Clinical trial NCT05409235
Conditions: Diabetic Retinopathy
Keywords: Diabetic Retinopathy Ophthalmic solution Non-proliferative diabetic retinopathy Proliferative diabetic retinopathy
Sponsor: OcuTerra Therapeutics, Inc.
Start date: 2022-07-29; Completion date: 2023-12-29
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety and efficacy of OTT166 Ophthalmic solution in participants with Diabetic Retinopathy.

Detailed description:
This randomized, double-masked, vehicle controlled, phase 2 study will evaluate the safety and efficacy of OTT166 ophthalmic solution in participants with diabetic retinopathy and select an optimum dosing regimen for Phase 3 pivotal trials. Approximately 210 participants diagnosed with moderately severe to severe non-proliferative diabetic retinopathy (NPDR) or mild proliferative diabetic retinopathy (PDR) and who are treatment naïve (ie, no prior anti-vascular endothelial growth factor \[anti-VEGF\] or laser \[focal, grid, pan-retinal photocoagulation (PRP)\] administered) will be randomized 2:2:1:1 into the following groups: OTT166 5% twice daily (BID), OTT166 5% four times daily (QID), vehicle control BID, vehicle control QID. Randomization will be stratified by baseline Diabetic Retinopathy Severity Scale (DRSS) score (47 or 53 or 61B). Participants with PDR (DRSS score 61B) will be capped at 20% of all randomized participants. Each group will self-administer one 50-μl eye drop of study solution (frequency as assigned) for 24 weeks.

Arms: arm 1: Participants will receive OTT166 5% twice a day (BID) for 24 weeks arm 2: Participants will receive OTT166 5% four times a day (QID) for 24 weeks arm 3: Participants will receive vehicle control BID for 24 weeks arm 4: Participants will receive vehicle control QID for 24 weeks
Interventions: intervention 1: OTT166 intervention 2: Vehicle control
Intervention descriptions: intervention 1: Participants will receive OTT166 ophthalmic solution intervention 2: Participants will receive vehicle control

Protocol documents:
Prot_000.pdf: 
Version: 5.0 
OTT166 201 Phase 2 DR Study 
CONFIDENTIAL 
October 10, 2023 
OcuTerra Therapeutics 
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OTT166-201 A Phase 2 Randomized, Double-Masked, 
Vehicle-Controlled, Multicenter Study to Evaluate the Safety and 
Efficacy of OTT166 Ophthalmic Solution in the Treatment of 
Diabetic Retinopathy (DR) 
 
Protocol Number: OTT166-201 
Brief Title: OTT166 in DR 
Version: 5.0 
 
Sponsor Name and Address: 
OcuTerra Therapeutics, Inc. 
50 Milk Street  
16th Floor 
Boston, MA 02109 
 
Regulatory Agency Identifier: 
FDA IND: 126944 
 
Study Responsible Medical Lead: 
David Tanzer, MD 
Chief Medical Officer, OcuTerra 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance 
of the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to 
parties not associated with the clinical investigation or its use for any other purpose without the prior written 
consent of the Sponsor is not permitted. 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document History 
Date 
Amendment 04 (V5.0) 
10 October 2023 
Amendment 03 (V4.0) 
21 December 2022 
Amendment 02 (V3.0) 
14 October 2022 
Amendment 01 (V2.0) 
11 May 2022 
Original Protocol (V1.0) 
02 March 2022 
 
Amendment 04 (V5.0), 10 OCT 2023 
A description of important changes in this amendment is provided in the table below: 
Section # and Name 
Description of Change 
Brief Rationale 
1.0 Study Synopsis 
2.20.2 Outcome 
Measures 
Secondary endpoints updated to include:  
“Proportion of participants developing VTC at Week 
24”, “Time to development of PDR worse than mild 
(DRSS 65 and above) or CI-DME”, and “Time to 
rescue therapy for participants who meet objective 
criteria for rescue therapy”. 
“Mean and median step change in DRSS step from 
baseline to Week 24” was removed.  
To clarify and further 
define the endpoints. 
1.0 Study Synopsis  
2.9 Exclusion 
Criteria 
Exclusion #1 updated to include “and there is a 
normal foveal contour as determined by the Central 
Reading Center”. 
To specify the 
exclusion criteria. 
1.0 Study Synopsis  
2.9 Exclusion 
Criteria 
Exclusion #33 list of medications extended to 
“Liraglutides, Dulaglutides, and Tirzepatides”. 
To reflect additional 
medications that are 
exclusionary. 
1.0 Study Synopsis 
2.14.9 Rescue 
Criteria  
Added “Development of ASNV”. 
To clarify the rescue 
criteria.  
1.0 Study Synopsis 
2.20 Statistical 
Considerations 
Updated safety summary sections to clarify what will 
be included in the Safety Analysis Set and summary 
of TEAEs.  
Primary estimand clarified and updated. 
To clarify the 
statistical 
considerations. 
2.4 OTT166 
Background 
Background on OTT166 updated to reflect current 
knowledge.  
To align with current 
knowledge of 
background. 
2.14.4 Study 
Intervention 
Compliance and 
Adherence 
2.15.1 Schedule of 
Activities 
Updated to clarify “compliance” per protocol and 
“adherence” for the MEMS Cap® use, and to 
emphasize the importance of continuously monitoring 
adherence to ensure participants are taking the correct 
number of prescribed doses.  
“IP adherence review” added to the SoA to ensure 
sites are discussing adherence with participants at 
each study visit and continuously monitoring this 
activity.  
To clarify 
“compliance” and 
“adherence”. 


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Section # and Name 
Description of Change 
Brief Rationale 
2.15.1 Schedule of 
Activities 
Visit 8 “continue study treatment” in the SoA 
removed as this is the end of study visit.  
Administrative update. 
2.15.1 Schedule of 
Activities 
Footnote “m” added to ensure cornea is assessed at 
the beginning of the visits before dilation.  
To ensure cornea is 
not impacted by other 
tests.  
2.16.9 Vision-
threatening 
Complications 
Updated more than mild PDR as “DRSS 65 and 
above” and added “CI-DME” to the list. 
To clarify the 
definition of vision-
threatening 
complication. 
3.2 Appendix 2 
ETDRS table updated to be more specific.  
To provide specific 
details for each level 
of severity. 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ....................................................2 
TABLE OF CONTENTS ...........................................................................................................4 
LIST OF TABLES .....................................................................................................................7 
LIST OF FIGURES ...................................................................................................................7 
LIST OF ABBREVIATIONS ....................................................................................................8 
1 
STUDY SYNOPSIS ..............................................................................................10 
2 
STUDY PROTOCOL ............................................................................................21 
2.1 
Study Rationale ................................................................................................21 
2.2 
Study Objectives ..............................................................................................21 
2.3 
Introduction DR ...............................................................................................22 
2.4 
OTT166 Background .......................................................................................23 
2.5 
Previous Clinical Studies .................................................................................25 
2.5.1 
OTT166 in DME ..................................................................................25 
2.5.2 
OTT166 in nAMD ...............................................................................26 
2.6 
Study Design ....................................................................................................26 
2.7 
Study Population ..............................................................................................27 
2.8 
Inclusion Criteria .............................................................................................27 
2.9 
Exclusion Criteria ............................................................................................28 
2.10 
Lifestyle Considerations ..................................................................................30 
2.11 
Screen Failures .................................................................................................30 
2.12 
Criteria for Temporarily Delaying Randomization / Study Intervention 
Administration .................................................................................................30 
2.13 
Selection of the Study Eye ...............................................................................31 
2.14 
Study Intervention(s) and Concomitant Therapy .............................................31 
2.14.1 
Study Intervention ................................................................................31 
2.14.2 
Preparation / Handling / Storage / Accountability ................................31 
2.14.3 
Measures to Minimize Bias: Randomization and Masking .................32 
2.14.4 
Study Intervention Compliance and Adherence ...................................32 
2.14.5 
Dose Modification ................................................................................33 
2.14.6 
Stopping Rules (Study Level) ..............................................................33 
2.14.7 
Continued Access to Study Intervention After the End of the Study ..34 
2.14.8 
Concomitant and Prohibited Therapy in the Study Eye.......................34 
2.14.9 
Rescue Therapy ....................................................................................34 
2.14.10 
Discontinuation of Study Intervention and Participant 
Discontinuation / Withdrawal ..............................................................35 
2.14.10.1 
Permanent Discontinuation .........................................................35 
2.14.10.2 
Temporary Discontinuation ........................................................35 


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2.14.11 
Participant Discontinuation / Withdrawal from the Study ...................35 
2.14.12 
Lost to Follow-up .................................................................................36 
2.15 
Study Assessments and Procedures .................................................................36 
2.15.1 
Schedule of Activities ..........................................................................38 
2.15.2 
Study Activities ....................................................................................40 
2.15.3 
Blood Sampling ...................................................................................40 
2.16 
Efficacy Assessments .......................................................................................40 
2.16.1 
Ophthalmology Assessments ...............................................................40 
2.16.2 
Color Fundus Photography (CFP) .......................................................40 
2.16.3 
Best Corrected Visual Acuity (BCVA) ................................................41 
2.16.4 
Fluorescein Angiography (FA) ............................................................41 
2.16.5 
Optical Coherence Tomography (OCT) ..............................................41 
2.16.6 
Optical Coherence Tomography Angiography (OCTA) .....................41 
2.16.7 
Slit Lamp Biomicroscopy (Anterior and Posterior Segment) ..............42 
2.16.8 
Tonometry (Intraocular Pressure (IOP) Measurement) .......................42 
2.16.9 
Vision-threatening Complications .......................................................42 
2.16.10 
DME and CI-DME ...............................................................................42 
2.17 
Safety Assessments ..........................................................................................43 
2.17.1 
Physical Examination ...........................................................................43 
2.17.2 
Vital Signs ............................................................................................43 
2.17.3 
Clinical Safety Laboratory Assessments ..............................................43 
2.17.4 
Pregnancy Testing ................................................................................44 
2.18 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting..........................................................................................................44 
2.18.1 
Time Period and Frequency for Collecting AE and SAE 
Information ..........................................................................................44 
2.18.2 
Method of Detecting AEs and SAEs ....................................................45 
2.18.3 
Follow-up of AEs and SAEs ................................................................45 
2.18.4 
Regulatory Reporting Requirements for SAEs.....................................45 
2.18.5 
Pregnancy .............................................................................................45 
2.18.6 
Adverse Events of Special Interest (AESI) ..........................................46 
2.19 
Pharmacokinetics .............................................................................................46 
2.20 
Statistical Considerations .................................................................................47 
2.20.1 
Statistical Hypotheses / Sample Size Determination ...........................47 
2.20.2 
Outcome Measures...............................................................................47 
2.20.3 
Analysis Sets ........................................................................................49 
2.21 
Statistical Analyses ..........................................................................................49 
2.21.1 
General Considerations ........................................................................49 
2.21.2 
Efficacy Analyses ................................................................................50 


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2.21.2.1 
Analysis of the Primary Endpoint ...............................................50 
2.21.2.2 
Analyses of Secondary and Other Efficacy Endpoints ...............51 
2.21.3 
Safety Analyses ....................................................................................52 
2.21.4 
Study Drug Exposure ...........................................................................52 
2.21.5 
Adverse Events ....................................................................................52 
2.21.6 
Vital Signs ............................................................................................54 
2.21.7 
Safety Laboratory Tests .......................................................................54 
2.21.8 
Other Analyses .....................................................................................54 
2.21.9 
Interim Analysis ...................................................................................54 
3 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .............................................................................................55 
3.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ..........55 
3.1.1 
Regulatory and Ethical Considerations ................................................55 
3.1.2 
Financial Disclosure .............................................................................56 
3.1.3 
Informed Consent Process ....................................................................56 
3.1.4 
Data Protection .....................................................................................56 
3.1.5 
Committees Structure ...........................................................................57 
3.1.5.1 
Central Reading Center ...............................................................57 
3.1.5.2 
Steering Committee ....................................................................57 
3.1.6 
Data quality Assurance .........................................................................57 
3.1.7 
Source Documents................................................................................58 
3.1.8 
Study and Site Start and Closure ..........................................................58 
3.1.8.1 
First Act of Recruitment .............................................................58 
3.1.8.2 
Study / Site Termination .............................................................59 
3.1.9 
Publication Policy ................................................................................59 
3.2 
Appendix 2: ETDRS Final Retinopathy Severity Scale ..................................61 
3.3 
Appendix 3: Clinical Laboratory Tests ............................................................63 
3.4 
Appendix 4: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .............................................................64 
3.4.1 
AE Definition .......................................................................................64 
3.4.2 
Events Meeting the AE Definition .......................................................64 
3.4.3 
Events NOT Meeting the AE Definition .............................................64 
3.4.4 
Recording and Follow-up of AE and / or SAE .....................................66 
3.4.5 
Assessment of Intensity .......................................................................66 
3.4.6 
Assessment of Causality ......................................................................66 
3.4.7 
Follow-up of AEs and SAEs ................................................................67 
3.4.8 
Reporting of SAEs ...............................................................................67 
3.5 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information ......................................................................................................69 
3.5.1 
Definitions............................................................................................69 


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3.5.2 
Contraception Guidance .......................................................................69 
3.5.3 
Collection of Pregnancy Information ...................................................70 
4 
REFERENCES ......................................................................................................72 
 
LIST OF TABLES 
Table 1 
OTT166 201 Phase 2 DR Study: Schedule of Activities (Through 
Week 24 – Primary Endpoint) ...................................................................38 
Table 2 
Analysis Sets ..............................................................................................49 
Table 3 
ETDRS Final Retinopathy Severity Scale (for Individual Eyes) ...............61 
Table 4 
Clinical Laboratory Tests ...........................................................................63 
Table 5 
Highly Effective Contraception Methods ..................................................70 
 
LIST OF FIGURES 
Figure 1 
RGD‑Binding Integrins Involved in the Pathogenesis of Diabetic 
Retinopathy ................................................................................................24 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
ASNV 
anterior segment neovascularization 
Anti-VEGF 
anti-vascular endothelial growth factor 
AUC 
area under the curve 
BCVA 
best corrected visual acuity 
BID 
twice daily 
BL 
baseline 
BMI 
body mass index 
CFP 
color fundus photography 
CI 
confidence interval 
CI-DME 
center-involved diabetic macular edema 
CNV 
choroidal neovascularization 
CST 
central subfield thickness 
CONSORT 
Consolidated Standards of Reporting Trials 
DD 
disk diameter 
DME 
diabetic macular edema 
DR 
diabetic retinopathy 
DRIL 
disorganization of retinal inner layers 
DRSS 
Diabetic Retinopathy Severity Scale 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ETRDR 
Early Treatment Report Diabetic Retinopathy 
eCRF 
Electronic Case Report Form 
EOS 
end of study 
FA 
fluorescein angiography 
FAS 
full analysis set 
FAZ 
foveal avascular zone 
GAT 
Goldmann applanation tonometry 
GCP 
Good Clinical Practice 
HbA1c 
glycosylated hemoglobin 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibition concentration 
ICF 
informed consent form 
ICE 
intercurrent event 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 


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Abbreviation 
Definition 
IRMAs 
intraretinal microvascular anomalies 
ITT 
intent-to-treat 
IVT 
intravitreal injection 
IWRS 
interactive web response system 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
milligram 
MH 
Mantel-Haenszel 
mmHg 
millimeter of mercury 
n 
sample size 
nAMD 
neovascular age-related macular degeneration 
NPDR 
non-proliferative diabetic retinopathy 
NVE 
neovascularization elsewhere 
OCT 
optical coherence tomography 
OCTA 
optical coherence tomography – angiography 
OU 
both eyes 
PK 
pharmacokinetic 
PDR 
proliferative diabetic retinopathy 
PRP 
pan-retinal photocoagulation 
PPS 
per-protocol set 
PT 
preferred term 
QID 
four times daily 
QTL 
quality tolerance limit 
SAP 
statistical analysis plan 
SAE 
serious adverse event 
SD 
standard deviation 
SD-OCT 
spectral-domain optical coherence tomography 
SE 
study eye 
SoA 
schedule of activities 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
MV 
macular volume 
VEGF 
vascular endothelial growth factor 
VTC 
visually threatening complications 
WHO DD 
World Health Organization Drug Dictionary 
YAG 
yttrium aluminum garnet 
 


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1 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
OcuTerra Therapeutics, Inc. 
Name of Investigational 
Product: 
OTT166 Ophthalmic Solution (5.0%) 
Title of Study: 
OTT166-201 A Phase 2 Randomized, Double-
Masked, Vehicle-Controlled, Multicenter Study to 
Evaluate the Safety and Efficacy of OTT166 
Ophthalmic Solution in the Treatment of Diabetic 
Retinopathy (DR) 
Protocol Number: 
OTT166-201 
Phase of Development: 
2 
Study Period: 
Up to 24 weeks of follow-up 
Methodology: 
A prospective, randomized, double-masked, vehicle-controlled Phase 2 study will be 
conducted to further evaluate safety and efficacy of OTT166 Ophthalmic Solution in 
diabetic retinopathy patient population and to select an optimum dosing regimen 
(frequency) for Phase 3 pivotal trials. Approximately 210 participants diagnosed with 
moderately severe to severe non-proliferative diabetic retinopathy (NPDR) or mild 
proliferative diabetic retinopathy (PDR) and who are treatment naïve (ie, no prior 
anti-vascular endothelial growth factor [anti-VEGF] or laser [focal, grid, pan-retinal 
photocoagulation (PRP)] administered) will be randomized 2:2:1:1 into the following 
groups: OTT166 5% twice daily (BID), OTT166 5% four times daily (QID), vehicle 
control BID, vehicle control QID. Randomization will be stratified by baseline Diabetic 
Retinopathy Severity Scale (DRSS) score (47 or 53 or 61B). Participants with PDR (DRSS 
score 61B) will be capped at 20% of all randomized participants. Each group will self-
administer one 50-µl eye drop of study solution (frequency as assigned) for 24 weeks. 
Sample size: 
The study will enroll approximately 210 participants randomized as above, approximately 
70 participants in each OTT166 treatment group and approximately 35 participants per 
group into each matching vehicle control group and allowing for around 5% study 
attrition; this will ensure approximately 66 participants per treatment group and combined 
vehicle control group. 
For the primary endpoint of improvement by at least 2 steps from baseline on the DRSS at 
Week 24, completing 66 participants per group (active treatment BID, QID, combined 
vehicle control) through Week 24 will yield 90% power to demonstrate that the active 


