considered clinically significant by the investigator will be captured as 
adverse events. 
Vital sign results will be listed by subject and timing of collection. 
Table 6:  Potentially Clinically Significant Values for Vital Sign Parameters 
Vital Sign 
Units 
Criteria for PCS Values 
(Observed values) 
Criteria for PCSC values 
(Change from Baseline values) 
 
 
High  
Low  
Increase  
Decrease  
Systolic Blood Pressure  
mmHg  >180 
<90  
≥30 
≥30 
Diastolic Blood pressure  mmHg  >110 
<50  
≥20 
≥20  
 
 
Electrocardiograms 
For each ECG measurement (heart rate and PR, QRS, QT, and QTcF intervals), the observed value at 
each scheduled visit and change from baseline at each scheduled visit will be summarized by treatment 
arm and overall for the Safety Set.  


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In addition, the number and percentage of subjects with PCS and potentially clinically significant change 
(PCSC) values will be summarized by scheduled visit and for any time post-baseline, by treatment arm 
and overall for the Safety Set. PCS and PCSC values will be identified for ECG parameters as outlined in 
Table 7.  
A shift table of overall ECG interpretation from baseline to scheduled post-baseline visits will be 
presented for the categories ‘Normal’ and ‘Abnormal’. The shift table will be presented by visit and 
treatment arms.  
Clinically significant abnormal findings will be reported as adverse events. The values of each ECG 
parameter will be listed by subject.  
Table 7:  Potentially Clinically Significant Values for QTcF 
 
Units 
Criteria for PCS Values 
(Observed Values) 
Criteria for PCSC Values 
(Change from Baseline) 
 
High 
Low 
Increase 
Decrease 
msec 
≤ 450 msec 
> 450 msec and ≤480 msec 
> 480 msec and ≤500 msec 
> 500 msec 
NA 
≤ 30 msec 
> 30 msec and ≤ 60 msec 
> 60 msec 
NA 
 
 
Intraocular Pressure Measurement 
For IOP, the observed value at each scheduled visit and change from baseline at each scheduled visit will 
be summarized descriptively by treatment arm and overall for the Safety Set, for study eye and non-study 
eye.  This summarization will include the number and percentage of subjects at each visit with observed 
IOP ≤25 mmHg and >25 mmHg, and the number and percentage of subjects with change from baseline 
≤10 mmHg and >10 mmHg. 
The IOP data will also be listed by subject. 
 
Ocular Examinations 
The observed values of categorical dilated ophthalmoscopy and slit lamp biomicroscopy parameters at 
each scheduled visit will be summarized by treatment arm and overall for the Safety Set for study eye and 
non-study eye. The ocular examination parameters will also be listed by subject.  
SD-OCT, SD-OCTA, and color fundus data will be presented in data listings. 
 
Best Corrected Visual Acuity 
Observed BCVA values and change from baseline to each follow-up visit are to be summarized 
descriptively (n, mean, SD, median, min, and max) for the FAS (identical to the Safety Set) by treatment 
arm and overall for the study eye and non-study eye as part of the efficacy analysis (Section 10.2). 
The following endpoints will be summarized descriptively for the Safety Set by treatment arm and overall 
for the study eye using counts and percentages of participants at each scheduled visit and a 
corresponding 95% Clopper-Pearson CI for proportion with response by treatment group. The difference 
in the proportion of subjects with the desired response will be presented for each active treatment arm 
minus sham IVT, and the corresponding 95% Chan-Zhang CI presented. 
 
Proportion of subjects with ≥5 BCVA letter loss 
 
Proportion of subjects with ≥5 BCVA letter gain 


 
Statistical Analysis Plan for Interventional Studies
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



Proportion of subjects with ≥10 BCVA letter loss
Proportion of subjects with ≥10 BCVA letter gain
Proportion of subjects with ≥15 BCVA letter loss
Proportion of subjects with ≥15 BCVA letter gain
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Statistical Analysis Plan for Interventional Studies 
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Pharmacokinetics 
 
Pharmacokinetic Endpoints 
The PK endpoint is systemic exposure to vorolanib and X-297, its main metabolite, measured through 
plasma levels up to Weeks 24, 36, and 48.  
 
Pharmacokinetic Sampling 
The plasma samples will be collected at Day 1, Weeks 12, 24, 36, and 48, and any early termination visit.  
 
Data Presentation  
Descriptive statistics of plasma concentrations by treatment arm will be presented for the PK Set; when 
calculating drug concentration descriptive statistics, values below the limit of quantification (BLQ) will be 
considered zero. Plasma concentration data will also be listed. The following plots, for the study drug 
vorolanib and X-297, its main metabolite, will be prepared. 
 
Linear and log-linear scale of mean (±SD) plasma concentrations versus scheduled time points.  
 
Linear and log-linear scale spaghetti plots of individual subject plasma concentrations versus 
actual time points by dose level 


Statistical Analysis Plan for Interventional Studies 
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Interim Analyses 
No interim analyses are planned for this study prior to the primary endpoint readout at Week 36. A final 
analysis of the primary efficacy endpoint will take place at Week 36 prior to the end of the study, once all 
subjects have completed Week 36 or discontinued early and all necessary data have been cleaned and 
finalized.  A data snapshot will be taken and Study Data Tabulation Model (SDTM) and Analysis Data 
Model (ADaM) datasets and necessary tables, figures, and listings will be generated and quality checked 
in a masked manner. Once the masked data and outputs are reviewed and approved by the masked 
sponsor team, the programming system will be transferred to an unmasked biostatistics team at Syneos 
Health, who will generate and quality check the package run in an unmasked manner and distribute it to a 
limited number of pre-specified individuals.  The unmasked biostatistics team at Syneos Health serving in 
this capacity will be otherwise uninvolved in the conduct of the study through database lock and full 
unmasking of the study.  
 


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Changes from Analyses Planned in Protocol 
Changes from the analyses planned in the protocol include the following. 
 
Whereas Protocol Section 11.3.5 indicates that there will be no adjustment of analyses for 
covariates, secondary efficacy endpoints will include baseline value as a covariate, when 
applicable (SAP Section 8.8). 
 
The protocol defines the ITT population as all subjects who received at least one dose of study 
treatment and defines the efficacy population as ITT subjects who continue to at least Week 36, 
having the primary efficacy endpoint assessed.  This SAP instead defines the FAS and Safety 
Set, which are both the equivalent of the protocol-defined ITT, and the PP Set, which is the 
equivalent of the protocol-defined efficacy population with the added criterion of subjects having 
no protocol deviation(s) that would significantly impact the primary endpoint.  This change from 
the protocol in analysis set definitions is consistent with the approach taken for the EYP-1901-201 
study.  
  


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Reference List 
There are no references applicable for this SAP. 
  


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Programming Considerations 
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for Windows, 
Release 9.4 (SAS Institute Inc., Cary, NC, United States of America). Computer-generated table, listing, 
and figure output will adhere to the following specifications. 
 
General Considerations 
 
One SAS program can create several outputs. 
 
One output file can contain several outputs. 
 
Output files will be delivered in Rich Text File format, readable in Microsoft Word.  
 
Numbering of TFLs will follow International Conference for Harmonization (ICH) E3 guidance.  
 
Table, Figure, and Listing Format 
 
General 
 All TFLs will be produced in landscape format on American letter size, unless otherwise specified 
 All TFLs will be produced using the Courier New font, size 8, which is the smallest acceptable point 
size for the Regulatory Authorities. 
 The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
 Headers and footers for figures will be in Courier New font, size 8, which is the smallest acceptable 
point size for the Regulatory Authorities. 
 Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 TFLs will be in black and white (no color), unless otherwise specified. 
 Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
 Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
 Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 
Headers 
 All output will have the following header at the top left of each page:  
 EyePoint Pharmaceuticals, Inc., Protocol EYP-1901-204 
 Draft/Final Run <date> 
 All output will have Page n of N at the top or bottom right corner of each page. TFLs are internally 
paginated in relation to the total length (i.e., the page number will appear sequentially as page n of 
N, where N is the total number of pages in the table). 


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 The date the output was generated will appear along with the program name as a footer on each 
page. 
 
Display Titles 
 Each TFL is identified by the designation and a numeral, i.e., Table 14.1.1. A decimal system (x.y 
and x.y.z) is used to identify TFLs with related contents. The title is centered. The analysis set is 
identified on the line immediately following the title. The title and table designation are single 
spaced. A solid line spanning the margins will separate the display titles from the column headers. 
There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Full Analysis Set 
 
Column Headers 
 Column headings are displayed immediately below the solid line described above in initial upper-
case characters. 
 In the case of efficacy tables, the variable (or characteristic) column is on the far left followed by the 
treatment arm columns and total column (if applicable). P-values may be presented under the total 
column or in separate p-value column (if applicable). Within-treatment comparisons may have p-
values presented in a row beneath the summary statistics for that treatment arm. 
 For numeric variables, include “unit” in column or row heading when appropriate. 
 Analysis set sizes will be presented for each treatment arm in the column heading as (N=xx) (or in 
the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 
 The order of treatment arms in the tables and listings will be Placebo first in the case of placebo 
controlled studies and Active comparators first in the case of active comparator trials, followed by a 
total column (if applicable). 
 