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treatment is superior to vehicle control using a 1-sided alpha of 0.05, provided that the true 
treatment effect (active treatment efficacy rate minus vehicle control efficacy rate) is at 
least 0.20 and the vehicle control efficacy rate is at most 0.06. 
The two OTT166 dose regimens will cover a 2-fold dose range in total daily dose 
(5.0 mg/day to 10.0 mg/day). 
Population:  
The population will be participants with Type 1 or Type 2 diabetes under adequate control 
as evidenced by glycosylated hemoglobin (HbA1c) less than or equal to 12.0% , who show 
typical fundus alterations, and diagnosed with moderately severe to severe NPDR or mild 
PDR, as defined by the DRSS Steps 47, 53, and 61B, with the PDR population capped at 
no more than 20% of all randomized participants. Baseline Best-Corrected Visual Acuity 
(BCVA) must be ≥ 69 Early Treatment Diabetic Retinopathy Study (ETDRS) letters 
(Snellen equivalent 20/40) and central subfield thickness (CST) must be ≤ 325 µm at the 
screening and baseline examinations. DRSS steps, CST measurements and the presence of 
a normal foveal contour must be confirmed by the central reading center. 
Primary Objectives: 
Primary Endpoints: 
To characterize the safety of 
topical OTT166 in participants 
with DR  
• Proportion of participants who develop treatment-
emergent adverse events (TEAEs) through 
Week 24 
To characterize the efficacy of 
topical OTT166 in participants 
with DR  
• Proportion of participants who have improved by 
≥ 2 steps from baseline at Week 24 as determined 
by central reading center assessment using the 
DRSS 
Secondary Objectives: 
Secondary Endpoints: 
To determine if topical OTT166 
will prevent or delay the 
occurrence of visually threatening 
complications (VTC), defined as 
PDR worse than mild and/or 
anterior segment 
neovascularization (ASNV) 
and/or CI-DME (defined below) 
 
To determine if topical OTT166 
will prevent or delay the 
occurrence of CI-DME. (CI-DME 
• Proportion of participants developing worse than 
mild PDR (DRSS 65 and above) at Week 24 
• Proportion of participants who develop ASNV 
determined by the investigator at Week 24 
• Time to development of PDR worse than mild 
(DRSS 65 and above) 
• Proportion of participants who develop CI-DME 
at Week 24 
• Time to development of CI-DME  


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is defined as the presence of fluid 
in the central subfield in 
participants who have no fluid at 
baseline or CST > 325 µm) 
• Proportion of participants developing VTC at 
Week 24 
• Time to development of PDR worse than mild 
(DRSS 65 and above) or CI-DME 
To determine the effect of 
OTT166 on DRSS in participants 
with moderately severe to severe 
NPDR and mild PDR treated with 
topical OTT166 
• Proportion of participants with change in DRSS 
steps at Week 24 compared to baseline 
- 
Change in DRSS steps is defined as DR 
worsening or improving by 1, 2, or ≥ 3 steps. 
• Proportion of participants with mild PDR (DRSS 
score 61B) at baseline who regress to NPDR 
(DRSS score ≤ 53) by Week 24 
To determine the effect of 
OTT166 on BCVA in participants 
with moderately severe to severe 
NPDR and mild PDR 
• Mean and median change in BCVA (ETDRS 
letters) from baseline to Week 24 
• Lines gained/lost in BCVA (± 5, 10, and 
15 ETDRS letters) at Week 24 
• Mean and median change in area under the curve 
(AUC) for change in BCVA from baseline to 
Week 24 
To determine the effect of 
OTT166 on central subfield 
thickness in participants with 
moderately severe to severe 
NPDR and mild PDR 
• Mean and median change in CST from baseline to 
Week 24 
• AUC for change in CST from baseline to 24 
weeks 
To determine the effect of 
OTT166 on the need for rescue 
therapy in participants with 
moderately severe to severe 
NPDR and mild PDR 
• Proportion of participants who met the objective 
rescue criteria as defined in protocol 
Section 2.14.9. 
• Time to meet objective rescue therapy criteria as 
defined in protocol Section 2.14.9. 
• Time to administration of rescue therapy 


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Exploratory Objectives 
Exploratory Endpoints 
To evaluate the change in DME in 
participants treated with OTT166 
• Change in Macular Volume (MV) from baseline 
to Week 24 for 1, 3, and 6 mm regions 
To assess the effects of treatment 
on anatomic markers other than 
DRSS and on retinal 
non-perfusion 
• Change in area of retinal non-perfusion from 
baseline to Week 24 seen on widefield fluorescein 
angiography (FA) 
• Proportion of participants with intact foveal 
avascular zone (FAZ) seen on widefield FA at 
Week 24 
• Optical coherence tomography angiography 
(OCTA) endpoints within the 6 mm area:  
- 
Change from baseline to Week 24 in FAZ area 
- 
Change from baseline to Week 24 in non-
perfusion area 
- 
Change from baseline to Week 24 in vessel 
caliber 
- 
Ischemic Index at Week 24 compared to 
baseline 
- 
Proportion of participants with new 
neovascularization at Week 24 
- 
Proportion of participants with new 
intraretinal microvascular anomalies (IRMA) 
at Week 24 
- 
Change in vessel density from baseline to 
Week 24 in the superficial and deep layers  
Key Inclusion Criteria: 
1. Men or women ≥ 18 years of 
age with type 1 or 2 diabetes 
mellitus who have moderately 
severe to severe NPDR [DRSS 
levels 47 or 53], or mild PDR 
[DRSS level 61B] NVE < 0.5 
DA in 1 + quadrants], 
confirmed by the central 
reading center, in whom PRP 
and/or anti-VEGF intravitreal 
injection (IVT) can be safely 
deferred for at least 6 months 
Key Exclusion Criteria: 
1. CST of > 325 µm  
a. Fluid in the central subfield is allowed so long 
as CST is ≤ 325 µm and there is a normal 
foveal contour as determined by the Central 
Reading Center 
2. Any prior focal or grid laser photocoagulation or 
any prior PRP in the study eye as it pertains to 
treatment of DME or DR (peripheral retinal hole 
treated with laser is allowed) 


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per the Investigator. (ETDRS 
Report 1991). 
2. BCVA ETDRS letter score in 
the study eye of ≥ 69 letters 
(approximate Snellen 
equivalent of 20/40 or better) 
3. Normal foveal contour  
4. Treatment -naïve (ie, no 
previous anti-VEGF or steroid 
treatment or PRP or laser)  
5. Willing and able to return for 
all study visits and comply 
with study-related procedures 
6. Able to adhere to the study 
dosing requirements 
7. Understands and signs the 
written informed consent form 
(ICF) 
3. Eyes with DRSS score 61 due to fibrous 
proliferations at disc or fibrous proliferations 
elsewhere  
a. DRSS score 61B with NVE only is allowed. 
Any sign of fibrosis proliferation is 
exclusionary 
4. Any prior systemic anti-VEGF or IVT anti-VEGF 
treatment in the study eye 
5. Any prior intraocular steroid injection in the study 
eye, inclusive of Iluvien® and Retisert® 
a. History of Ozurdex® and triamcinolone use 
prior to 12 months before study enrollment is 
allowed 
6. Current ASNV, vitreous hemorrhage, or tractional 
retinal detachment visible at the screening 
assessments in the study eye 
7. Uncontrolled glaucoma or ocular hypertension in 
the study eye defined as an intraocular pressure 
(IOP) > 25 millimeter of mercury (mmHg) 
regardless of concomitant treatment with 
IOP-lowering medications 
8. Hypertension defined as systolic > 180 mmHg or 
> 160 mmHg on 2 consecutive measurements 
(during the same visit) or diastolic > 100 mmHg  
9. Screening HbA1c blood test > 12.0% 
10. Renal failure (stage 4 or end-stage), dialysis, or 
history of renal transplant 
11. 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 an investigational drug or that might affect 
interpretation of the results of the study or render 
the participant at high risk for treatment 
complications 
12. Initiation of intensive insulin treatment (a pump 
or multiple daily injections) within 4 months prior 
to randomization or plans to do so in the next 
4 months 


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13. Epiretinal membrane, posterior hyaloidal traction, 
and/or vitreomacular traction in the study eye as 
determined to be significant by the Investigator 
14. Previous pars plana vitrectomy in the study eye 
15. Any intraocular surgery in the study eye within 
90 days (3 months) prior to study enrollment 
16. Yttrium Aluminum Garnet (YAG) laser treatment 
in the study eye within 90 days prior to study 
enrollment 
17. Concomitant use of any topical ophthalmic 
medications in the study eye, including dry eye or 
glaucoma medications, unless on a stable dose for 
at least 90 days prior to study enrollment and 
expected to stay on stable dose throughout study 
participation. Topical eyedrops are not allowed 
within ± 10 minutes of study drop application 
18. Contact lens use from time of screening 
throughout the study  
19. Central corneal changes from dry eye that are 
visually significant and/or Sjogren’s syndrome 
20. Visually significant Fuchs endothelial dystrophy 
or other diagnosed conditions of corneal 
compromise including Anterior Basement 
Membrane Dystrophy, or any corneal dystrophy 
affecting central vision (peripheral processes are 
not exclusionary) 
21. Chronic or recurrent uveitis in the study eye 
22. Ongoing ocular infection or inflammation in 
either eye 
23. A history of cataract surgery complicated by 
vitreous loss in the study eye 
24. Congenital eye malformations in the study eye 
25. A history of penetrating ocular trauma in the 
study eye 
26. Cognitive impairment that, in the opinion of the 
investigator, could compromise compliance with 
the requirements of the study  
27. Females of childbearing potential (ie, who are not 
postmenopausal for at least 1 year or surgically 
sterile for at least 6 weeks prior to Visit 1 – 


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Screening/Randomization) who are lactating, or 
who are pregnant as determined by a positive 
serum pregnancy test at Visit 1 – Screening/ 
Randomization. Women of childbearing potential 
must agree to use acceptable methods of birth 
control throughout the study. 
a. Women who are breastfeeding or who have a 
positive serum hCG/urine pregnancy test at 
the screening or Baseline (BL) Visit 
28. Females and males of childbearing potential 
unwilling or unable to utilize the following 
acceptable methods of birth control: tubal 
ligation, transdermal patch, intrauterine 
devices/systems, oral/implantable/injectable or 
contraceptives, diaphragm or cervical cap with 
spermicide, or vasectomized partner for females; 
condoms with spermicidal agent and vasectomy 
for males; or sexual abstinence for males and 
females 
29. Participation in any other investigational device or 
drug clinical research study within 12 weeks of 
Visit 1 – Screening/ Randomization and during 
the duration of enrollment  
30. Contraindication to the study medications or 
fluorescein dye 
31. Other ocular pathologies that, in the investigator’s 
opinion, would interfere with the participant’s 
vision in the study eye 
32. Ocular media of insufficient quality to obtain 
fundus photographs, fluorescein angiography, and 
OCT images in the study eye 
33. Concomitant use of Semaglutide (Wegovy®, 
Ozempic®, Rybelsus®),Thiazolidinediones 
(Actos®, Avandia®), Liraglutides (Victoza®, 
Saxenda®), Dulaglutide (Trulicity®), or 
Tirzepatide (Mounjaro®) within 12 months prior 
to Visit 1(allowed if a stable dose has been 
established for at least1 year of use) 
a. Plans to start concomitant use of 
Semaglutides,Thiazolidinediones, 
Liraglutides, Dulaglutides, or Tirzepatides 
during the study duration is exclusionary 


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Note: The inclusion and exclusion criteria apply through study duration for 
non-emergency ocular procedures and surgery. 
Duration of Treatment: 
24 weeks 
Designation of Study Eye: 
Only one eye will be designated as the study eye in every participant. For participants who 
meet eligibility criteria in both eyes during the screening phase, the eye with the higher 
reading center confirmed DRSS should be selected. If both eyes have the same score, the 
eye with the clearest lens and ocular media will be selected. If there is no objective basis 
for selecting the study eye, factors such as ocular dominance (better focus ability), other 
ocular pathology, and participant preference should be considered in making the selection. 
The final selection will be done by the Investigator in discussion with the participant at 
baseline and must not be changed during the course of the study. 
The non-study eye is eligible for treatment according to the standard of care treatments 
through the duration of the study. 
Study procedures/assessments: 
Assessments will be performed monthly during each clinic visit unless indicated otherwise 
in the Schedule of Activities (SoA), and include the following: 
• Adverse event recording 
• Review of concomitant medications  
• Vital signs 
• Physical examination (Screening Visit only) 
• Laboratory testing (hematology, blood chemistry, urinalysis, and HbA1c) 
• Pregnancy testing (as applicable)  
• BCVA (ETDRS) 
• Slit-lamp bio-microscopy 
• Ocular surface health [fluorescein stain of the cornea] 
• IOP 
• Indirect ophthalmoscopy/dilated fundus examination 
• Spectral domain OCT (SD-OCT) (central subfield thickness, macular volume, foveal 
contour) at every visit 


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• 7-field or 4-wide field color fundus photography at every visit [optional wide-field if 
available] 
• DRSS scoring, based on 7-field or 4-wide field photos by the PI at baseline to confirm 
eligibility 
• Fluorescein angiography (FA) (wide field if available) at baseline and end of study 
• OCTA if available (for exploratory endpoints) at baseline and end of study 
• Rescue therapy initiation, per alignment between Investigator and Medical Monitor 
• HbA1c at screening and end of treatment 
• Gonioscopy 
Visit Timeline: 
Screening – Visit 1; Baseline (BL) – Visit 2; Week 4 – Visit 3; Week 8 – Visit 4; 
Week 12 – Visit 5; Week 16 – Visit 6; Week 20 – Visit 7; Week 24 – Visit 8 
Rescue Criteria: 
Participants meeting any of the following criteria would qualify for rescue with anti-VEGF 
therapy and/or PRP laser after consultation with the Medical Monitor: 
Objective Rescue Therapy Criteria: 
• Worsening DRSS level to 65 or higher as confirmed by the central reading center 
• Development of ASNV 
• Decrease in BCVA of ≥ 10 ETDRS letters from baseline associated with presence of 
new fluid or an increase in fluid in the central subfield compared to baseline at any 
visit 
• Decrease in BCVA of 5 to 9 ETDRS letters from baseline at two consecutive visits 
4 weeks apart associated with presence of new fluid or an increase in fluid in the 
central subfield compared to baseline  
• Increase in CST of ≥ 75 microns from baseline associated with presence of new fluid 
or an increase in fluid in the central subfield compared to baseline 
 
Subjective Rescue Criteria: 
• Any condition that, in the clinical opinion of the Investigator, warrants rescue therapy 
after consultation with the Medical Monitor 


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Statistical Analyses: 
Statistical analyses will include tabulations of summary data, inferential analyses, by 
participant listings, and figures. 
All statistical tests will be one-sided and will be performed at the 5% level of significance, 
unless otherwise stated. The vehicle control group will be combined for all efficacy 
analyses and two-sided 90% confidence intervals will be presented. Frequency counts (n 
and percentages) will be made for each qualitative variable. Descriptive statistics (n, mean, 
standard deviation [SD], median, minimum, and maximum) will be calculated for each 
quantitative variable, unless otherwise stated. All data will be summarized by treatment 
group. 
The baseline value for analysis and reporting will be based on the last (non-missing) 
measurement before dosing on Day 1. 
Comparison of the primary endpoint will be made between each dose group and the 
combined vehicle control group using a Mantel-Haenszel (MH) test of the difference in 
2 proportions stratified by the randomization stratification factor (BL DRSS score 47 or 53 
or 61B). The estimated MH risk difference will be summarized along with the 2-sided 
90% CI using MH stratum weights and the Sato variance estimator. The primary efficacy 
analysis will be performed on the ITT, while the PP set will be used as supplementary 
analyses. 
All secondary endpoint analyses will be performed on the ITT analysis set. The secondary 
endpoints involving proportions of participants will be analyzed using the same approach 
(MH test) as described for the primary efficacy analysis. Time to event secondary 
endpoints will be analyzed using a stratified log-rank test adjusting for the randomization 
stratification factor. Continuous secondary endpoints involving change from BL will be 
analyzed using an analysis of covariance (ANCOVA) model with BL measurement of the 
variable as a covariate and treatment group and the randomization stratification factor as 
fixed factors. The pair-wise comparisons of each OTT166 dose group versus combined 
vehicle control will be done in the ANCOVA model. Two-sided 90% confidence intervals 
for the difference of each OTT166 dose group minus combined vehicle control will be 
calculated. 
All safety summaries and analyses will be based on the Safety Analysis Set by treatment 
group (i.e., vehicle control doses (5% BID, 5% QID), vehicle control combined, active 
OTT166 doses (5% BID, 5% QID), and OTT166 combined). and overall. AEs will be 
coded using MedDRA and summarized by system organ class (SOC) and preferred term 
(PT). Analysis and reporting for AEs will be based on TEAEs. A TEAE is defined as an 
AE occurring (onset date/time) at the time of or after dosing on Day 1. Summaries of 
TEAEs by treatment group, SOC, and PT will include the following: All TEAEs, ocular 
TEAEs and TESAEs in the study eye, ocular TEAEs and TESAEs in the fellow eye, 
non-ocular TEAEs and TESAEs, all TESAEs, TEAEs and TESAEs leading to 


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discontinuation of study drug, TEAEs and TESAEs leading to discontinuation of study, 
drug-related TEAEs and TESAEs, TEAEs by intensity, AESIs. 


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2 
STUDY PROTOCOL 
2.1 
Study Rationale 
This study is designed to provide proof -of -concept that NPDR and mild PDR can be 
effectively treated with a topical eye drop formulation of OTT166. Furthermore, this study is 
designed to determine the dose-exposure response of OTT166 in terms of efficacy and safety 
in order to support the dose selection for the subsequent pivotal Phase 3 studies with 
OTT166 in DR. 
OTT166 is a representative from a new class of drugs (ie, a topical integrin inhibitor targeted 
to the back of the eye). It is being developed for treatment of DR. The study is intended to 
show in particular that OTT166: 
• Is overall safe and well tolerated 
• Prevents progression of DR 
• Prevents VTCs and/or CI-DME  
• Reverses retinal changes attributed to DR 
• Maintains visual acuity 
 
2.2 
Study Objectives 
The primary objectives for this study are: 
• To characterize the safety of topical OTT166 in participants with DR 
• To characterize the efficacy of topical OTT166 in participants with DR 
 
The secondary objectives of this study are: 
• To determine if topical OTT166 will prevent or delay the occurrence of VTC, defined as 
PDR worse than mild and/or ASNV and/or CI_DME 
• To determine if topical OTT166 will prevent or delay the occurrence of CI-DME 
• To determine the effect of OTT166 on DRSS in participants with moderately severe to 
severe NPDR and mild PDR treated with topical OTT166 
• To determine the effect of OTT166 on BCVA in participants with moderately severe to 
severe NPDR and mild PDR 
• To determine the effect of OTT166 on central subfield thickness in participants with 
moderately severe to severe NPDR and mild PDR 


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• To determine the effect of OTT166 on the need for rescue therapy in participants with 
moderately severe to severe NPDR and mild PDR 
 
The exploratory objectives of this study are: 
• To evaluate the change in DME in participants treated with OTT166 
• To assess the effects of treatment on anatomic markers other than DRSS and on retinal 
non-perfusion 
 
2.3 
Introduction DR 
NPDR has a multifactorial origin and is caused by hyperglycemia-induced oxidative stress, 
hypoxia, pericyte loss, endothelial cell loss, leukostasis, and inflammation. It leads to a 
breakdown of the blood-retinal barrier. There is extensive evidence that angiogenic cytokines 
(eg, VEGF) and inflammatory cytokines are involved in the development of DR. DR is 
categorized based on the presence of vascular and vascular associated lesions and the 
absence (in NPDR) or presence (in PDR) of neovascularization. Earlier clinical features of 
DR include microaneurysm, hemorrhage, cotton wool spots, hard exudates and IRMAs. As 
the severity of DR progresses, capillary non-perfusion leads to retinal ischemia. This induces 
an upregulation of pro-angiogenic and pro-inflammatory cytokines, leading to proliferation 
of aberrant retinal vasculature. When left untreated, these new, fenestrated, brittle and leaky 
vessels extend and grow and result in vitreous hemorrhage and/or exudation. This is 
associated with the formation of gliosis and fibrous tissue formation. These scars contract 
and can result in tractional retinal detachment and loss of vision (Lechner 2017, 
Cheung 2010, Wang 2018). 
Treatment options for moderately severe and severe NPDR and PDR include PRP, 
anti-VEGF agents, and vitrectomy for PDR (Wang 2018). PRP has been the gold standard for 
> 40 years for the treatment of PDR. The DR Study has shown that PRP reduces the risk of 
severe vision loss by over 50% (Aiello et al. 1973). However, PRP is destructive and causes 
permanent peripheral vision loss that may interfere with driving and impair night vision, 
color vision, and contrast sensitivity. It may also exacerbate DME (Brucker 2009, 
Ferris 1987). Anti-VEGF therapies are globally approved for DR, regardless of severity, but 
they can require monthly intravitreal injections, with the continuous risk of serious side 
effects, such as endophthalmitis or retinal detachment, and the inconvenience of traveling to 
a retina specialist office for every injection. Thus, there is an unmet clinical need for 
non-invasive efficient treatment options. 
OTT166 is intended to address the current limitations in the treatment of DR. As outlined 
above, anti-VEGF treatment requires IVT every 4 to 12 weeks under topical anesthesia. The 
frequent visits to a retina specialist represent a significant burden to participants, particularly 
for DR participants, many of whom are of working age. An alternative mode of drug 
administration, particularly topical eye drops, represents a very attractive treatment option. 


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The objective of this study is to determine an efficacy and safety profile of OTT166 in the 
treatment of participants with DR, with the objective to evaluate the potential to improve 
therapeutic outcomes, while minimizing treatment burden for participants. Preclinical and 
clinical studies with OTT166 have demonstrated notable anti-angiogenic activity and have 
shown that the fluorination in the compound has a positive impact on the ability for the 
treatment to reach the back of the eye. Activity of OTT166 in VEGF-driven models appears 
similar to anti-VEGF biologics. Moreover, OTT166 also blocks angiogenic signaling driven 
by other growth factors (platelet-derived and fibroblast growth factor), so clinical efficacy 
could exceed that of marketed drugs that only target VEGF. 
Based on the pre-clinical information, it is expected that the benefits of OTT166 outweigh 
the risks of its use. 
2.4 
OTT166 Background 
DR is caused by damage to retinal blood vessels in patients with diabetes and is the leading 
cause of blindness among the United States working-age population. The disease starts with 
the formation of microaneurysms and progresses to hemorrhages and neovascularization of 
the retina and vitreous. At any point along this continuum, vessels can leak fluid into the 
macula, causing diabetic macular edema (DME) and consequently cause loss of eyesight, 
particularly if the fluid accumulates in the center of the macula. Patients with mild or 
moderate DR have an approximately 23% chance of progressing to severe disease over 
5 years and an approximately 60% chance of developing DME (Cheung 2010, Ferris 1987, 
Wang 2018).  
Integrins are proteins found on the surface of cells that help them attach to, and communicate 
with nearby cells, and play an important role in cell growth, cell movement, and other cell 
functions. Integrins are comprised of an α subunit and a β subunit and 24 αβ combinations 
have been identified. Integrins that recognize ligands with an RGD sequence, called 
RGD‑binding integrins, play key roles in the 4 hallmarks of DR: vascular leakage, 
neovascularization, inflammation, and fibrosis (Figure 1). Expression of high levels of the 
integrin αvβ3 and αvβ5 in human retinal membranes from patients with proliferative DR have 
been reported. 


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Figure 1 
RGD‑Binding Integrins Involved in the Pathogenesis of Diabetic 
Retinopathy 
 
RGD = arginine-glycine-aspartic acid. 
Source: Van Hove I, Hu TT, Beets K, et al. Targeting RGD-binding integrins as an integrative therapy for 
diabetic retinopathy and neovascular age-related macular degeneration. Prog Retin Eye Res. 2021;85:100966. 
 
Small molecule inhibitors (antagonists) of RGD-binding integrins have shown efficacy in 
animal models of retinal neovascularization when administered by subcutaneous injection, 
intraperitoneal injection, periocular injection, or topically. A reported RGD-binding integrin 
inhibitor, risuteganib (Allegro Ophthalmics), that is delivered by intravitreal injection (IVT) 
has completed a Phase 2b study for the treatment of DME (ClinicalTrials.gov: 
NCT02348918). This integrin inhibitor has been studied in more than 200 participants and 
has shown efficacy similar to anti-VEGF (vascular endothelial growth factor) with a reduced 
number of injections. Another small molecule RGD‑binding integrin inhibitor, THR-687 
(Oxurion NV), administered by IVT, has recently been studied in a single‑dose‑escalation 
Phase 1 trial. The Phase 2 INTEGRAL trial data showed THR‑687 to be safe and well 
tolerated with no serious adverse events (SAEs) and none of the patients required rescue 
medication through Month 3, however, there was insufficient evidence of efficacy on the key 
endpoints (best corrected visual acuity [BCVA] and central subfield thickness). As a result, 
Oxurion NV has decided not to continue the clinical development of THR-687. No topically 
administered RGD‑binding integrin inhibitor, other than OTT166, has advanced into clinical 
testing to date. 
OTT166 is a potent and selective small molecule RGD‑binding integrin inhibitor with a 
balance of physiochemical properties to allow it to distribute to the retina in high 
concentrations after topical administration. The company discovered OTT166 by applying 
in-depth knowledge of the impact of incorporating fluorine substituents into small molecules 
drugs to alter their chemical and pharmacological properties. MK-0429, the predicate 
molecule to OTT166, was tested in clinical trials for the treatment of osteoporosis in high 
oral doses and was found to be safe and well tolerated but was not further developed for 
commercial reasons. OcuTerra demonstrated that while MK-0429 does not distribute to the 
back of the eye after topical administration, addition of fluorine substituents in specific 
positions on MK-0429 resulted in OTT166 with high potency and selectivity for 
Fibrosis 


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RGD-binding integrins and OTT166 does distribute to the back of the eye after 
administration as an eye drop. 
2.5 
Previous Clinical Studies 
OTT166 topical ophthalmic solution has been studied in 2 Phase 1b clinical trials, 1 in 
participants with center-involving (CI) DME and the other in participants with nAMD. Each 
study enrolled 44 participants who were treated with OTT166 eye drops twice daily (BID) 
for 28 days and then followed for an additional 28 days after concluding treatment. There 
were 2 dose groups in each study: 2.5% (1.25 mg/eye) BID and 5% (2.5 mg/eye) BID; 
participants were randomized 1:1 to the 2 groups. The primary objective of each study was to 
determine safety and tolerability of the study treatments. The safety evaluations included 
adverse event (AE) reporting, intraocular pressure (IOP) and BCVA measurements, slit-lamp 
and fundus examinations, and fluorescein angiography (FA). Exploratory efficacy (ie, 
evidence of biological activity) was assessed by change from baseline (BL) in retinal 
thickness parameters measured by spectral-domain optical coherence tomography and 
change from BL in BCVA. 
2.5.1 
OTT166 in DME 
The results of the first study indicate that both doses of OTT166 (1.25 and 2.5 mg/eye BID) 
are safe and well tolerated in adult participants with CI-DME. Six participants, 5 (22.7%) in 
the OTT166 1.25 mg/eye group and 1 (4.5%) in the OTT166 2.5 mg/eye group, had a serious 
TEAE, but all were non-ocular in nature and unrelated to study drug. Six participants 
experienced ocular TEAEs in the study eye, 2 (9.1%) in the OTT166 1.25 mg/eye group and 
4 (18.2%) in the OTT166 2.5 mg/eye group. All the ocular TEAEs in the study eye were mild 
in intensity. One event, ocular hyperemia, was considered possibly drug related. 
One participant (OTT166 1.25 mg/eye) was discontinued from study drug due to an AE 
(hypersensitivity [verbatim: whole body allergic reaction/itching]). Given the onset and 
resolution pattern of the event, the investigator reported the event as probably related to study 
drug. 
Mean changes from BL in IOP were nominal in both treatment groups throughout the study. 
There were no TEAEs of ocular hypertension or increased IOP. None of the participants had 
a clinically relevant change from BL in the study eye in the slit-lamp, dilated fundoscopy, or 
FA results. 
Four participants received rescue treatment during the 28-day follow-up period, none during 
the treatment phase. None of the 4 participants rescued during the recovery phase met the 
rescue criteria. 
There were insignificant changes in the exploratory efficacy measures, change in central 
retinal thickness from BL, and change in BCVA from BL, on a group mean basis; however, 
there was a subset of participants that showed significant improvement by OCT as judged by 
a panel of 3 retina specialists who reviewed all the OCT scans. Applying their expert 
assessment to the review of the scans of every participant, they determined there were 


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14 participants who showed evidence of response (ie, biological activity), constituting 37% 
of the completed participants in the study. 
2.5.2 
OTT166 in nAMD 
The results of the second study indicate that both doses of OTT166 (1.25 and 2.5 mg/eye 
BID) are safe and well tolerated in adult participants with nAMD. One participant (OTT166 
2.5 mg/eye group) had a serious TEAE; the event was non-ocular in nature (peripheral artery 
thrombosis) and not considered related to study drug. In terms of ocular events in the study 
eye, 4 participants, 1 (4.3%) in the OTT166 1.25 mg/eye group and 3 (14.3%) in the OTT166 
2.5 mg/eye group, had a total of 1 and 3 ocular TEAEs, respectively. None of the participants 
had > 1 ocular TEAE in the study eye during the study. All the ocular TEAEs in the study 
eye were mild or moderate in intensity. One participant (OTT166 2.5 mg/eye group) had an 
ocular TEAE, dry eye, that was possibly related to study drug. 
Two participants (both in the OTT166 2.5 mg/eye group) were discontinued from study drug 
due to an AE; these events were headache and retinal hemorrhage in the study eye 
(1 participant each). The retinal hemorrhage in the study eye was considered by the 
investigator to be unrelated to study drug. 
Throughout the study, mean changes from BL in IOP were nominal in each treatment group. 
Few slit lamp abnormalities were observed in the study eye during the study, regardless of 
treatment group. Two participants had a worsening in opacity status in both the study and 
non-study eyes. There were no clinically relevant shifts from normal to abnormal in the 
fundus examination findings. 
Ten participants were rescued by administration of an anti-VEGF drug, 2 during the 
treatment phase and 8 during the follow-up phase of the study, although the criteria for 
rescue were not met in any of the cases. 
There were insignificant changes in the exploratory efficacy measures, change in central 
retinal thickness from BL, and change in BCVA from BL, on a group mean basis; however, 
there was a subset of participants that showed significant improvement by OCT as judged by 
a panel of 3 retina specialists who reviewed all the OCT scans. The retina specialists 
determined that there were 8 participants (19.5%) in the PP population who showed evidence 
of response (ie, biological activity). 
Additional details about the clinical data are provided in the IB. 
2.6 
Study Design 
The OTT166 201 Phase 2 will be conducted to select an optimum dosing regimen 
(frequency) for Phase 3 pivotal trials. Approximately 210 participants diagnosed with 
moderately severe to severe NPDR or mild PDR and who are treatment naïve (ie, no prior 
anti-VEGF or laser [focal, grid, PRP] administered) will be randomized 2:2:1:1 into the 
following groups: OTT166 5% BID, OTT166 5% QID, vehicle control BID, or vehicle 
control QID. Randomization will be stratified by BL DRSS score (47 or 53 or 61B). 
Participants with PDR (DRSS score 61B) will be capped at 20% of all randomized 


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participants. Each group will self-administer one 50-microliter (µL) eye drop of study 
solution (frequency as assigned) for 24 weeks. 
2.7 
Study Population 
Participants should show typical fundus alterations with moderately severe to severe NPDR 
or mild PDR (participants with mild PDR will be capped at 20% of all randomized 
participants), as defined by the DRSS Steps 47, 53, and 61B. Participants may have fluid in 
the macula with BCVA of ≥ 69 ETDRS letters (Snellen equivalent 20/40) and CST of 
≤ 325 µm, and a normal foveal contour, which need to be confirmed by an independent 
central reading center, in at least 1 eye. 
Treatment of DR with OTT166 targets the retina and is being investigated for signs of 
efficacy in this clinical trial. To be able to examine the retina appropriately at screening and 
during the study, participants whose eyes have anomalies that interfere with 
protocol -required examinations are excluded. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
2.8 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Men or women ≥ 18 years of age with type 1 or 2 diabetes mellitus who have 
moderately severe to severe NPDR [DRSS levels 47 or 53], or mild PDR [DRSS 
level 61B] NVE < 0.5 DA in 1 + quadrants], in whom PRP and/or anti-VEGF IVT 
can be safely deferred for at least 6 months per the Investigator (ETDRS report 1991). 
2. BCVA ETDRS letter score in the study eye of ≥ 69 letters (approximate Snellen 
equivalent of 20/40 or better) 
3. Normal foveal contour  
4. Treatment naïve (ie, no previous anti-VEGF or steroid treatment or PRP or laser) 
5. Willing and able to return for all study visits and comply with study-related 
procedures 
6. Able to adhere to the study dosing requirements 
7. Understands and signs the written ICF 
 


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2.9 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. CST of > 325 µm 
a. Fluid in the central subfield is allowed so long as CST is ≤325 µm and there is a 
normal foveal contour as determined by the Central Reading Center 
2. Any prior focal or grid laser photocoagulation or any prior PRP in the study eye as it 
pertains to treatment of DME or DR (peripheral retinal hole treated with laser is 
allowed) 
3. Eyes with DRSS score 61 with fibrous proliferations at disc or fibrous proliferations 
elsewhere  
a. DRSS score 61B with NVE only is allowed. Any sign of fibrosis proliferation is 
exclusionary 
4. Any prior systemic anti-VEGF treatment or IVT anti-VEGF treatment in the study 
eye 
5. Any prior intraocular steroid injection in the study eye, inclusive of Iluvien® and 
Retisert® 
a. History of Ozurdex® and triamcinolone use prior to 12 months before study 
enrollment is allowed 
6. Current ASNV, vitreous hemorrhage, or tractional retinal detachment visible at the 
screening assessments in the study eye 
7. Uncontrolled glaucoma or ocular hypertension in the study eye defined as an 
IOP > 25 mmHg regardless of concomitant treatment with IOP-lowering medications 
8. Hypertension defined as systolic > 180 mmHg or > 160 mmHg on 2 consecutive 
measurements (during the same visit) or diastolic > 100 mmHg 
9. Screening HbA1c blood test > 12.0% 
10. Renal failure (stage 4 or end-stage), dialysis, or history of renal transplant 
11. 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 an investigational drug or that might affect interpretation of 
the results of the study or render the participant at high risk for treatment 
complications 
12. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 
4 months prior to randomization or plans to do so in the next 4 months 
13. Epiretinal membrane, posterior hyaloidal traction, and/or vitreomacular traction in the 
study eye as determined to be significant by the Investigator 
14. Previous pars plana vitrectomy in the study eye 