Body of the Data Display 
16.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
 Alphanumeric values will be left-justified; 
 Whole numbers (e.g., counts) will be right-justified; and 
 Numbers containing fractional portions will be decimal aligned. 
16.2.5.2. 
Table Conventions 
 Units will be included where available 
 For categorical parameters, all categories will be presented in the table, even if n=0 for all 
treatment arms in a given category. For example, the frequency distribution for symptom severity 
would appear as: 


 
Statistical Analysis Plan for Interventional Studies
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204
Severity Rating
Severe
N
0
8
3
Moderate
Mild
Where percentages are presented in these tables, zero percentages will not be presented and so counts
of 0 will be presented as 0 and not as 0 (0%).

An Unknown or Missing category will be added to each parameter for which information is not
available for 1 or more subjects.

Unless otherwise specified, the estimated mean and median for a set of values will be printed out
to 1 more significant digit than the original values, and standard deviations will be printed out to 2
more significant digits than the original values. The minimum and maximum will report the same
significant digits as the original values. For example, systolic blood pressure will be presented as
follows:
N
XX
Mean
XXX.X
X.XX
XXX.X
XXX
Std Dev
Median
Minimum
Maximum
XXX


P-values will be output in the format ‘0.xxx’, where xxx is the value rounded to 3 decimal places.
Every p-value less than 0.001 will be presented as <0.001. If a p-value should be less than 0.0001,
then present as <0.0001. If a p-value is returned as >0.999, then present as >0.999.
Percentage values will be printed to 1 decimal place, in parentheses with no spaces, 1 space after
the count (e.g., 7 (12.8%), 13 (5.4%)). A pre-determination will be made regarding how to display
values that round down to 0.0; a common convention is to display as '<0.1', or as appropriate with
additional decimal places. Unless otherwise noted, for all percentages, the number of subjects in
the analysis set for the treatment arm who have an observation will be the denominator.
Percentages after zero counts will not be displayed and percentages equating to 100% will be
presented as 100%, without decimal places.

Tabular display of data for medical history, prior/concomitant medications, and all tabular displays
of adverse event data will be presented by the body system, treatment class, or SOC with the
highest occurrence in the active treatment arm in decreasing order, assuming all terms are coded.
Within the body system, drug class and SOC, medical history (by preferred term), drugs (by ATC1
code), and adverse events (by preferred term) will be displayed in decreasing order. If incidence for
more than 1 term is identical, they will then be sorted alphabetically. Missing descriptive statistics
or p-values which cannot be estimated will be reported as ‘-’
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Statistical Analysis Plan for Interventional Studies 
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204 
 
 
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 The percentage of subjects will normally be calculated as a proportion of the number of subjects 
assessed in the relevant treatment arm (or overall) for the analysis set presented. However, careful 
consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Details will be described in 
footnotes or programming notes, as necessary. 
 For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than 1 category, a footnote or programming note will be added describing whether the 
subject is included in the summary statistics for all relevant categories or just 1 category as well as 
the selection criteria. 
 Where a category with a subheading (such as SOC) has to be split over more than 1 page, output 
the subheading followed by ‘(cont)’ at the top of each subsequent page. The overall summary 
statistics for the subheading should only be output on the first relevant page. 
16.2.5.3. 
Listing Conventions 
 Listings will be sorted for presentation in order of treatment arms as above, subject number, 
visit/collection day, and visit/collection time. 
 Dates will be printed in SAS DATE9.format (‘DD_MMM_YYYY’: 01JUL2000). 
 All observed time values will be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26 or 11:26:45). Time will only be reported if it was measured as part of the study. 
 Units will be included where available. 
16.2.5.4. 
Figure Conventions 
 Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment arm mean change from Baseline) values will be displayed on the Y-axis. 
 