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15. Any intraocular surgery in the study eye within 90 days (3 months) prior to study 
enrollment 
16. YAG laser treatment in the study eye within 90 days prior to study enrollment 
17. Concomitant use of any topical ophthalmic medications in the study eye, including 
dry eye or glaucoma medications, unless on a stable dose for at least 90 days prior to 
study enrollment and expected to stay on stable dose throughout study participation. 
Topical eyedrops are allowed but not within ± 10 minutes of study drop application 
18. Contact lens use from time of screening throughout the study  
19. Central corneal changes from dry eye that are visually significant and/or Sjogren’s 
syndrome 
20. Visually significant Fuchs endothelial dystrophy or other diagnosed conditions of 
corneal compromise including Anterior Basement Membrane Dystrophy, or any 
corneal dystrophy affecting central vision (peripheral processes are not exclusionary) 
21. Chronic or recurrent uveitis in the study eye 
22. Ongoing ocular infection or inflammation in either eye 
23. A history of cataract surgery complicated by vitreous loss in the study eye 
24. Congenital eye malformations in the study eye 
25. A history of penetrating ocular trauma in the study eye 
26. Cognitive impairment that, in the opinion of the investigator, could compromise 
compliance with the requirements of the study 
27. Females of childbearing potential (ie, who are not postmenopausal for at least 1 year 
or surgically sterile for at least 6 weeks prior to Visit 1 – Screening/Randomization) 
who are lactating, or who are pregnant as determined by a positive serum pregnancy 
test at Visit 1 – Screening/Randomization. Women of childbearing potential must 
agree to use acceptable methods of birth control throughout the study 
a. Women who are breastfeeding or who have a positive serum hCG/urine 
pregnancy test at the screening or BL Visit 
28. Females and males of childbearing potential unwilling or unable to utilize the 
following acceptable methods of birth control: tubal ligation, transdermal patch, 
intrauterine devices/systems, oral/implantable/injectable or contraceptives, diaphragm 
or cervical cap with spermicide, or vasectomized partner for females; condoms with 
spermicidal agent and vasectomy for males; or sexual abstinence for males and 
females 
29. Participation in any other investigational device or drug clinical research study within 
12 weeks of Visit 1 – Screening/Randomization and during the duration of enrollment 
30. Contraindication to the study medications or fluorescein dye 
31. Other ocular pathologies that, in the investigator’s opinion, would interfere with the 
participant’s vision in the study eye 


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32. Ocular media of insufficient quality to obtain fundus photographs, fluorescein 
angiography, and OCT images in the study eye 
33. Concomitant use of Semaglutide (Wegovy®, Ozempic®, Rybelsus®), 
Thiazolidinediones (Actos®, Avandia®), Liraglutides (Victoza®, Saxenda®), 
Dulaglutide (Trulicity®), or Tirzepatide (Mounjaro®) within 12 months prior to Visit 
1 (allowed if a stable dose has been established for at least 1 year of use) 
a. Plans to start concomitant use of Semaglutide, Thiazolidinediones, Liraglutides, 
Dulaglutides, or Tirzepatides during the study duration is exclusionary 
 
2.10 
Lifestyle Considerations 
No study specific lifestyle restrictions are required. Participation in this study does not 
require modifications of lifestyle. Participants should follow their usual lifestyle, as part of 
their diabetes management plan. 
2.11 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, and eligibility criteria. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
only be rescreened once. In any case, the Investigator must ensure that the repeated screening 
procedures do not expose the participant to an unjustifiable health risk. For re-screening, the 
participant must re-sign the ICF, even if it was not changed after the participant's previous 
screening. 
Rescreened participants will be assigned a new participant number. 
In case of abnormal or implausible results, which may be caused by intercurrent diseases, 
short-term treatable conditions, other temporary health disorders (eg, acute infection, 
laboratory changes, blood pressure outside defined range), or inappropriate circumstances 
(eg, inadequate rest when required, hemolysis), the investigator may decide to repeat the 
respective screening parameter(s) twice without rescreening (within 21 days). 
2.12 
Criteria for Temporarily Delaying Randomization / Study Intervention 
Administration 
If a participant is otherwise eligible, the participant’s study intervention may be postponed 
to allow acute intercurrent conditions to resolve. Under these circumstances, the screening 
period may be extended to 6 weeks upon discussion with the medical monitor. 


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2.13 
Selection of the Study Eye 
Only one eye will be designated as the study eye in each participant. For participants who 
meet eligibility criteria in both eyes during the screening phase, the eye with the higher 
reading center confirmed DRSS should be selected. If both eyes have the same score, the eye 
with the clearest lens and ocular media will be selected. If there is no objective basis for 
selecting the study eye, factors such as ocular dominance (better focus ability), other ocular 
pathology, and participant preference should be considered in making the selection. The final 
selection will be performed and documented by the investigator in discussion with the 
participant at BL and must not be changed during the study. 
The non-study eye is eligible for treatment according to the standard of care treatments 
through the duration of the study. 
2.14 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
vehicle control, or medical device(s) intended to be administered to a study participant, 
according to the study protocol. 
2.14.1 
Study Intervention 
In this study, 5% OTT166 ophthalmic solution or vehicle control, will be given to the 
participants who will self-administer one 50-µL eye drop of study solution at the prescribed 
frequency based on randomization, for 24 weeks. Approximately 210 participants diagnosed 
with moderately severe to severe NPDR or mild PDR (participants with mild PDR will be 
capped at 20% of all randomized participants ) and who are treatment naïve (ie, no prior 
anti-VEGF or laser [focal, grid, PRP] administered) will be randomized 2:2:1:1 into the 
following groups: OTT166 5% BID (5.0 mg/day),OTT166 5% QID (10 mg/day), vehicle 
control BID, or vehicle control QID. Randomization will be stratified by baseline DRSS 
score (47 or 53 or 61B). 
Eye dropper bottles containing active treatment of OTT166, and corresponding vehicle 
control, are identical in appearance (size, color, shape) and associated with a unique number. 
Eye dropper bottles will be dispensed at the study visits summarized in the SoA 
(Section 2.15.1). Returned eye dropper bottles should not be re-dispensed to the participants. 
2.14.2 
Preparation / Handling / Storage / Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all eye dropper bottles received and any discrepancies are 
reported and resolved before use of the eye dropper bottle. 
Only participants randomized in the study may receive eye dropper bottles, and only 
authorized site staff may supply the eye dropper bottles. All eye dropper bottles must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 


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accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
The investigator or the head of the institution (where applicable) is responsible for eye 
dropper bottle accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). Drug receipt, reconciliation, and destruction 
information on the study sites will be captured in the interactive web response system 
(IWRS). 
Further guidance and information for the final disposition of unused eye dropper bottles are 
provided in the Investigator Site File. 
2.14.3 
Measures to Minimize Bias: Randomization and Masking 
All participants will be centrally assigned to randomized study intervention using IWRS. 
Participants will be randomized 2:2:1:1 into the following groups: OTT166 5% twice daily 
(BID), OTT166 5% four times daily (QID), vehicle control BID, vehicle control QID. 
Randomization will be stratified by BL DRSS score (47 or 53 or 61B). Participants with PDR 
(DRSS score 61B) will be capped at 20% of all randomized participants. 
The participant and the clinical assessor will be masked to the treatment group / dose. 
The IWRS will be programmed with instructions on how to break/unmask a participant’s 
randomized treatment. In case of an emergency, the investigator has the responsibility for 
determining if unmasking of a participant’s intervention assignment is warranted. If the 
investigator is unavailable, and a treating physician not associated with the study requests 
emergency unmasking, the emergency unmasking requests are forwarded to the emergency 
medical advice 24-hour/7-day service. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unmasking is 
warranted, the investigator should make every effort to contact the medical monitor prior to 
unmasking a participant’s intervention assignment, unless this could delay emergency 
treatment of the participant. If a participant’s intervention assignment is unmasked, the 
sponsor must be notified within 24 hours after the unmasking. Date and reason for the 
unmasking must be recorded in the source documentation and case report form, as 
applicable. 
2.14.4 
Study Intervention Compliance and Adherence 
The clinical investigation uses the Medication Event Monitoring System (MEMS®, 
AARDEX Group, Belgium) during the complete study follow-up period to automatically 
compile dosing history data in participants remotely. Study medication will be provided to 
the participants in dropper bottles which should be placed in the MEMS® Cap and bottle 
system when in use for the MEMS Cap ® to electronically record the date and time of each 
opening of the medication container. Site personnel will dispense at the baseline visit and 
then read the MEMS® Caps at each clinic visit using the MEMS Adherence Software 
(MEMS AS®). The purpose of using the MEMS® is to monitor the participant’s medication 
intake behavior and related adherence metrics longitudinally in the participant’s home 


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environment during the clinical investigation. Adherence is calculated in the MEMS AS® 
dashboard and is a feedback tool for sites to intervene when participants deviate from the 
dosing regimen. When a participant deviates from the dosing regimen (i.e., overdoses, 
underdoses, missed data transfer), the dashboard displays suboptimal adherence or absence 
of data transfer, and an email is sent to notify the applicable site to intervene. This 
intervention should be properly documented in the patient dashboard to indicate what type of 
intervention was needed (e.g., retraining on dosing adherence, retraining on MEMS ® Cap 
use, retraining on MEMS ® app, etc.). Adherence to study medication should be monitored 
continuously by sites between visits to ensure participants are taking the correct number of 
prescribed doses.  
Compliance is calculated per protocol and is the number of doses taken divided by the 
number of expected doses. Compliance will be calculated for the final analysis and will be 
determined monthly and overall, through W24. Non-compliance is defined as a dosing record 
of < 75% of the expected number of dosing events, based on the participants’ dosing 
schedule prescribed at randomization.  
A record of the quantity of bottles dispensed to and administered by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or missed doses, will also be 
recorded. 
IWRS will be used for drug accountability on a participant basis. Drug returns, 
reconciliation, and destruction information will be captured in the IWRS. 
Taken together, these measures are deemed appropriate to support participants’ adherence 
and to detect participants who are systematically non-adherent in the opinion of the 
investigator. 
2.14.5 
Dose Modification 
The doses to be administered are 5% OTT166 (or vehicle control) either BID or QID. 
No dose modification is planned. 
2.14.6 
Stopping Rules (Study Level) 
The following criteria result in an immediate stop of dosing and will result in a temporary 
halt of the study: 
Any relevant information, from this trial or from outside of this trial, indicating a relevant 
deterioration of the benefit-risk ratio. In particular, consistently observed serious adverse 
events (SAEs) or severe drug-related AEs will be thoroughly assessed by the medical 
monitor and Study Steering Committee. 
Resuming the trial after a temporary halt requires an approved substantial amendment. For 
discontinuation of study intervention for individual study participants, see Section 2.14.10. 


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2.14.7 
Continued Access to Study Intervention After the End of the Study 
No treatment with study medication will be provided after the end of the planned 24-week 
treatment period or after early withdrawal of treatment. 
2.14.8 
Concomitant and Prohibited Therapy in the Study Eye 
No other ocular topical drugs (eye drops) should be taken during the study unless prescribed 
by the treating study physician and after discussion with the sponsor and medical monitor. If 
topical therapy (eye drops) is prescribed, the application of such therapy should not occur 
within 10 minutes (before or after) of instillation of study therapy. Other approved or 
investigational therapies for retinal disease (ie, oral, topical, and/or intravitreal injected drugs 
like steroids or anti-VEGFs) are not permitted, unless applied as rescue therapy 
(Section 2.14.9). Such intake is to be recorded (see below). Contact lens wear is strictly 
prohibited from the time of screening throughout the study. If participant has current contact 
lens use at screening, contact lens use should be discontinued immediately, and a 14 day 
ocular surface stabilization period is needed between screening and baseline. 
Concomitant medications are to be recorded in the eCRF. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
2.14.9 
Rescue Therapy 
Participants meeting any of the following criteria would qualify for rescue with anti-VEGF 
therapy and/or PRP laser after consultation with the medical monitor: 
Objective Rescue Therapy Criteria: 
• Worsening DRSS level to 65 or higher as confirmed by the central reading center 
• Development of ASNV 
• Decrease in BCVA of ≥ 10 ETDRS letters from BL associated with presence of new fluid 
or an increase in fluid in the central subfield compared to baseline at any visit 
• Decrease in BCVA of 5 to 9 ETDRS letters from BL at two consecutive visits 4 weeks 
apart associated with presence of new fluid or an increase in fluid in the central subfield 
compared to baseline 
• Increase in CST of ≥ 75 microns from BL associated with presence of new fluid or an 
increase in fluid in the central subfield compared to baseline 
 
Subjective Rescue Criteria: 
• Any other condition that, in the clinical opinion of the investigator, warrants rescue 
therapy after consultation with the medical monitor 


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2.14.10 
Discontinuation of Study Intervention and Participant Discontinuation / 
Withdrawal 
2.14.10.1 
Permanent Discontinuation 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is permanently discontinued, the 
participant may remain in the study for continued assessment of safety and efficacy 
outcomes. 
Unscheduled visits may be performed as deemed appropriate by the investigator, in 
particular, in case of withdrawal due to an AE. 
Participants must be withdrawn from the study intervention for any of the following reasons: 
• If rescue therapy has been initiated 
• Safety concerns for a participant by the investigator or the sponsor 
• Vision threatening complication meeting rescue criteria and/or progression to worse than 
mild PDR with DRSS > 61 
• Pregnancy (see Section 2.17.4 for details) 
 
Necessity to withdraw the participant from the study will be assessed case-by-case by the 
investigator in consultation with the medical monitor. 
2.14.10.2 
Temporary Discontinuation 
Treatment should be withheld temporarily if any of the following conditions apply: 
• Occurrence of hypersensitivity after instillation of the eye drops 
• Rechallenge can be considered at the discretion of the investigator in consultation with 
the medical monitor 
 
The investigator may decide to temporarily discontinue treatment for other reasons if deemed 
appropriate for the safety and well-being of the participant. The medical monitor should be 
informed. 
2.14.11 
Participant Discontinuation / Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This includes cases in which, in the investigator's opinion, continued 
participation in the study would be harmful to the participant's well-being. This is expected to 
be uncommon. 


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• At the time of discontinuing from the study, if possible, the final study visit should be 
conducted as early discontinuation visit, followed by safety follow-up as determined by 
the investigator in keeping with standard of care. See SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need to 
be completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
 
2.14.12 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
Discontinuation of specific sites or of the study as a whole are handled separately. 
2.15 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1). Protocol waivers or 
exemptions are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 


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Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or BL purposes, 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA. 
 


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2.15.1 
Schedule of Activities 
Table 1 
OTT166 201 Phase 2 DR Study: Schedule of Activities (Through Week 24 – Primary Endpoint) 
Study Procedure 
Screening Visit 1 Baseline (BL) Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8a 
Week 
-- 
0 
4 
8 
12 
16 
20 
24 
Day (visit window) 
-21 to -1 
1 
29 ± 
7 days 
57 ± 
7 days 
85 ± 
7 days 
113 ± 
7 days 
141 ± 
7 days 
169 ± 
7 days 
Screening/Baseline (BL):  
 
 
 
 
 
 
 
 
Informed consent  
X 
Inclusion/exclusion  
X 
X 
Medical and ophthalmic history  
X 
 
 
 
 
 
 
 
Demographics  
X 
Randomization  
X 
Interval Medical Review:  
Review of concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
Continue study treatmentb  
X 
X 
X 
X 
X 
X 
Ocular Assessmentsn:  
Refraction and BCVA (ETDRS) 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Slit lamp examination  
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Assessment of corneac 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Intraocular pressured  
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Indirect ophthalmoscopy 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
4-wide or 7-field color fundus photography (mandatory)e 
OU 
OU 
SE 
SE 
OU 
SE 
SE 
OU 
SD-OCT (widefield if available) 
OU 
OU 
SE 
SE 
OU 
SE 
SE 
OU 
OCTA (if available) 
OU 
OU 
Wide field Fluorescein Angiographym 
OU 
OU 
Gonioscopy 
OU 
 
 
 
 
 
 
OU 


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Study Procedure 
Screening Visit 1 Baseline (BL) Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8a 
Week 
-- 
0 
4 
8 
12 
16 
20 
24 
Day (visit window) 
-21 to -1 
1 
29 ± 
7 days 
57 ± 
7 days 
85 ± 
7 days 
113 ± 
7 days 
141 ± 
7 days 
169 ± 
7 days 
Non-Ocular Assessments: 
Physical examinationf 
X 
 
 
 
 
 
 
 
Vital signsg  
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsh  
X 
X 
X 
X 
X 
X 
X 
X 
IP adherence reviewo 
 
 
X 
X 
X 
X 
X 
X 
Laboratory Testing:i 
 
 
 
 
 
 
 
 
Hematology, blood chemistry, urinalysis, and HbA1cj,l  
X 
X 
Pregnancy test, women of childbearing potentialk  
serum 
urine 
urine 
urine 
urine 
urine 
urine 
urine 
Abbreviations: BCVA: best corrected visual acuity; BL: baseline; ETDRS: Early Treatment Diabetic Retinopathy Study; HbA1c: glycosylated hemoglobin; OCTA: optical 
coherence tomography – angiography; OU: both eyes; SD-OCT: spectral-domain optical coherence tomography; SE: study eye. 
a 
Participants who are withdrawn from the study before Week 24/Visit 8 will be asked to return to the clinic to complete the end of study assessments. 
b 
Participants will continue to receive study treatment based on exam findings, AE review, and verification that rescue criteria are not met. 
c 
Cornea health assessment following instillation of fluorescein stain, including epithelium and endothelium, for signs of toxicity. 
d 
Intraocular pressure should be measured at approximately the same time of day from visit to visit, if possible. 
e 
An FP and FA must be performed once a participant has been diagnosed with worse than mild PDR, ASNV, or new onset or worsening CI-DME in the study eye, and before 
rescue treatment is given. 
f 
May be performed at Visit 1 or Visit 2, Including height, weight, and body temperature. 
g 
Vital signs (blood pressure and heart rate) will be measured after the participant has been sitting for 5 minutes at the screening visit. From baseline through end of study only 
blood pressure and heart rate will be measured. 
h 
AEs will be collected from the time the ICF is signed until early termination or the end of study visit. If a participant withdraws from the study, ongoing AEs will be followed 
to the end of study visit or until the participant withdraws consent. 
i 
All samples collected for laboratory assessments will be obtained prior to administration of study drug. 
j 
At visits at which FA is performed, urinalysis samples will be collected before FA in order to avoid false elevations in urine protein values. 
k 
For women of childbearing potential, a negative screening serum pregnancy test at Visit 1 is required before randomization. All women of childbearing potential will have a 
urine pregnancy test at each treatment visit starting at Visit 2 (Day 1); a negative urine pregnancy test is required before treatment is continued (randomized treatment, rescue 
treatment). 
l 
Refer to Appendix 3 for clinical laboratory test details. 
m 
Screening Fluorescein angiography is valid for 3 months. Participants undergoing rescreen do not need IVFA repeated within 3 months of original angiogram. 
n 
Cornea should be assessed at the beginning before dilation. 
o 
Adherence to the dosing regimen should be monitored continuously and discussed with the participant at each visit. Sites are expected to intervene if there is suboptimal 
adherence or absence of data transfer and document the intervention in the patient dashboard. 


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2.15.2 
Study Activities 
After signing an informed consent, participants will be invited to a screening visit, Visit 1, to 
evaluate their eligibility for this study. Eligible participants with DR who meet all the 
inclusion criteria and none of the exclusion criteria will be randomized to treatment with 
one of two dosing frequencies (BID/QID) of 5% OTT166 or vehicle control. During the 
treatment period, participants will be monitored for AEs and concomitant medication, and 
undergo the assessments outlined in the SoA (Section 2.15.1). 
The treatment period comprises Visits 2 to 8 (BL/Day 1 to End of 
Treatment/Study/Week 24), at which the primary endpoint will be assessed. 
2.15.3 
Blood Sampling 
Blood will be taken at Visits 1 and 8 for laboratory assessments. 
• The amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will be approximately 30 mL. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
 
2.16 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 2.15.1). 
2.16.1 
Ophthalmology Assessments 
Ophthalmology examinations will be done for the study eye and/or both eyes as described in 
the SoA (Section 2.15.1). 
2.16.2 
Color Fundus Photography (CFP) 
The anatomical state of the retinal vasculature will be evaluated by an ophthalmologist from 
posterior segment examination and CFP. All digital CFP images need to be taken by a 
certified technician following an acquisition protocol for modified 7-field stereoscopic color 
fundus photographs or 4-wide field imaging of the central reading center at the visits 
indicated in the SoA (Section 2.15.1). 
All CFPs will be transmitted to the central reading center for ETDRS DRSS (see Appendix 2) 
grading and storage. The images from the screening visit of both eyes will be used as part of 
the eligibility assessment regarding the severity of diabetic retinopathy. 
CFPs may, in addition, be evaluated for additional, exploratory, endpoints. This may include 
assessment of microaneurysm turnover (Nunes 2009) or measurement of diameters of retinal 
vessels as described previously (Lundberg 2013). This may involve transmission of CFP to 
additional central reading centers.  


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2.16.3 
Best Corrected Visual Acuity (BCVA) 
Visual function will be assessed using a modified ETDRS protocol starting at 4 meters 
(AREDS 1999). Visual Acuity examiners must be qualified to ensure consistent measurement 
of BCVA and will be masked to study treatment assignment. 
2.16.4 
Fluorescein Angiography (FA) 
The anatomical state of the retinal vasculature of the study eye and the fellow eye (only at 
BL and end of study [EOS]) will be evaluated by FA (widefield preferred). All FAs will be 
conducted by a qualified technician following an acquisition protocol of the central reading 
center. The angiographic images will be evaluated by a study ophthalmologist for individual 
safety decisions. All FA images will be archived electronically at the site as part of the 
source documentation and sent to the central reading center for evaluation and storage on 
visits stated in the SoA (Section 2.15.1). 
At screening, a standardized set of FA images will be sent to the central reading center for 
evaluation and eligibility assessment. 
2.16.5 
Optical Coherence Tomography (OCT) 
Structural OCT (widefield preferred) will be performed by using spectral domain devices. 
The specific device models accepted for the study will be defined by the central reading 
center. OCTs will be performed at every visit by qualified technicians following an 
acquisition protocol of the central reading center. OCTs will also be used for local safety 
assessment. Newly found clinically significant pathologies should be reported as AEs. All 
obtained images will be sent to the central reading center for evaluation, and central reading 
center data will be used for the final analysis. 
At screening, a standardized set of OCT images will be sent to the central reading center for 
evaluation and eligibility assessment. Beside central subfield thickness within the central 
1 mm (CST) and whole macular volume also the presence of center involving and non-center 
involving macular edema will be assessed. SD-OCT will be also assessed for foveal contour 
and several exploratory outcome parameters and morphologic predictive biomarkers. 
2.16.6 
Optical Coherence Tomography Angiography (OCTA) 
OCTA is optional at sites that have an OCTA. The OCTA needs to be performed by a 
qualified technician following an acquisition protocol of the central reading center at Visits 1 
and 8, as scheduled in the SoA (Section 2.15.1). The specifications of this OCTA can be 
found in the acquisition protocol of the central reading center. Images obtained via OCTA 
will be sent to the Central Reading Center for evaluation. Several quantitative and qualitative 
parameters, including the FAZ and area of nonperfusion, which have been shown to be 
associated with DR severity, will be assessed. 


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2.16.7 
Slit Lamp Biomicroscopy (Anterior and Posterior Segment) 
The slit lamp examination (anterior and posterior segment) will be performed according to 
local medical practice and applicable medical standards at the site at every visit, as stated in 
the SoA (Section 2.15.1). Abnormal findings are to be recorded in the eCRF as either medical 
history or AE, as applicable. 
2.16.8 
Tonometry (Intraocular Pressure (IOP) Measurement) 
IOP is to be measured at every visit with any locally approved non-contact tonometer. 
If there is no non-contact tonometer available at the site, applanation tonometry (Goldmann, 
Tonopen, or other locally approved alternatives) may be used. In any case, where both 
methods are available, the non-contact method is to be used. In cases in which Goldmann 
applanation tonometry (GAT) is used, assessment of corneal health using fluorescein stain 
should be performed prior to tonometer applanation.  
The same method of IOP measurement must be used throughout the study for each individual 
participant and should be performed at approximately the same time of day, if possible. 
Values, including time of day and measuring type, are to be recorded in the eCRF. 
2.16.9 
Vision-threatening Complications 
VTC is defined as the composite outcome of PDR (inclusive of participants who have 
vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or 
ASNV identified by Investigators (participants with neovascularization of the iris [at least 
2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle) 
and/or CI-DME as defined in Section 2.16.10 below.  
VTCs are defined as occurrence of any of the following AEs: 
• More than mild PDR (DRSS 65 and above) 
• Iris neo-vascularization 
• CI-DME  
 
2.16.10 
DME and CI-DME 
DME is defined as fluid in the macula. 
CI-DME is defined as the presence of fluid in the central subfield in participants who have no 
fluid at baseline or CST > 325 µm. 
The assessment will be continued after treatment discontinuation until end of study. 


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2.17 
Safety Assessments 
Safety will be assessed, and TEAEs recorded (as indicated) at every visit.  
2.17.1 
Physical Examination 
A physical examination (by means of inspection, palpation, auscultation) will be performed 
at Screening (Visit 1) as described in the SoA (Section 2.15.1) by a physician at the study site 
and will cover at least the organs of the cardiovascular, respiratory, and abdominal systems; 
measuring body temperature will be included. Abnormal physical examination findings are 
recorded either as medical history or as AEs in the eCRF. Body weight will be measured by a 
member of the investigator’s team. The body mass index (BMI) will be calculated by Data 
Management or the eCRF based on weight and height. 
2.17.2 
Vital Signs 
Pulse rate and systolic / diastolic blood pressure will be measured repeatedly as outlined in 
the SoA (Section 2.15.1). Blood pressure and heart rate will be measured in a supine or semi 
supine position after ≥ 5 minutes rest. Blood pressure and heart rate should always be 
measured before blood draws when scheduled at the same time point. 
2.17.3 
Clinical Safety Laboratory Assessments 
A lab assessment (hematology, blood chemistry, urinalysis, and HbA1c) will be performed at 
Screening (Visit 1) and at Week 24 (Visit 8) as described in the SoA (Section 2.15.1). Blood 
and urine samples will be taken. See Section 3.3 for a table of clinical laboratory tests to be 
performed. 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes, including any lab test that was in the age-adjusted normal 
range and became abnormal at EOS, occurring during the study as an AE. The laboratory 
reports must be filed with the source documents. 
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within one month after the last dose of study intervention should 
be repeated until the values return to normal or BL or are no longer considered clinically 
significant by the investigator or the medical monitor. 
If such values do not return to normal/BL within a period of time judged reasonable by the 
investigator, the etiology should be identified, and the sponsor notified. 
All protocol-required laboratory tests must be conducted in accordance with the laboratory 
manual and the SoA (Section 2.15.1). If laboratory values from non-protocol specified 
laboratory tests performed at the institution’s local laboratory require a change in participant 


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management or are considered clinically significant by the investigator (eg, SAE or AE or 
dose modification), then the results must be recorded. 
2.17.4 
Pregnancy Testing 
Both urine and serum ß-hCG pregnancy tests are planned to be conducted in woman of 
childbearing potential enrolled in this clinical study. A serum test is planned at Screening 
(Visit 1); during all other visits, urine tests will be performed. Dip stick urine pregnancy tests 
allow the investigator to take action while the participant is at site in case of a positive test.  
If the urine pregnancy test is positive, the study medication should be discontinued 
immediately. The urine pregnancy test results should be however confirmed using a serum 
pregnancy test at a local lab before permanently discontinuing the participant from the study. 
2.18 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Appendix 3 and will conform to the current 
Medical Dictionary for Regulatory Activities (MedDRA) standard. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs reported during the study until resolution or until the end of the study. 
2.18.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs/SAEs will be collected from the signing of the ICF until end of study. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of learning of the event, as indicated in 
Section 2.21.5. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
TEAEs will be defined as those AEs that occurred after first dosing and those existing 
pre-dose AEs that worsened in severity post-dose during the main treatment period until the 
end of study. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation/the End-of-Study visit. However, if the investigator learns of any 
AE/SAE, including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor. 


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2.18.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
2.18.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in 
Section 2.18.6), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 2.14.12). Further 
information on follow-up procedures is provided in Appendix 4. 
2.18.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC), and Investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it and will notify the IRB/IEC, if appropriate according to local 
requirements. 
• For all studies, investigator safety reports must be prepared for suspected unexpected 
serious adverse reactions (SUSARs) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
 
2.18.5 
Pregnancy 
• Details of all pregnancies in female participants and, female partners of male participants 
will be collected after the start of study intervention and until the end-of study visit. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours after obtaining the 
necessary signed informed consents from the pregnant participant. Study medication 
should be discontinued immediately upon receipt of a positive pregnancy test. 


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• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs, and will be reported as 
such. 
• The participant /pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate, and the information will be 
forwarded to the sponsor. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
 
2.18.6 
Adverse Events of Special Interest (AESI) 
AESI must be reported to the Sponsor along the timelines set for SAEs (even though they 
may not be classified as serious), ie, within 24 hours of the investigator´s awareness, as 
described in Appendix 4. 
AESI are: 
• Hypersensitivity reactions. Symptoms of hypersensitivity reactions (allergic reactions) 
include: 
- 
Rash 
- 
Wheezing and difficulty breathing  
- 
Dizziness and fainting  
- 
Swelling around the mouth, throat or eyes 
- 
A fast pulse  
- 
Sweating  
 
2.19 
Pharmacokinetics 
In this study, no PK analysis will be done. 


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2.20 
Statistical Considerations 
2.20.1 
Statistical Hypotheses / Sample Size Determination 
This study is designed to evaluate the superiority of two doses of OTT166 (5 mg/day and 
10 mg/day) compared to vehicle control for the treatment of DR. For each dose within each 
endpoint, the null hypothesis is that there is no difference between OTT166 and vehicle 
control or the difference is in the direction of inferiority of OTT166, and the alternative 
hypothesis is that there is a difference between OTT166 and vehicle control in the direction 
of superiority of OTT166. The vehicle control groups will be combined for all statistical 
analyses. No multiplicity adjustment is planned for this study. 
The study will enroll approximately 210 participants randomized as described in 
Section 2.14.3, 70 participants per group into each treatment arm and 35 participants per 
group into each matching vehicle control group and allowing for around 5% study attrition, 
aiming for at least 66 participants per treatment group and combined vehicle control group. 
For the primary endpoint of improvement by at least 2 steps from BL on the DRSS at 
Week 24, completing 66 participants per group (active treatment BID, active treatment QID, 
combined vehicle control) through Week 24 will yield at least 90% power to demonstrate 
that the active treatment is superior to vehicle control using a 1-sided alpha of 0.05, provided 
that the true treatment effect (active treatment efficacy rate minus vehicle control efficacy 
rate) is at least 0.20 and the vehicle control efficacy rate is at most 0.06. 
The sample size calculation was computed in nQuery 8.7 using a Chi square test for 
two proportions (continuity corrected). 
2.20.2 
Outcome Measures 
The primary safety outcome measure of the study will be the proportion of participants who 
develop TEAEs through Week 24. 
The primary efficacy outcome measure of the study will be the proportion of participants 
who have improved by ≥ 2 steps from baseline at Week 24 as determined by central reading 
center assessment using DRSS. 
The secondary outcome measures are as follows: 
• Proportion of participants developing worse than mild PDR (DRSS 65 and above) at 
Week 24 
• Proportion of participants who develop ASNV at Week 24 
• Time to development of PDR worse than mild (DRSS 65 and above) 
• Proportion of participants who develop CI-DME at Week 24 
• Time to development of CI-DME  


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• Proportion of participants developing VTC at Week 24 
• Time to development of PDR worse than mild (DRSS 65 and above) or CI-DME 
• Proportion of participants with change in DRSS steps at Week 24 compared to baseline 
- 
Change in DRSS steps is defined as DR worsening or improving by 1, 2, or ≥ 3 steps  
• Proportion of participants with mild PDR (DRSS score 61B) at baseline who regress to 
NPDR (DRSS score ≤ 53) by Week 24 
• Mean and median change in BCVA (ETDRS letters) from baseline to Week 24 
• Lines gained/lost in BCVA (± 5, 10, and 15 ETDRS letters) at Week 24 
• Mean and median change in AUC for change in BCVA from baseline to Week 24 
• Mean and median change in CST from baseline to Week 24 
• AUC for change in CST from baseline to 24 weeks 
• Proportion of participants who met the objective rescue criteria as defined in 
Section 2.14.9. 
• Time to meet objective rescue therapy criteria as defined in Section 2.14.9. 
• Time to administration of rescue therapy. 
 
Exploratory outcomes measures will include: 
• Change in Macular Volume (MV) from baseline to Week 24 for 1, 3, and 6 mm regions 
- 
MV will be defined as the sum of the 9 subfield measurements as provided by the 
imaging center 
• Change in area of retinal non-perfusion from baseline to Week 24 seen on widefield 
fluorescein angiography (FA) 
• Proportion of participants with intact foveal avascular zone (FAZ) seen on widefield FA 
at Week 24 
• Optical coherence tomography angiography (OCTA) endpoints within the 6 mm area: 
- 
Change from baseline to Week 24 in FAZ area 
- 
Change from baseline to Week 24 in non-perfusion area 
- 
Change from baseline to Week 24 in vessel caliber 
- 
Change from baseline in ischemic Index at Week 24 defined as total area of 
non-perfusion divided by total area of retina visualized (28.3 mm2) 
- 
Proportion of participants with new neovascularization at Week 24 


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- 
Proportion of participants with new IRMA at Week 24 
- 
Change in vessel density from baseline to Week 24 in the superficial and deep layers 
 
2.20.3 
Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
Table 2 
Analysis Sets 
Analysis Set 
Description 
Enrolled Set (ES) 
All participants who signed informed consent. 
Intent-to-Treat (ITT) 
Analysis Set 
All randomized participants who received at least one dose of study 
drug. Participants will be included into the analysis as randomized. 
This corresponds to what is referred to in ICH E9 as the Full 
Analysis Set.  
Per-Protocol Set (PPS) 
All ITT participants without any major protocol deviations that 
could impact the primary endpoint. 
Safety Analysis Set (SS) 
All participants who receive at least one dose of study drug. 
Participants will be included into the analysis based on treatment 
actually received, regardless of the treatment randomized. 
 