Footnotes 
 A solid line spanning the margins will separate the body of the data display from the footnotes. 
 All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
 Footnotes will always begin with ‘Note:’ if an informational footnote, or 1, 2, 3, etc. if a reference 
footnote. Each new footnote will start on a new line, where possible. 
 Subject specific footnotes are avoided, where possible. 
 Footnotes will be used sparingly and add value to the TFL. If more than 6 lines of footnotes are 
planned, then a cover page is strongly recommended to be used to display footnotes, and only 
those essential to comprehension of the data will be repeated on each page. 
 The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, the date the program was run, and the listing source 
(i.e., ‘Program : myprogram.sas  Listing source: 16.x.y.z’). 
 Sources and/or cross-references in footnotes will use the keyword prefix (in singular form) for each 
reference and will be separated by a comma when multiple cross-references are displayed. 
Example 
Reference: Listing 16.2.4.1.1, 16.2.4.1.2, 16.2.4.2.1 


Statistical Analysis Plan for Interventional Studies 
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Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures, or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health Developing Statistical Programs Standard Operation Procedure (3907). 
Syneos Health Developing Statistical Programs Standard Operating Procedure (3907), Conducting the 
Transfer of Biostatistical Deliverables Standard Operating Procedure (3908), and the SAS Programming 
and Validation Plan describes the quality control procedures that are performed for all SAS programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify 
that the SAS programs produce the output by checking for their logic, efficiency, and commenting, and by 
review of the produced output.  


Statistical Analysis Plan for Interventional Studies 
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204 
 
 
This document is confidential. 
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Page 46 of 53 
 
Index of Tables 
14.1.1 
Subject Disposition (All Subjects) 
14.1.2 
Major Protocol Deviations (Full Analysis Set) 
14.1.3.1.1 
Demographics  (Full Analysis Set) 
14.1.3.1.2 
Baseline Characteristics (Full Analysis Set) 
14.1.3.2.1 
Ocular Medical History for the Study Eye by System Organ Class and Preferred Term 
(Safety Set) 
14.1.3.2.2 
Ocular Medical History for the Non-study Eye by System Organ Class and Preferred 
Term (Safety Set) 
14.1.3.2.3 
Non-ocular Medical History by System Organ Class and Preferred Term (Safety Set) 
14.1.4.1.1 
Ocular Prior Medications for the Study Eye (Safety Set) 
14.1.4.1.2 
Ocular Prior Medications for the Non-study Eye (Safety Set) 
14.1.4.1.3 
Non-ocular Prior Medications  (Safety Set) 
14.1.4.2.1 
Ocular Concomitant Medications for the Study Eye (Safety Set) 
14.1.4.2.2 
Ocular Concomitant Medications for the Non-study Eye (Safety Set) 
14.1.4.2.3 
Non-ocular Concomitant Medications  (Safety Set) 
14.1.5 
Exposure to Study Drug Injection  (Randomized Set) 
14.2.1.1 
Percentage of Subjects With ≥2-step Improvement in Diabetic Retinopathy Severity 
Scale (DRSS) Score in the Study Eye at Each Follow-up Visit (Full Analysis Set) 
14.2.1.2 
Percentage of Subjects With ≥2-step Improvement in Diabetic Retinopathy Severity 
Scale (DRSS) Score in the Study Eye at Each Follow-up Visit (Per Protocol Set) 
14.2.1.3 
Percentage of Subjects With ≥2-step Improvement in Diabetic Retinopathy Severity 
Scale (DRSS) Score in the Study Eye at Each Follow-up Visit – Subgroup Analyses 
(Full Analysis Set) 
14.2.1.4 
Sensitivity Analysis: Percentage of Subjects With ≥2-step Improvement in Diabetic 
Retinopathy Severity Scale (DRSS) Score in the Study Eye at Each Follow-up Visit, 
Last Observation Carried Forward (Full Analysis Set) 
14.2.1.5 
Sensitivity Analysis: Percentage of Subjects With ≥2-step Improvement in Diabetic 
Retinopathy Severity Scale (DRSS) Score in the Study Eye at Each Follow-up Visit, 
Last Observation Carried Forward Using Numeric Portion of Indeterminate DRSS 
Scores (Full Analysis Set) 
14.2.2.1 
Percentage of Subjects With ≥3-step Improvement in Diabetic Retinopathy Severity 
Scale (DRSS) Score in the Study Eye at Each Follow-up Visit (Full Analysis Set) 
14.2.2.2 
Percentage of Subjects With ≥3-step Improvement in Diabetic Retinopathy Severity 
Scale (DRSS) Score in the Study Eye at Each Follow-up Visit (Per Protocol Set) 
14.2.3.1 
Percentage of Subjects With ≥2-step Worsening in Diabetic Retinopathy Severity 
Scale (DRSS) Score in the Study Eye at Each Follow-up Visit (Full Analysis Set) 