The ITT Analysis Set will be used for all efficacy and BL analyses except participant 
disposition which will be shown for the ITT Analysis Set and for the Safety Analysis Set if 
the two analysis sets differ. All randomized participants are expected to be dosed and any 
exceptions will be described in the CSR. The PP set will be determined prior to database lock 
and will be used as supplementary analyses of the primary endpoint. All safety analyses will 
be based on the Safety Analysis Set (SS). 
2.21 
Statistical Analyses 
2.21.1 
General Considerations 
Statistical analyses will include tabulations of summary data, inferential analyses, by 
participant listings, and figures. 
All statistical tests will be one-sided and will be performed at the 5% level of significance, 
unless otherwise stated. The vehicle control group will be combined for all efficacy analyses, 
and two-sided 90% confidence intervals will be presented. Frequency counts (n and 
percentages) will be made for each qualitative variable. Descriptive statistics (n, mean, 
standard deviation [SD], median, minimum, and maximum) will be calculated for each 
quantitative variable, unless otherwise stated. All data will be summarized by treatment 
group. All safety summaries and analyses will be based upon the Safety Analysis Set by 
treatment group (i.e., vehicle control doses (5% BID, 5% QID), vehicle control combined, 
active OTT166 doses (5% BID, 5% QID), and OTT166 combined). 


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The BL value for analysis and reporting will be based on the last (non-missing) measurement 
before dosing on Day 1. If any safety measurements are repeated after dosing on Day 1, then 
the last (non-missing) value of any repeated measurements will be used in the descriptive 
statistics and in the calculation of changes from BL. 
2.21.2 
Efficacy Analyses 
2.21.2.1 
Analysis of the Primary Endpoint 
The primary estimand for the primary endpoint analysis is as follows: 
 
Primary Estimand 
Treatment 
conditions of 
interest 
OTT166 5 mg/day, OTT166 10 mg/day and matching vehicle control 
Participant 
Population 
DR participants with Type 1 or Type 2 diabetes under adequate control 
(HbA1c ≤12.0%) who show typical fundus alterations and have been 
diagnosed with moderately severe to severe NPDR or mild PDR as 
defined by the DRSS Steps 47, 53, and 61B, with BCVA ≥ 69 ETDRS 
letters, CST of ≤ 325 μm, and a normal foveal contour.  
Endpoint 
≥ 2 steps improvement from BL in DRSS score at Week 24. 
Population level 
summary 
Difference in proportion of participants achieving ≥ 2 steps 
improvement from BL in DRSS score at Week 24 between each 
OTT166 treatment group and the combined vehicle control group.  
Intercurrent events 
(ICEs) and 
strategies to handle 
ICEs 
a. Rescue treatment due to worsening DRSS level to 65 or higher prior to 
assessment of DRSS at Week 24 
Composite strategy (non-response) 
Death prior to DRSS assessment at Week 24  
Hypothetical strategy  
Use of rescue treatment for any other reason prior to DRSS assessment 
at Week 24 
Composite strategy (non-response) 
Premature discontinuation of study drug for any reason prior to DRSS 
assessment at Week 24 
Hypothetical strategy 
Study drug compliance < 75% through Week 24 
Treatment policy strategy 
b. Study drug compliance between 75% to < 90% through Week 24 
Treatment policy strategy 
 
ICE(s) with a composite variable strategy take priority over ICEs with 
other strategies. And ICEs with a hypothetical strategy take priority over 
ICEs with treatment policy strategy. 
 
Handling of missing DRSS response data at Week 24 in participants without ICEs: 
• multiple imputation assuming missing at random (MAR) 
 


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Handling of DRSS response data at Week 24 missing after ICEs: 
• single imputation (non-response) when applying composite variable strategy 
• multiple imputation assuming MAR when applying hypothetical and treatment policy 
strategy 
 
Handling of DRSS response data at Week 24 observed after ICEs: 
• replaced by non-response (single imputation) in the analysis when applying composite 
variable strategy 
• replaced by multiple imputation algorithm based on data from participants not affected by 
the respective ICE when applying hypothetical strategy 
• kept in the analysis when applying treatment policy strategy 
 
Comparison of the primary endpoint will be made between each dose group and the 
combined vehicle control group using a Mantel-Haenszel (MH) test of the difference in 
2 proportions stratified by the randomization stratification factor (BL DRSS score 47 or 53 or 
61B). The estimated MH risk difference will be summarized along with the 2-sided 90% CI 
using MH stratum weights and the Sato variance estimator. The primary efficacy analysis 
will be performed on the ITT Analysis Set, while the PP set will be used as supplementary 
analyses. ICEs and missing data will be handled as described above. 
The primary efficacy analysis will also be performed by demographic subgroups including 
age, gender, and race to assess the consistency of the treatment effect. Additional subgroup 
analyses may also be conducted and will be described in the Statistical Analysis Plan (SAP). 
2.21.2.2 
Analyses of Secondary and Other Efficacy Endpoints 
Estimands for the secondary endpoint analyses will be described in the SAP. 
The secondary endpoints involving proportions of participants will be analyzed using the 
same approach (MH test) as described for the primary efficacy analysis and based on the 
ITT. 
Time to event secondary endpoints will be analyzed using a stratified log-rank test adjusting 
for the randomization stratification factor. 
Continuous secondary endpoints involving change from BL will be analyzed using an 
analysis of covariance (ANCOVA) model with BL measurement of the variable as a 
covariate and treatment group and the randomization stratification factor as fixed factors. The 
pair-wise comparisons of each OTT166 dose group versus combined vehicle control will be 
done in the ANCOVA model. Two-sided 90% confidence intervals for the difference of each 
OTT166 dose group minus combined vehicle control will be calculated. Additional details on 


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sensitivity analyses and missing data imputation of the secondary endpoints will be provided 
in the SAP. 
Analyses of exploratory imaging outcome measures will be described in the SAP. 
2.21.3 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. No inferential statistics will 
be performed for safety variables. 
2.21.4 
Study Drug Exposure 
Exposure to study drug will be summarized using the ITT analysis Set and also Safety 
Analysis Set. The total number of doses administered and the duration of treatment for each 
participant will be summarized using descriptive statistics by treatment group. 
2.21.5 
Adverse Events 
AEs will be coded using MedDRA version 24.1 or higher and summarized by system organ 
class (SOC) and preferred term (PT). Analysis and reporting for AEs will be based on 
TEAEs. A TEAE is defined as an AE occurring (onset date/time) at the time of or after 
dosing on Day 1. AEs with missing start and/or end dates and/or times (if applicable) will be 
handled as described in the SAP. 
All TEAEs will be listed for each participant. Separate listings will be presented for TEAEs 
leading to discontinuation of study drug and treatment-emergent serious adverse events 
(TESAEs). Any AEs occurring between signing of ICF and dosing on Day 1 will be 
presented in a separate listing. All listings will be done by treatment group and participant, 
detailing verbatim, SOC, PT, start date, stop date (if resolved), intensity, seriousness, 
outcome, action taken with respect to study drug, and relationship to study drug. The AE 
onset will also be shown relative (in number of days) to the day of the first study drug 
administration. 
An overview of all TEAEs will be presented by treatment group. The overview will include 
the following: 
• Number and percentage of participants with TEAEs 
• Number and percentage of participants with drug-related TEAEs 
• Number and percentage of participants with TEAEs leading to discontinuation of study 
drug 
• Number and percentage of participants with TEAEs leading to study discontinuation 
• Number and percentage of participants with TESAEs 
• Number and percentage of participants with drug-related TESAEs 


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• Number and percentage of participants with TESAEs leading to discontinuation of study 
drug 
• Number and percentage of participants with TESAEs leading to study discontinuation 
• Number and percentage of participants by intensity of TEAEs (mild, moderate, severe) 
• Number and percentage of participants who experienced death from any cause  
• Number and percentage of participants with AESIs 
 
Summaries of TEAEs by treatment group, SOC, and PT will be presented for the following: 
• All TEAEs 
• Ocular TEAEs in the Study Eye 
• Ocular TEAEs in the Fellow Eye 
• Non-Ocular TEAEs 
• TEAEs leading to discontinuation of study 
• TEAEs leading to discontinuation of study drug 
• Drug-related TEAEs 
• All TESAEs 
• Ocular TESAEs in the Study Eye 
• Ocular TESAEs in the Fellow Eye 
• Non-Ocular TESAEs 
• TESAEs leading to discontinuation of study 
• TESAEs leading to discontinuation of study drug 
• Drug-related TESAEs 
• TEAEs by intensity 
• AESIs 
• AESIs leading to discontinuation of study 
• AESIs leading to discontinuation of study drug 
 
Additional details on AE summaries will be provided in the SAP. 


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2.21.6 
Vital Signs 
Vital signs measurements will be listed by participant and time point including changes from 
BL and any repeated/unscheduled measurements. Descriptive statistics (n, mean, SD, 
minimum, median, maximum) will be provided by treatment group and time point for both 
absolute values and changes from BL. 
2.21.7 
Safety Laboratory Tests 
Laboratory safety assessments will be listed by participant and time point including changes 
from BL, flags for any measurements that are outside the reference ranges, and any 
repeated/unscheduled assessments. Descriptive statistics (n, mean, SD, minimum, median, 
maximum) will be provided by treatment group and time point for both absolute values and 
changes from BL. A shift from BL table describing shifts to out-of-normal range will be 
provided by treatment group. 
Urinalysis results will be listed by participant and time point including changes from BL for 
numeric variables, flags for any measurements that are outside the reference ranges, and any 
repeated/unscheduled assessments. 
The results of pregnancy and HbA1c testing will be listed for each participant. 
2.21.8 
Other Analyses 
Descriptive summaries of participant disposition and BL characteristics (including 
demographic data and medical and ophthalmic history) will be presented by treatment group. 
In addition, a listing of participants who discontinued from the study along with 
discontinuation reason will be provided. Listings of BL characteristics and prohibited 
medications will also be provided. 
Protocol deviations will be listed and summarized by treatment group and category. 
Medications will be coded using the World Health Organization Drug Dictionary (WHO DD) 
and listed by participant. A summary of concomitant medications by treatment group and 
medication class will also be tabulated. 
2.21.9 
Interim Analysis 
There are no interim analyses planned. 


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3 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
3.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
3.1.1 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
- 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
- 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. Any substantial modification of the protocol will 
be submitted to the competent authorities as substantial amendments for approval, in 
accordance with ICH GCP and national and international regulations. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
 


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3.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the study 
and for 1 year after completion of the study. 
3.1.3 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
participants and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act requirements, where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participants. 
• Participants who are rescreened are required to sign a new ICF. 
 
3.1.4 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records, 
datasets or biological samples that are transferred to the Sponsor will contain the 
identifier only; participant names or any information which would make the participant 
identifiable will not be transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
 


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3.1.5 
Committees Structure 
3.1.5.1 
Central Reading Center 
The digital retinal images, OCT scans, fluorescence angiographies, and other images as 
applicable will be assessed by independent central reading centers. Details pertaining to each 
imaging technique are as follows: 
• FP: DRS 4W/7M standard 2-step plus adjudication 
• OCT: CI-DME, SRF/IRF, DRIL, TMV (1, 3, and 6mm) 
• FA: We will grade ONLY study eye 
• OCTA: vessel density, FAZ area, and nonperfusion 
 
3.1.5.2 
Steering Committee 
A steering committee consisting of experts in the field is created to provide scientific and 
operational recommendations to the study protocol and to potential day-to-day decisions in 
study conduct. The OcuTerra team and Steering Committee members will collaborate to 
ensure that the scope for the study is constrained to what is relevant with regard to the 
clinical indication, outcomes, and product under investigation, and most importantly, study 
participant safety. The composition of the committee, the functional roles, and 
responsibilities can be found in the Steering Committee charter. 
3.1.6 
Data quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• All data objective and subjective will be captured in the EDC and reported on. 
• Guidance on completion of CRFs will be provided in eCRF completion guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
 
Quality tolerance limits (QTLs) will be pre-defined in the Integrated Data Review Plan to 
identify systematic issues that can impact participant safety and/or reliability of study results. 
These pre-defined parameters will be monitored during the study and important deviations 
from the QTLs and remedial actions taken will be summarized in the clinical study report. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 


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Monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
 
3.1.7 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the Source Data Location List. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
 
3.1.8 
Study and Site Start and Closure 
3.1.8.1 
First Act of Recruitment 
The first act of recruitment is the first participant visit and will be the study start date. 


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3.1.8.2 
Study / Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the investigator 
• Total number of participants included earlier than expected. 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
3.1.9 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 


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• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 


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3.2 
Appendix 2: ETDRS Final Retinopathy Severity Scale 
Table 3 
ETDRS Final Retinopathy Severity Scale (for Individual Eyes) 
Level 
Severity 
Definition 
10 
DR absent 
Microaneurysms and other characteristics absent 
12 ٭ 
Non-DR abnormalities 
14 ٭ 
DR questionable 
14A HE definite; microaneurysms absent 
14B SE definite; microaneurysms absent 
14C IRMA definite; microaneurysms absent 
14Z Venous loops > D/1; microaneurysms absent 
15 ٭ 
DR questionable 
Hemorrhage(s) definite; microaneurysms absent 
20 
Microaneurysms only 
Microaneurysms definite, other characteristics absent 
35† 
Mild NPDR 
35A Venous loops ≥ D/1 
35B SE, IRMA, or VB = Q 
35C Retinal hemorrhages present 
35D HE ≥ D/1 ( < STD 3 in any field ) 
35E HE ≥ M/1 ( ≥ STD 3 in any field ) 
35F SE ≥ D/1 ( any definite ) 
43 
Moderate NPDR 
43A H/Ma = M/4-5 (> STD 1(4+ fields) -OR- ≥ STD 
2A (1 field) )  
43B IRMA = D1-3 (any definite < STD 8A ) 
47 
Moderately Severe NPDR 
47A Both L43 characteristics 
47B IRMA = D/4-5 ( < STD 8A ) 
47C H/Ma = S/2-3 ( < STD 2B ) 
47D VB = D/1 
53 
Severe NPDR 
53A ≥ 2 of the L47 characteristics 
53B H/Ma ≥ S/4-5 ( ≥ STD 2A in 4+ fields or ≥ 2B in any 
field )  
53C IRMA ≥ M/1 ( ≥ STD 8A ) 
53D VB ≥ D/2-3 or S1 ( ≥ STD 6 in 2+ fields or ≥ 6B in any 
field)  
53E 
Very Severe NPDR 
53E ≥ 2 of 53B, 53C, and 53D 
60 
Inactive PDR 
60 Scatter or Local Rx 
61 
Mild PDR 
61A FPD and/or FPE only (regressed PDR) 
61B NVE < ½ DA in ≥ 1 field 
65 
Moderate PDR 
65A NVE ≥ M/1 ( ≥ ½ DA in ≥ 1 field) 
65B NVD = D ( < STD 10A ) ; and VH and PRH = A or Q 
65C VH or PRH = D ( < 1 DA) and NVE < M (< ½ DA ) and 
NVD absent  


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71/75 
High-risk PDR 
71A VH or PRH ≥ M/1 ( ≥ 1 DA ) 
71B NVE ≥ M/1 ( ≥ ½ DA 1 field ) and VH or PRH ≥ D/1 
( any )  
71C NVD = D ( < STD 10A ) and VH or PRH ≥ D/1 ( any ) 
71D NVD ≥ M ( ≥ STD 10A ) 
75 NVD ≥ M ( ≥ STD 10A) and VH or PRH ≥ D/1 (any) 
81 
Advanced PDR: fundus partially 
obscured, center of macula attached 
NVD = cannot grade, or NVD < D and NVE = cannot grade 
in ≥ 1 field and absent in all others; and retinal detachment at 
center of macula < D  
85 
Advanced PDR: posterior fundus 
obscured, or center of macula 
detached  
85A VH = VS (obscuring) in Field 1 or 2 85B Retinal 
detachment at center of macula = D (present)  
90 
Cannot grade, even for 81 or 85 
Abbreviations: DR = diabetic retinopathy; NPDR = nonproliferative DR; PDR = proliferative DR; HE = hard 
exudates; SE = soft exudates; IRMA = intraretinal microvascular abnormalities; VB = venous beading; 
H/Ma = hemorrhages/microaneurysms; NVE = new vessels elsewhere; NVD = new vessels on or adjacent to 
optic disc; VH = vitreous hemorrhage; PRH = preretinal hemorrhage 
Severity categories are of the form (maximum severity/extent), where maximum severity can be absent (A), 
questionable (Q), definitely present (D), moderate (M), severe (S), or very severe (VS), and extent is the 
number of photographic fields at that severity level. For example, M/2-3 means there are two or three fields 
from fields 3 to 7 with moderate severity, and none with higher severity. 
 ٭Levels 12, 14, and 15 are not considered separate steps in the scale, but are pooled with level 10 or 20 
(or excluded). 
† 
NPDR levels 35 and above all require presence of microaneurysms. 