 
Statistical Analysis Plan for Interventional Studies
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204
14.2.3.2
14.2.4.1
14.2.4.2
14.2.5.1.1
14.2.5.1.2
Percentage of Subjects With ≥2-step Worsening in Diabetic Retinopathy Severity
Scale (DRSS) Score in the Study Eye at Each Follow-up Visit (Per Protocol Set)
Percentage of Subjects With ≥3-step Worsening in Diabetic Retinopathy Severity
Scale (DRSS) Score in the Study Eye at Each Follow-up Visit (Full Analysis Set)
Percentage of Subjects With ≥3-step Worsening in Diabetic Retinopathy Severity
Scale (DRSS) Score in the Study Eye at Each Follow-up Visit (Per Protocol Set)
Percentage of Subjects Developing Vision-Threatening Complication Due to Diabetic
Retinopathy in Study Eye at Each Follow-up Visit (Full Analysis Set)
Percentage of Subjects Developing Vision-Threatening Complication Due to Diabetic
Retinopathy in Study Eye at Each Follow-up Visit – Subgroup Analyses (Full Analysis
Set)
14.2.5.2
Percentage of Subjects Developing Vision-Threatening Complication Due to Diabetic
Retinopathy in the Study Eye at Each Follow-up Visit (Per Protocol Set)
14.2.6.1.1
14.2.6.1.2
14.2.6.2.1
14.2.6.2.2
14.2.6.3.1
14.2.6.3.2
14.2.7.1
Percentage of Subjects Developing Center Involved - Diabetic Macular Edema (CI-
DME) in Study Eye at Each Follow-up Visit (Full Analysis Set)
Percentage of Subjects Developing Center Involved - Diabetic Macular Edema (CI-
DME) in Study Eye at Each Follow-up Visit (Per Protocol Set)
Percentage of Subjects Developing Macular Edema, Definition 1, in Study Eye at
Each Follow-up Visit (Full Analysis Set)
Percentage of Subjects Developing Macular Edema, Definition 1, in Study Eye at
Each Follow-up Visit (Per Protocol Set)
Percentage of Subjects Developing Macular Edema, Definition 2, in Study Eye at
Each Follow-up Visit (Full Analysis Set)
Percentage of Subjects Developing Macular Edema, Definition 2, in Study Eye at
Each Follow-up Visit (Per Protocol Set)
Summary of Time to Develop Any Vision Threatening Complication (PDR/ASNV) in
the Study Eye Through Week 24 (Full Analysis Set)
14.2.7.2
Summary of Time to Develop Any Vision Threatening Complication (PDR/ASNV) in
the Study Eye Through Week 24 (Per Protocol Set)
14.2.8.1
Summary of Time to Develop Any Vision Threatening Complication (PDR/ASNV) in
the Study Eye Through Week 36 (Full Analysis Set)
14.2.8.2
Summary of Time to Develop Any Vision Threatening Complication (PDR/ASNV) in
the Study Eye Through Week 36 (Per Protocol Set)
14.2.9.1
Summary of Time to Develop Any Vision Threatening Complication (PDR/ASNV) in
the Study Eye Through Week 48 (Full Analysis Set)
14.2.9.2
Summary of Time to Develop Any Vision Threatening Complication (PDR/ASNV) in
the Study Eye Through Week 48 (Per Protocol Set)
14.2.10.1
Summary of Time to Develop Center Involved – Diabetic Macular Edema (CI-DME) in
the Study Eye Through Week 24 (Full Analysis Set)
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Statistical Analysis Plan for Interventional Studies
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204
14.2.10.2
14.2.11.1
14.2.11.2
14.2.12.1
14.2.12.2
14.2.13.1
Summary of Time to Develop Center Involved – Diabetic Macular Edema (CI-DME) in
the Study Eye Through Week 24 (Per Protocol Set)
Summary of Time to Develop Center Involved – Diabetic Macular Edema (CI-DME) in
the Study Eye Through Week 36 (Full Analysis Set)
Summary of Time to Develop Center Involved – Diabetic Macular Edema (CI-DME) in
the Study Eye Through Week 36 (Per Protocol Set)
Summary of Time to Develop Center Involved – Diabetic Macular Edema (CI-DME) in
the Study Eye Through Week 48 (Full Analysis Set)
Summary of Time to Develop Center Involved – Diabetic Macular Edema (CI-DME) in
the Study Eye Through Week 48 (Per Protocol Set)
Percentage of Subjects Receiving anti-VEGF or Additional Standard of Care
Intervention Due to Ocular Diabetic Complications in the Study Eye at Each Follow-
up Visit (Full Analysis Set)
14.2.13.2
Percentage of Subjects Receiving anti-VEGF or Additional Standard of Care
Intervention Due to Ocular Diabetic Complications in the Study Eye at Each Follow-
up Visit (Per Protocol Set)
14.2.14.1
14.2.14.2
14.2.15.1
14.2.15.2
14.2.16.1
14.2.16.2
Percentage of Subjects Receiving Pan-retinal Photocoagulation (PRP) in the Study
Eye at Each Follow-up Visit (Full Analysis Set)
Percentage of Subjects Receiving Pan-retinal Photocoagulation (PRP) in the Study
Eye at Each Follow-up Visit (Per Protocol Set)
Summary of Best Corrected Visual Acuity and Area Under the Curve (AUC) for
Change from Baseline Through Week 48 (Full Analysis Set)
Summary of Best Corrected Visual Acuity and Area Under the Curve (AUC) for
Change from Baseline Through Week 48 (Per Protocol Set)
Summary of Change from Baseline in Diabetic Retinopathy Severity Scale (DRSS)
Step in the Study Eye at Each Follow-up Visit (Full Analysis Set)
Summary of Change from Baseline in Diabetic Retinopathy Severity Scale (DRSS)
Step in the Study Eye at Each Follow-up Visit – Mixed Effect Model for Repeated
Measures (MMRM) (Full Analysis Set)
14.2.17
Percentage of Subjects With ≥2-step Improvement From Screening in Diabetic
Retinopathy Severity Scale (DRSS) Score in the Study Eye at Each Follow-up Visit
(Full Analysis Set)
14.2.18.1
14.2.18.2
Summary of Systemic Exposure to EYP-1901 Through Plasma Concentration
(Pharmacokinetic Set)
Summary of Systemic Exposure to X-297 (EYP-1901 metabolite) Through Plasma