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3.3 
Appendix 3: Clinical Laboratory Tests 
•
The tests detailed in Section 2.15.1 and the table below (Table 4) will be performed
locally at the study site and sent to the central laboratory for analysis with the exception
of urine pregnancy tests, which will be performed and analyzed locally at the site.
•
Additional tests may be performed at any time during the study as determined necessary
by the investigator or required by local regulations.
Investigators must document their review of each laboratory safety report. 
The laboratory parameters to be analyzed are defined below in Table 4. The time points of 
analysis are at Screening and EOS as defined in the SoA (Section 2.15.1). All labs are 
expected to be random (non-fasting). 
Additional local laboratory tests may be performed as deemed appropriate by the Investigator 
(eg, in case of signs of any toxicity). 
Table 4 
Clinical Laboratory Tests 
CHEM 20 
CBC 
Urinalysis 
Glucose 
Hemoglobin 
Sp. Gravity (SG) 
Sodium 
Hematocrit 
pH 
Potassium 
MCV 
Leukocyte esterase 
Carbon dioxide 
MCH 
Nitrites 
Chloride 
Red Cell Count 
Hemoglobin 
BUN 
White Cell Count 
Protein (Total) 
Creatinine 
Neutrophils (%) 
Glucose 
Calcium 
Total Lymphs (%) 
Ketones 
Iron 
Monocytes (%) 
Urobilinogen 
Albumin 
Eosinophils(%) 
Bilirubin 
Total protein 
Basophils (%) 
ALP 
Neutrophils (Abs) 
ALT (SGPT) 
Total Lymphs (Abs) 
AST (SGOT) 
Monocytes (Abs) 
LDH 
Eosinophils(Abs) 
GGT 
Basophils (Abs) 
Bilirubin (total) 
Platelets 
Uric acid 
Amylase 
Lipase 


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3.4 
Appendix 4: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
 
3.4.1 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, associated with 
the use of study intervention, whether or not considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated with 
the use of study intervention. 
 
3.4.2 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, radiological scans, vital signs measurements), including 
those that worsen from BL, considered clinically significant in the medical and scientific 
judgment of the Investigator (ie, not related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• This includes progression of DR New conditions detected or diagnosed after study 
intervention administration even though it may have been present before the start of the 
study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
 
3.4.3 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 


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• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
An SAE is defined as any AE that, at any dose: 
a. Results in death 
b. Is life-threatening 
- 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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 severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
- 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from BL is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment 
for allergic bronchospasm, blood dyscrasias, convulsions, or development of 
intervention dependency or intervention abuse. 


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3.4.4 
Recording and Follow-up of AE and / or SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Sponsor in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 
3.4.5 
Assessment of Intensity 
• The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
3.4.6 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 


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• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study 
• intervention administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
 
3.4.7 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
 
3.4.8 
Reporting of SAEs 
SAE reporting to Sponsor via an electronic data collection tool 
The primary mechanism for reporting an SAE to Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) to report the event within 24 hours. 


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• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool. 
• will be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) 
or to the Sponsor’s Medical Monitor by telephone. 
• Contacts for SAE reporting can be found in the Investigator Site File. 
 
SAE reporting to Sponsor via paper data collection tool 
 
• Email transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor. 
• In rare circumstances and if email transmission is not feasible, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or 
courier service. 
• Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• Contacts for SAE reporting can be found in the Investigator Site File. 
 


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3.5 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information 
3.5.1 
Definitions 
Woman of childbearing potential 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered women of childbearing potential 
a. Premenarchal 
b. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
3.5.2 
Contraception Guidance 
Female participants of childbearing potential must use a highly effective method of 
contraception, as shown in the table below. Male participants must agree to use condoms. 
This applies from the time of ICF signature until the end of the study period. 


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Table 5 
Highly Effective Contraception Methods 
• Implantable hormonal contraception associated with inhibition of ovulation 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Hormonal contraception with inhibition of ovulation, either estrogen and progestogen containing 
or progesterone-only 
• Vasectomized partner if sole sexual partner 
• Sexual abstinence 
Modified from: Clinical Trial Facilitation Group 2014: Recommendations related to contraception and 
pregnancy testing in clinical trials (CTFG 2014). 
 
3.5.3 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a participant's pregnancy. 
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 


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pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure. 
- 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
- 
A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will 
be reported as such. 
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Appendix 4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
 


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4 
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photographs--an extension of the modified Airlie House classification. Early Treatment 
Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98(5 Suppl):786-806. 
Ferris FL 3rd, Podgor MJ, Davis MD. Macular edema in Diabetic Retinopathy Study 
patients. Diabetic Retinopathy Study Report Number 12. Ophthalmology. 1987;94(7):754-
760. 
Friedman SM, Almukhtar TH, Baker CW, et al. Topical nepafenec in eyes with noncentral 
diabetic macular edema. Retina. 2015;35(5):944-956. 
Lechner J, O'Leary O, Stitt AW. The pathology associated with diabetic retinopathy. Vision 
Res. 2017;139:7-14. 
Lundberg K, Kawasaki R, Sjølie AK, Wong TY, Grauslund J. Localized changes in retinal 
vessel caliber after focal/grid laser treatment in patients with diabetic macular edema: a 
measure of treatment response? Retina. 2013;33(10):2089-95. 
Nunes S, Pires I, Rosa A, Duarte L, Bernardes R, Cunha-Vaz J. Microaneurysm Turnover Is 
a Biomarker for Diabetic Retinopathy Progression to Clinically Significant Macular Edema: 
Findings for Type 2 Diabetics with Nonproliferative Retinopathy. Ophthalmologica. 
2009;223(5):292-7. 


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OTT166 201 Phase 2 DR Study 
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73 
Staurenghi G, Feltgen N, Arnold JJ, et al. Impact of baseline Diabetic Retinopathy Severity 
Scale scores on visual outcomes in the VIVID-DME and VISTA-DME studies. Br J 
Ophthalmol. 2018;102(7):954-958. 
Wang W, Lo ACY. Diabetic Retinopathy: Pathophysiology and Treatments. Int J Mol Sci. 
2018;19(6):1816. 


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OTT166 201 Phase 2 DR Study 
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74 
SPONSOR SIGNATURES 
Study Title: 
OTT166-201 A Phase 2 Randomized, Double-Masked, 
Vehicle-Controlled, Multicenter Study to Evaluate the Safety and 
Efficacy of OTT166 Ophthalmic Solution in the Treatment of 
Diabetic Retinopathy (DR) 
Study Number: 
OTT166-201 
Version Number: 
V5.0 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor. The following personnel contributed to writing and/or approving this protocol: 
Signed: 
Date: 
David J. Tanzer, MD 
OcuTerra Therapeutics 
Chief Medical Officer 
October 11, 2023


Version: 5.0 
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75 
INVESTIGATOR’S SIGNATURE 
Study Title: 
OTT166-201 A Phase 2 Randomized, Double-Masked, 
Vehicle-Controlled, Multicenter Study to Evaluate the Safety and 
Efficacy of OTT166 Ophthalmic Solution in the Treatment of 
Diabetic Retinopathy (DR) 
Study Number: 
OTT166-201 
 
I have read the clinical study described herein, recognize its confidentiality, and agree to 
conduct the described study in compliance with Good Clinical Practices (GCP), the ethical 
principles contained within the Declaration of Helsinki, this protocol, and all applicable 
regulatory requirements, including United States (US) Food and Drug Administration (FDA) 
21 Code of Federal Regulations (CFR) 312 
 
 
 
 
 
Study Center: 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator:  
(Print Name) 
 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
Date:  
 
 
 

SAP_001.pdf: 
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Parexel International 
OcuTerra Therapeutics, Inc. 
OTT166-201  
OTT166-201 A Phase 2 Randomized, Double-Masked, Vehicle-Controlled, Multicenter Study 
to Evaluate the Safety and Efficacy of OTT166 Ophthalmic Solution in the Treatment of 
Diabetic Retinopathy (DR) 
Statistical Analysis Plan 
Version: 3.0 
Parexel Project Number: 268475 
 
 


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SPONSOR SIGNATURE PAGE 
 
Approved by 
 
Signed: 
 
 
Date:  
 
David J. Tanzer, MD  
OcuTerra Therapeutics  
Chief Medical Officer 
 
 
 
 
 
 


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Parexel Signature Page 
Signatures below confirm that the Statistical Analysis Plan was developed in accordance with 
SOP-GDO-WW-019 and that it is approved for release. 
This document has been approved and signed electronically on the final page by the following: 
 
 
 
Signatory 
Author 
Kathleen Russell 
Project Role: Biostatistics Lead  


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TABLE OF CONTENTS 
1 
INTRODUCTION .................................................................................................................... 10 
2 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................... 10 
3 
INVESTIGATIONAL PLAN................................................................................................... 12 
3.1 
Overall Study Design and Plan ........................................................................................ 12 
3.2 
Endpoints ......................................................................................................................... 13 
3.2.1 
Primary Endpoint - Safety .......................................................................................... 13 
3.2.2 
Primary Efficacy Endpoint and Estimand .................................................................. 13 
3.2.3 
Secondary Endpoints .................................................................................................. 14 
3.2.4 
Exploratory Endpoints ................................................................................................ 15 
3.2.5 
Pharmacokinetic, Pharmacodynamic and Immunogenicity Endpoints ...................... 16 
4 
STATISTICAL METHODS..................................................................................................... 16 
4.1 
Data Quality Assurance ................................................................................................... 16 
4.2 
General Presentation Considerations ............................................................................... 16 
4.2.1 
Handling of Incomplete Dates .................................................................................... 17 
4.3 
Software 18 
4.4 
Study Participants ............................................................................................................ 18 
4.4.1 
Analysis Sets ............................................................................................................... 18 
4.4.2 
Disposition of Participants .......................................................................................... 19 
4.4.3 
Protocol Deviations ..................................................................................................... 19 
4.5 
Demographics and Baseline Characteristics .................................................................... 20 
4.6 
Medical and Surgical History .......................................................................................... 21 
4.7 
Prior and Concomitant Medications ................................................................................ 21 
4.8 
Rescue Therapy ............................................................................................................... 21 
4.9 
Treatment Exposure and Compliance .............................................................................. 22 
4.9.1 
Treatment Exposure .................................................................................................... 22 
4.9.2 
Treatment Compliance ................................................................................................ 22 
4.10 Efficacy Evaluation ......................................................................................................... 23 
4.10.1 
Analysis and Data Conventions .................................................................................. 23 
4.10.1.1 Adjustments for Covariates ........................................................................................ 23 
4.10.1.2 Handling of Missing Data and Data After Intercurrent Events .................................. 23 
4.10.1.3 Multiple Comparisons/Multiplicity ............................................................................ 24 
4.10.1.4 Examination of Subgroups .......................................................................................... 25 
4.10.2 
Primary Efficacy Analysis .......................................................................................... 25 
4.10.3 
Secondary Efficacy Analysis ...................................................................................... 26 
4.10.4 
Exploratory Analysis .................................................................................................. 27 
4.11 Safety Evaluation ............................................................................................................. 28 
4.11.1 
Adverse Events ........................................................................................................... 28 
4.11.2 
Clinical Laboratory Evaluation ................................................................................... 30 
4.11.3 
Vital Signs ................................................................................................................... 30 
4.11.4 
Physical Examination ................................................................................................. 31 
4.11.5 
Data and Safety Monitoring Board (DSMB) .............................................................. 31 
4.12 Planned Interim Analyses ................................................................................................ 31 
4.13 Determination of Sample Size ......................................................................................... 31 
4.14 Changes in the Conduct of the Study or Planned Analysis ............................................. 31 
5 
REFERENCES ......................................................................................................................... 31 


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6 
APPENDIX .............................................................................................................................. 33 
6.1 
Schedule of Activities ...................................................................................................... 33 
6.2 
ETDRS Final Diabetic Retinopathy Severity Scale (For Individual Eye) ...................... 36 
6.3 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) ...................... 37 
6.3.1 
Amendment 1 .............................................................................................................. 37 
6.3.2 
Amendment 2 .............................................................................................................. 46 
 
 


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REVISION HISTORY 
Version No. 
Effective Date 
Summary of Change(s) 
1.0 
12-May-2022 
New document 
2.0 
30-June-2023 
All the changes made in this version are described in Appendix 
6.3 
3.0 
TBD 
All the changes made in this version are described in Appendix 
6.3 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation/Acronym 
Definition/Expansion 
AE 
Adverse Event  
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
Anti-VEGF 
Anti-Vascular Endothelial Growth Factor  
ASNV 
Anterior Segment Neovascularization 
ATC 
Anatomical Therapeutic Chemical  
AUC 
Area Under the Curve  
BCVA 
Best Corrected Visual Acuity 
BID 
Twice Daily  
BL 
Baseline 
BMI 
Body Mass Index  
CFP 
Color fundus photography 
CI 
Confidence interval 
CI-DME 
Center-Involved Diabetic Macular Edema  
CNV 
Choroidal Neovascularization 
CSR 
Clinical Study Report  
CST 
Central Subfield Thickness 
DME 
Diabetic Macular Edema  
DR 
Diabetic Retinopathy  
DRIL 
Disorganization of Retinal Inner Layers 
DRSS 
Diabetic Retinopathy Severity Scale  
eCRF 
Electronic Case Report Form  
EOS 
End of Study 
EOT 
End of Treatment 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ETRDR 
Early Treatment Report Diabetic Retinopathy 
FA 
Fluorescein Angiography 
FAS 
Full analysis set 
FAZ 
Foveal Avascular Zone  


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Abbreviation/Acronym 
Definition/Expansion 
HbA1c 
Glycosylated Hemoglobin 
ICH 
International Conference on Harmonisation 
ICE 
Intercurrent Event 
IOP 
Intraocular Pressure 
IRMA 
Intraretinal microvascular abnormality 
ITT 
Intent-to-Treat 
IVT 
Intravitreal Injection  
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Mantel-Haenszel 
MV 
Macular Volume 
nAMD 
Neovascular Age-Related Macular Degeneration 
NPDR 
Non-Proliferative Diabetic Retinopathy  
OCT 
Optical Coherence Tomography 
OCTA 
Optical Coherence Tomography – Angiography  
OU 
Both eyes 
PDR 
Proliferative Diabetic Retinopathy  
PPS 
Per-Protocol Set 
PRP 
Pan-retinal Photocoagulation 
PT 
Preferred Term 
QID 
Four Times Daily 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan  
SD 
Standard deviation 
SD-OCT 
Spectral-Domain Optical Coherence Tomography 
SE 
Standard error 
SE 
Study eye 
SI 
Standard International  
SoA 
Schedule of Activities  
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event  


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Abbreviation/Acronym 
Definition/Expansion 
TESAE 
Treatment Emergent Serious Adverse Event  
VEGF 
Vascular Endothelial Growth Factor 
VTC 
Visually Threatening Complications  


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1 
INTRODUCTION 
OTT166 is a representative from a new class of drugs, i.e., a topical integrin inhibitor targeted to the 
back of the eye. It is being developed for treatment of Diabetic Retinopathy (DR). This study is 
designed to provide the proof of concept that non-proliferative diabetic retinopathy (NPDR) and mild 
proliferative diabetic retinopathy (PDR) can be effectively treated with a topical eye drop formulation 
of OTT166. Furthermore, this study is designed to determine the dose-exposure response of OTT166 
in terms of efficacy and safety in order to support the dose selection for the subsequent pivotal Phase 
3 studies with OTT166 in DR. 
This Statistical Analysis Plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of Phase 2 Randomized, Double-Masked, Vehicle-Controlled, Multicenter Study to Evaluate 
the Safety and Efficacy of OTT166 Ophthalmic Solution in the Treatment of DR. 
The structure and content of the SAP are based upon the International Conference on Harmonisation 
(ICH) E3 – Guideline for Industry Structure and Content of Clinical Study Reports. 
The content of this SAP is based on following study document: 
• Study Protocol Version 5.0 dated October 10, 2023. 
2 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Objectives: 
Primary Endpoints: 
To characterize the safety of topical OTT166 
in participants with DR  
• Proportion of participants who develop 
treatment-emergent adverse events 
(TEAEs) through Week 24 
To characterize the efficacy of topical 
OTT166 in participants with DR  
• Proportion of participants who have 
improved by ≥ 2 steps from baseline at 
Week 24 as determined by central reading 
center assessment using the DRSS 
Secondary Objectives: 
Secondary Endpoints: 
To determine if topical OTT166 will prevent 
or delay the occurrence of visually 
threatening complications (VTC), defined as 
PDR worse than mild and/or anterior segment 
neovascularization (ASNV) determined by 
the investigator and/or CI-DME (defined 
below) 
 
 
• Proportion of participants developing 
worse than mild PDR (DRSS 65 and 
above) at Week 24 
• Time to development of PDR worse than 
mild (DRSS 65 and above)  
Proportion of participants who develop 
ASNV determined by the investigator at 
Week 24 
• Proportion of participants who develop 
VTC at Week 24 
• Time to development of PDR worse than 
mild (DRSS 65 and above) or CI-DME 


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To determine if topical OTT166 will prevent 
or delay the occurrence of CI-DME (CI-DME 
is defined as the presence of fluid in the 
central subfield in participants who have no 
fluid at baseline or CST> 325 µm) 
 
• Proportion of participants who develop 
CI-DME at Week 24 
• Time to development of CI-DME 
 
To determine the effect of OTT166 on DRSS 
in participants with moderately severe to 
severe NPDR and mild PDR treated with 
topical OTT166 
• Proportion of participants with change in 
DRSS steps at Week 24 compared to 
baseline 
− Change in DRSS steps is defined as 
DR worsening or improving by 1, 2, 
or ≥ 3 steps. 
• Proportion of participants with mild PDR 
(DRSS score 61B) at baseline who 
regress to NPDR (DRSS score ≤ 53) by 
Week 24 
To determine the effect of OTT166 on 
BCVA in participants with moderately severe 
to severe NPDR and mild PDR 
• Mean and median change in BCVA 
(ETDRS letters) from baseline to 
Week 24 
• Lines gained/lost in BCVA (± 5, 10, and 
15 ETDRS letters) at Week 24 
• Mean and median change in area under 
the curve (AUC) for change in BCVA 
from baseline to Week 24 
To determine the effect of OTT166 on central 
subfield thickness in participants with 
moderately severe to severe NPDR and mild 
PDR 
• Mean and median change in CST from 
baseline to Week 24 
• AUC for change in CST from baseline to 
24 weeks 
To determine the effect of OTT166 on the 
need for rescue therapy in participants with 
moderately severe to severe NPDR and mild 
PDR 
• Proportion of participants who met the 
objective rescue criteria as defined in 
protocol Section 2.14.9. 
• Time to meet objective rescue therapy 
criteria as defined in protocol Section 
2.14.9. 
Exploratory Objectives 
Exploratory Endpoints 
To evaluate the change in DME in 
participants treated with OTT166 
• Change in Macular Volume (MV) from 
baseline to Week 24 for 1-, 3-, and 6-mm 
regions 