Concentration (Pharmacokinetic Set)
14.3.1.1.1
14.3.1.1.2
Ocular Treatment-emergent Adverse Events – Overall Summary (Safety Set)
Non-ocular Treatment-emergent Adverse Events – Overall Summary (Safety Set)
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Statistical Analysis Plan for Interventional Studies
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204
14.3.1.2.1
14.3.1.2.2
14.3.1.3.1
14.3.1.3.2
14.3.1.4.1
14.3.1.4.2
14.3.1.5.1
14.3.1.5.2
14.3.1.6.1
14.3.1.6.2
14.3.1.7.1
14.3.1.7.2
14.3.1.8.1
14.3.1.8.2
14.3.1.9.1
14.3.1.9.2
Ocular Treatment-emergent Adverse Events by System Organ Class and Preferred
Term (Safety Set)
Non-ocular Treatment-emergent Adverse Events by System Organ Class and
Preferred Term (Safety Set)
Ocular Treatment-related Treatment-emergent Adverse Events by System Organ
Class and Preferred Term (Safety Set)
Non-ocular Treatment-related Treatment-emergent Adverse Events by System Organ
Class and Preferred Term (Safety Set)
Ocular Serious Treatment-emergent Adverse Events by System Organ Class and
Preferred Term (Safety Set)
Non-ocular Serious Treatment-emergent Adverse Events by System Organ Class
and Preferred Term (Safety Set)
Ocular Serious Treatment-related Treatment-emergent Adverse Events by System
Organ Class and Preferred Term (Safety Set)
Non-ocular Serious Treatment-related Treatment-emergent Adverse Events by
System Organ Class and Preferred Term (Safety Set)
Ocular Treatment-emergent Adverse Events by System Organ Class and Preferred
Term and Maximum Severity (Safety Set)
Non-ocular Treatment-emergent Adverse Events by System Organ Class and
Preferred Term and Maximum Severity (Safety Set)
Ocular Treatment-emergent Adverse Events by System Organ Class and Preferred
Term and Worst Relationship to Study Treatment (Safety Set)
Non-ocular Treatment-emergent Adverse Events by System Organ Class and
Preferred Term and Worst Relationship to Study Treatment (Safety Set)
Ocular Treatment-emergent Adverse Events Leading to Study Treatment
Discontinuation by System Organ Class and Preferred Term (Safety Set)
Non-ocular Treatment-emergent Adverse Events Leading to Study Treatment
Discontinuation by System Organ Class and Preferred Term (Safety Set)
Ocular Treatment-emergent Adverse Events Leading to Study Withdrawal by System
Organ Class and Preferred Term (Safety Set)
Non-ocular Treatment-emergent Adverse Events Leading to Study Withdrawal by
System Organ Class and Preferred Term (Safety Set)
14.3.1.10.1
14.3.1.10.2
14.3.2.1
Ocular Treatment-emergent Adverse Events by Preferred Term (Safety Set)
Non-ocular Treatment-emergent Adverse Events by Preferred Term (Safety Set)
Deaths, Listing (Safety Set) 80
14.3.2.2
Serious Treatment Emergent Adverse Events, Listing (Safety Set)
14.3.2.3
Treatment Emergent Adverse Events Leading to Study Treatment Discontinuation,
Listing (Safety Set)
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Statistical Analysis Plan for Interventional Studies
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204
14.3.2.4
Treatment Emergent Adverse Events Leading to Study Withdrawal, Listing (Safety
Set)
14.3.4.1.1
14.3.4.1.2
14.3.4.2.1
14.3.4.2.2
14.3.4.3.1
14.3.4.3.2
14.3.4.4.1
14.3.4.4.2
14.3.4.4.3
14.3.5.1.1
14.3.5.1.2
14.3.6.1.1
14.3.6.1.2
14.3.6.1.3
14.3.7.1
Summary of Clinical Hematology by Visit (Safety Set)
Shift Table of Clinical Hematology by Visit (Safety Set
Summary of Clinical Chemistry by Visit (Safety Set)
Shift Table of Clinical Chemistry by Visit (Safety Set)
Summary of Coagulation by Visit (Safety Set
Shift Table of Coagulation by Visit (Safety Set)
Summary of Urinalysis, Continuous Parameters (Safety Set)
Summary of Urinalysis, Categorical Parameters (Safety Set)
Shift Table of Urinalysis by Visit (Safety Set)
Summary of Vital Signs by Visit (Safety Set)
Potentially Clinically Significant (PCS) Values in Vital Signs by Visit (Safety Set)
Summary of 12-lead Electrocardiogram by Visit (Safety Set)
Shift Table of Overall Electrocardiogram Interpretation by Visit (Safety Set)
Potentially Clinically Significant (PCS) QTcF Values by Visit (Safety Set)
Summary of Intraocular Pressure by Visit - Study Eye (Safety Set)
Summary of Intraocular Pressure by Visits – Non-study Eye (Safety Set)
Summary of Dilated Ophthalmoscopy by Visits – Study Eye (Safety Set)
Summary of Dilated Ophthalmoscopy by Visits – Non-study Eye (Safety Set)
Summary of Slit Lamp Biomicroscopy by Visits – Study Eye (Safety Set)
Summary of Slit Lamp Biomicroscopy by Visits – Non-study Eye (Safety Set)
14.3.7.2
14.3.8.1.1
14.3.8.1.2
14.3.8.2.1
14.3.8.2.2
14.3.9
Proportion of Subjects with ≥5 BCVA Letter Loss at Each Follow-up Visit – Study Eye
(Safety Set)
14.3.10
14.3.11
14.3.12
14.3.13
14.3.14
Proportion of Subjects with ≥5 BCVA Letter Gain at Each Follow-up Visit – Study Eye
(Safety Set)
Proportion of Subjects with ≥10 BCVA Letter Loss at Each Follow-up Visit – Study
Eye (Safety Set)
Proportion of Subjects with ≥10 BCVA Letter Gain at Each Follow-up Visit – Study
Eye (Safety Set)
Proportion of Subjects with ≥15 BCVA Letter Loss at Each Follow-up Visit – Study
Eye (Safety Set)
Proportion of Subjects with ≥15 BCVA Letter Gain at Each Follow-up Visit – Study
Eye (Safety Set)
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Statistical Analysis Plan for Interventional Studies 
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204 
 
 
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Index of Figures 
14.2.1.1 
Kaplan-Meier Estimates of Time to Develop Any Vision Threatening Complication 
(PDR/ASNV) in the Study Eye Through Week 24 (Full Analysis Set) 
14.2.1.2 
Kaplan-Meier Estimates of Time to Develop Any Vision Threatening Complication 
(PDR/ASNV) in the Study Eye Through Week 36 (Full Analysis Set) 
14.2.1.3 
Kaplan-Meier Estimates of Time to Develop Any Vision Threatening Complication 
(PDR/ASNV) in the Study Eye Through Week 48 (Full Analysis Set) 
14.2.2.1 
Kaplan-Meier Estimates of Time to Develop Center Involved - Diabetic Macular 
Edema (CI-DME) in the Study Eye Through Week 24 (Full Analysis Set) 
14.2.2.2 
Kaplan-Meier Estimates of Time to Develop Center Involved – Diabetic Macular 
Edema (CI-DME) in the Study Eye Through Week 36 (Full Analysis Set) 
14.2.2.3 
Kaplan-Meier Estimates of Time to Develop Center Involved - Diabetic Macular 
Edema (CI-DME) in the Study Eye Through Week 48 (Full Analysis Set) 
14.2.3 
Mean Change in Best Corrected Visual Acuity Over Time (Full Analysis Set) 
14.2.4.1 
Mean (± SD) EYP-1901 Plasma Concentration Curves (Linear Scale)  
(Pharmacokinetic Set) 
14.2.4.2 
Mean (± SD) EYP-1901 Plasma Concentration Curves (Log-Linear Scale)  
(Pharmacokinetic Set) 
14.2.5.1 
Individual EYP-1901 Plasma Concentration Curves by Dose Level (Linear Scale)  
(Pharmacokinetic Set) 
14.2.5.2 
Individual EYP-1901 Plasma Concentration Curves by Dose Level (Log-Linear Scale)  
(Pharmacokinetic Set) 
14.2.6.1 
Mean (± SD) X-297 Plasma Concentration Curves (Linear Scale)  (Pharmacokinetic 
Set) 
14.2.6.2 
Mean (± SD) X-297 Plasma Concentration Curves (Log-Linear Scale)  
(Pharmacokinetic Set) 
14.2.7.1 
Individual X-297 Plasma Concentration Curves by Dose Level (Linear Scale)  
(Pharmacokinetic Set) 
14.2.7.2 
Individual X-297 Plasma Concentration Curves by Dose Level (Log-Linear Scale)  
(Pharmacokinetic Set) 


Statistical Analysis Plan for Interventional Studies 
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204 
 
 
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Index of Listings 
16.2.1.1 
Subject Disposition (Randomized Set) 
16.2.1.2 
Informed Consent and Randomization (Screened Set) 
16.2.2 
Protocol Deviations (Safety Set) 
16.2.3.1 
Inclusion and Exclusion Criteria Violations (Screened Set) 
16.2.3.2 
Exclusions from Analysis Sets (Screened Set) 
16.2.4.1.1 
Demographics and Baseline Characteristics (Safety Set) 
16.2.4.1.2 
Baseline Disease Characteristics (Safety Set) 
16.2.4.2.1 
Non-Ocular Medical History (Safety Set) 
16.2.4.2.2 
Ocular Medical History (Safety Set)  
16.2.4.3.1 
Prior Medications (Safety Set) 
16.2.4.3.2 
Concomitant Medications (Safety Set) 
16.2.4.4.1 
Procedures, Ophthalmic (Safety Set) 
16.2.4.4.2 
Procedures, Non-ophthalmic (Safety Set) 
16.2.5.1 
Study Drug Administration (Safety Set) 
16.2.5.2 
Pharmacokinetic Blood Sample Collection (Safety Set) 
16.2.6.1 
Diabetic Retinopathy Severity Scale (DRSS) Score (Full Analysis Set) 
16.2.6.2.1 
Best Corrected Visual Acuity Assessment (Full Analysis Set) 
16.2.6.2.2 
Best Corrected Visual Acuity Assessment – Low Vision Testing (Full Analysis Set) 
16.2.6.2.3 
Best Corrected Visual Acuity Assessment – Change From Baseline, Gains, and 
Losses (Full Analysis Set) 
16.2.6.3 
Spectral Domain Optical Coherence Tomography (SD-OCT) (Full Analysis Set) 
16.2.6.4 
Centrally Read Central Subfield Thickness Using Custom Algorithm (Full Analysis Set) 
16.2.6.5 
Macular Edema Events (Full Analysis Set) 
16.2.7.1 
Adverse Events (Safety Set) 
16.2.7.2 
Ocular Adverse Events (Safety Set) 
16.2.7.3 
Treatment-Related Adverse Events (Safety Set) 
16.2.7.4 
Treatment-Related Serious Adverse Events (Safety Set) 
16.2.7.5 
Listing of Deaths (Safety Set) 
16.2.8.1.1 
Hematology (Safety Set) 
16.2.8.1.2 
Serum Chemistry (Safety Set) 
16.2.8.1.3 
Coagulation (Safety Set) 
16.2.8.1.4 
Urinalysis (Safety Set) 
16.2.8.2 
Pregnancy Test (Safety Set) 
16.2.8.3 
Vital Signs (Safety Set) 
16.2.8.4 
12-lead Electrocardiogram (Safety Set) 


 
Statistical Analysis Plan for Interventional Studies
Sponsor: EyePoint Pharmaceuticals, Inc.; Protocol No.: EYP-1901-204
16.2.8.5
16.2.8.6
16.2.8.7
16.2.8.8
Intraocular Pressure Measurement (IOP) (Safety Set)
Dilated Ophthalmoscopy (Safety Set)
Slit Lamp Biomicroscopy (Safety Set)
Color Fundus Photography (Safety Set)
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