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To assess the effects of treatment on 
anatomic markers other than DRSS and on 
retinal non-perfusion 
• Change in area of retinal non-perfusion 
from baseline to Week 24 seen on 
widefield fluorescein angiography (FA) 
• Proportion of participants with intact 
foveal avascular zone (FAZ) seen on 
widefield FA at Week 24 
• Optical coherence tomography 
angiography (OCTA) endpoints within 
the 6 mm area:  
- 
Change from baseline to Week 24 in 
FAZ area 
- 
Change from baseline to Week 24 in 
non-perfusion area 
- 
Change from baseline to Week 24 in 
vessel caliber 
- 
Ischemic Index at Week 24 compared 
to baseline 
- 
Proportion of participants with new 
neovascularization at Week 24 
- 
Proportion of participants with new 
intraretinal microvascular abnormality 
(IRMA) at Week 24 
- 
Change in vessel density from 
baseline to Week 24 in the superficial 
and deep layers  
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 2 randomized, double-masked, vehicle-controlled, multicenter study to evaluate the 
safety and efficacy of OTT166 ophthalmic solution in the treatment of DR. The OTT166 201 Phase 
2 will be conducted to select an optimum dosing regimen (frequency) for Phase 3 pivotal trials.  
The study population will be participants with Type 1 or Type 2 diabetes under adequate control as 
evidenced by glycosylated hemoglobin (HbA1c≤12.0%), who show typical fundus alterations and 
have been diagnosed with moderately severe to severe NPDR or mild PDR, as defined by the DRSS 
Steps 47, 53 and 61B (Appendix 6.2). Participants may have fluid in the macula with BCVA of ≥69 
Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent 20/40) and Central 
Subfield Thickness (CST) of ≤ 325 µm, and a normal foveal contour, which needs to be confirmed 
by an independent central reading center, in at least 1 eye. 
Approximately 210 participants diagnosed with moderately severe to severe NPDR or mild PDR and 
who are treatment naïve (i.e., no prior anti-Vascular Endothelial Growth Factor [VEGF] or laser 
(focal, grid, Pan-Retinal Photocoagulation [PRP]) administered) will be randomized 2:2:1:1 into the 
following groups: OTT166 5% BID, OTT166 5% QID, vehicle control 5% BID, vehicle control 5% 
QID. Randomization will be stratified by Screening DRSS score (47 or 53 or 61B). Participants with 
PDR (DRSS score 61B) will be capped at 20% of all randomized participants. 5% OTT166 


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ophthalmic solution or vehicle control, will be given to the participants who will self-administer one 
50-microliter eye drop of study solution at the prescribed frequency based on randomization, for 24 
weeks. 
Eyedropper bottles containing active treatment of OTT166, and corresponding vehicle control are 
identical in appearance (size, color, shape) and associated with a unique number. Eye dropper bottles 
will be dispensed at the study visits summarized in the schedule of activities (SoA) in Appendix 6.1. 
3.2 
Endpoints 
3.2.1 Primary Endpoint - Safety 
The primary safety outcome measure of the study will be the proportion of participants who develop 
TEAEs through Week 24.  
3.2.2 Primary Efficacy Endpoint and Estimand 
The primary efficacy outcome measure of the study will be the proportion of participants who have 
improved by ≥ 2 steps from baseline at Week 24 as determined by central reading center assessment 
using the DRSS. The primary clinical question of interest is to determine the effectiveness of different 
doses of OCT166 versus vehicle control on ≥2 steps improvement from BL in DRSS score at Week 
24 without requiring rescue treatment if the study drug is not discontinued prior to Week 24. This 
will support the dose selection for subsequent pivotal studies of OTT166. The estimand for the 
primary efficacy analysis is defined as follows: 
 
Primary Estimand 
Treatment 
conditions of 
interest 
OTT166 5 mg/day, OTT166 10 mg/day and matching vehicle control 
Participant 
Population 
DR participants with Type 1 or Type 2 diabetes under adequate control 
(HbA1c ≤12.0%) who show typical fundus alterations and have been 
diagnosed with moderately severe to severe NPDR or mild PDR as defined 
by the DRSS Steps 47, 53, and 61B, with BCVA ≥ 69 ETDRS letters, CST 
of ≤ 325 µm, and a normal foveal contour.   
Endpoint 
≥2 steps improvement from BL in DRSS score at Week 24 
Population level 
summary 
Difference in proportion of participants achieving ≥2 steps improvement 
from BL in DRSS score at Week 24 between each OTT166 treatment group 
and the combined vehicle control group. 


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Primary Estimand 
Intercurrent events 
(ICEs) and 
strategies to handle 
ICEs 
a) Rescue treatment in the study eye due to worsening DRSS level to 65 
or higher prior to assessment of DRSS at Week 24 
Composite strategy (non-response)  
b) Death prior to DRSS assessment at Week 24   
Hypothetical strategy 
c) Use of rescue treatment in the study eye for any other reason prior to 
DRSS assessment at Week 24 
Composite strategy (non-response) 
d) Premature discontinuation of study drug for any reason prior to 
DRSS assessment at Week 24 
Hypothetical strategy  
e) Study drug compliance <75% through Week 24 
Treatment policy strategy  
f) Study drug compliance between 75% to <90% through Week 24  
Treatment policy strategy  
 
 
ICE(s) with a composite variable strategy take priority over ICEs with 
other strategies. And ICEs with a hypothetical strategy take priority over 
ICEs with treatment policy strategy. 
A Supplemental Estimand will be defined and analyzed where the ICEs defined above will be 
handled using alternative strategies as follows: c and e are changed to Hypothetical strategy. 
3.2.3 Secondary Endpoints 
The secondary outcome measures are as follows: 
• Proportion of participants developing worse than mild PDR (DRSS 65 and above) at Week 
24. 
• Proportion of participants who develop ASNV determined by the investigator at Week 24. 
• Time to development of PDR worse than mild (DRSS 65 and above). 
• Proportion of participants who develop CI-DME at Week 24. 
o CI-DME is defined as the presence of fluid in the central subfield in participants who 
have no fluid at baseline or CST> 325 µm. 
• Time to development of CI-DME. 
• Proportion of participants with change in DRSS steps at Week 24 compared to baseline. 
o Change in DRSS steps is defined as DR worsening or improving by 1, 2, or ≥3 steps.  


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• Proportion of participants with mild PDR (DRSS score 61B) at baseline who regress to NPDR 
(DRSS score ≤ 53) by Week 24. 
• Mean and median change in BCVA (ETDRS letters) from baseline to Week 24. 
• Lines gained/lost in BCVA (± 5, 10, and 15 ETDRS letters) at Week 24. 
• Mean and median change in Area Under the Curve (AUC) for change in BCVA from baseline 
to Week 24. 
o AUC from baseline to 24 weeks will be calculated by the linear trapezoidal method:  
 
𝐴𝑈𝐶(𝑡𝑖−𝑡𝑖−1) = (𝑡𝑖−𝑡𝑖−1) ∗𝑓(𝑡𝑖) + 𝑓(𝑡𝑖−1)
2
 
𝐴𝑈𝐶(24−0) = ∑𝐴𝑈𝐶(𝑡𝑖−𝑡𝑖−1)
24
𝑡0=0
 
where, ti = # of weeks since baseline, which may include 0, 4, 8, 12, 16, 20, 24 
according to schedule of visits, if available. 
• Mean and median change in CST from baseline to Week 24. 
• AUC for change in CST from baseline to Week 24. 
• Proportion of participants who met the objective rescue criteria as defined in protocol section 
2.14.9. 
• Time to meet the objective rescue therapy criteria as defined in protocol section 2.14.9.  
• Proportion of participants who develop VTC at Week 24 
• Time to development of PDR worse than mild (DRSS 65 and above) or CI-DME 
3.2.4 Exploratory Endpoints 
Exploratory imaging outcome measures are as follows: 
• Change in Macular Volume (MV) from baseline to Week 24 for 1, 3, and 6 mm regions.  
o MV for the 1 mm region is the central 1 subfield, for the 3 mm region is the middle 5 
subfields and for the 6 mm region is all 9 subfields as provided by the imaging center 
• Change in area of retinal non-perfusion from baseline to Week 24 seen on widefield 
Fluorescein Angiography (FA). 
• Proportion of participants with intact foveal avascular zone (FAZ) seen on widefield FA at 
Week 24. 
• Optical coherence tomography angiography (OCTA) endpoints within the 6mm area:  
o Change from baseline to Week 24 in FAZ area  
o Change from baseline to Week 24 in non-perfusion area 
o Change from baseline to Week 24 in vessel caliber  
o Change from baseline in Ischemic Index at Week 24 defined as total area of non-
perfusion divided by total area of retina visualized (28.3 mm2) 


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OTT166-201 
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: 09-Feb-2024 
Related to:  SOP-GDO-WW-019 
Page 16 of 53 
o Proportion of participants with new neovascularization at Week 24 
o Proportion of participants with new IRMA at Week 24  
o Change in vessel density from baseline to Week 24 in the superficial and deep layers 
3.2.5 Pharmacokinetic, Pharmacodynamic and Immunogenicity Endpoints 
In this study, no pharmacokinetic, pharmacodynamic or immunogenicity data are collected. 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures, and data listings to be included in the report will be independently checked for 
consistency, integrity, and in accordance with standard Parexel procedures. 
4.2 
General Presentation Considerations 
‘Baseline’ is defined as the last available pre-treatment assessment for safety assessments. For DRSS 
score, the Baseline value is defined as the Screening/Visit 1 result.  Pre-treatment values for DRSS 
were collected at the Screening/Visit 1 using fluorescein angiography in addition to fundus 
photography whereas Baseline/Visit 2 used fundus photography only. Participants were enrolled into 
the study and randomized to the study treatment based on the Screening/Visit 1 DRSS result. All 
other efficacy analyses that do not use DRSS score will use the last available pre-treatment assessment 
as Baseline. If an assessment is taken on the same day as first administration of study drug, it is 
eligible to be used as the Baseline value. This is considered acceptable as this measurement is still 
the best representation of the Baseline value of the given assessment since it is highly unlikely that 
the study drug could have an impact on any measurement in a short period of time. 
‘End of Study’ is defined as the last available post-treatment assessment.   
‘Study Day’ will be calculated relative to the date of randomization for untreated randomized 
participants and relative to the date of first dose for treated participants. If event is prior to the first 
dose, then study day is calculated as: 
Date of Event – Date of Day 1. 
If event is after the first dose, then study day is calculated as: 
Date of Event – Date of Day 1 + 1. 
‘Study day 1’ is defined as the date of randomization for untreated randomized participants or the 
date of first dose for treated participants. 
Time to event analyses will be calculated from Study Day 1, including time to DRSS-related 
endpoints comparing to the Baseline value.  These analyses will consider only post-Baseline 
assessments. The Visit 2/Baseline visit will not be considered. 
Duration of Treatment (days) will be calculated as: 
Last Date of Dose – First Date of Dose + 1. 
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, upper 
quartile, lower quartile, minimum, maximum and number of observations, unless otherwise stated. 
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database.  The mean, median, lower quartile and upper quartile will be reported to 
one more decimal place than the raw data recorded in the database.  The SD (and SE, if applicable) 


Parexel International 
OcuTerra Therapeutics, Inc. 
OTT166-201 
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: 09-Feb-2024 
Related to:  SOP-GDO-WW-019 
Page 17 of 53 
will be reported to two more decimal places than the raw data recorded in the database.  In general, 
the maximum number of decimal places reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of participants providing data at the 
relevant time point (n), frequency counts and percentages.  
Percentages will be presented to one decimal place except 100%. 100% will be presented as 100% 
instead of 100.0%.  Percentages will not be presented for zero counts.  Percentages will be calculated 
using the number of participants (n) as the denominator.  If sample sizes are small, the data displays 
will show the percentages, but any textual report will describe frequencies only.  A missing category 
shall be included only for categorical variables with missing data.  The missing category will be 
omitted if there were no missing values for that variable. 
Changes from baseline in categorical data will be summarized using shift tables where appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  P-values 
less than 0.001 will be presented as “<0.001”. P-values greater than 0.999 will be presented as 
“>0.999”. 
Confidence intervals (CIs) will be presented to one more decimal place than the raw data. 
4.2.1 Handling of Incomplete Dates 
Every effort will be undertaken to avoid any missing or incomplete data.  If variables are imputed, 
the analysis dataset will contain a new variable with imputed value and the original variable will 
contain the original missing value. 
Inevitable partial dates will be imputed for start/end dates of AEs or concomitant medications.  
Partial AE Start Date 
• If only day is missing, then it will be set to: 
o First day of the month that the AE occurred, if month/year of the AE start date is 
different than the month/year of the first dose date. 
o The day of first dose date, if month/year of the AE start date is the same as month/year 
of the first dose date and month/year of the AE end date is different. 
o The day of first dose date or day of AE end date, whichever is earliest, if the 
month/year of the AE start and month/year of the first dose date and month/year of the 
AE end date are the same. 
• If only month is missing, then it will be set to the earliest of the following: 
o January, as long as this date is after the first dose date 
o Month of the first dose date, if this date is the same day and year that the AE occurred 
• If the day and month are both missing, then it will be set to the earliest of the following: 
o January 1 of the year, as long as this date is after the first dose date 
o Month and day of the first dose date, if this date is the same year that the AE occurred 
o The AE end date 
• If dates are completely missing, then no imputation will be made. 
Partial AE End Date 


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Statistical Analysis Plan 
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• If only day is missing, then it will be set to the earliest of the last follow-up date, last day of 
the month, or the date of death. 
• If only month is missing, then it will be set to the earliest of the last follow-up date, December, 
or the date of death. 
• If year is missing or AE is ongoing, the end date will not be imputed. 
• If dates are completely missing, then no imputation will be made. 
If the imputed AE end date is before the corresponding AE start date, then the AE end date will be 
set to the AE start date. 
The same rule above will be applied to the start and end dates of concomitant medications. 
4.3 
Software 
All report outputs will be produced using SAS® version 9.4 or later in a secure and validated 
environment.  
4.4 
Study Participants 
4.4.1 Analysis Sets 
For purposes of analysis, analysis sets are defined as follows: 
Analysis Set 
Description 
Enrolled Set (ES)  
All participants who signed informed consent. 
Intent-to-Treat Analysis 
Set (ITT) 
All randomized participants who received at least one dose of the study 
drug. Participants will be included into the analysis as randomized. This 
corresponds to what is referred to in ICH E9 as the Full Analysis Set. 
Per-Protocol Set (PPS) 
All ITT participants without any major protocol deviations that could 
impact the primary endpoint. 
Safety 
Analysis 
Set  
(SS) 
All participants who receive at least one dose of study drug. Participants 
will be included into the analysis based on treatment actually received, 
regardless of the treatment randomized. 
 
The ITT Analysis Set will be used for all efficacy analyses and BL data analyses except participant 
disposition which will be shown for the ITT Analysis Set and for the Safety Analysis Set if the two 
analysis sets differ. All randomized participants are expected to be dosed and any exceptions will be 
described in the CSR. The PP set will be determined prior to database lock and will be used as a 
supplementary analysis of the primary endpoint.  
For analyses based on the SS, participants randomized to a control treatment group who receive any 
dose of active OTT166 treatment will be analyzed in the corresponding OTT166 treatment group 
(BID or QID).   
A Data Review Meeting will be arranged to identify analysis sets or data to be included/excluded 
from analysis, including a review/confirmation of participants with ICEs. Decisions made regarding 


Parexel International 
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Statistical Analysis Plan 
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Project Document Effective Date: 09-Feb-2024 
Related to:  SOP-GDO-WW-019 
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the exclusion of participants and/or participants data from analyses will be made prior to unmasking 
and will be documented and approved by OcuTerra Therapeutics, Inc. 
All safety analyses will be based on the Safety Analysis Set (SS).  
If a participant is stratified incorrectly, the participant will be included into the analysis as stratified 
per the ITT principle. 
The number and percentage of participants in each analysis set will be summarized by treatment 
group for the ES.  Inclusion in the PP set will be indicated in the listing of participant disposition for 
the ITT Analysis Set. 
Unless otherwise specified, participant disposition, demographics, and baseline characteristics will 
be summarized by the randomized treatment group (i.e., vehicle control doses (5% BID, 5% QID), 
vehicle control combined, active OTT166 doses (5% BID, 5% QID)), and overall. 
4.4.2 Disposition of Participants 
A clear accounting of the disposition of all participants who enter the study will be provided, from 
screening to study completion. 
Participant disposition will be summarized for the ITT Analysis Set by treatment and overall, for: 
• Number of participants randomized 
• Number and percentage of participants received at least one dose of study drug 
• Number and percentage of participants completed study drug 
• Number and percentage of participants discontinued from study drug and primary reason for 
premature discontinuation 
• Number and percentage of participants completed study 
• Number and percentage of participants discontinued from study and primary reason for 
premature discontinuation 
Participant disposition for participants who were screen failures (defined as participants in the 
Enrolled Set who were not randomized) will be summarized and will include the reason for screen 
failure.  
By-participant listings of participant disposition details will also be provided. 
4.4.3 Protocol Deviations 
Protocol deviations will be classified as “major” or “minor” on ongoing basis by the clinical study 
team and sponsor. 
Major protocol deviations are defined as those deviations from the protocol likely to have an impact 
on the perceived efficacy and/or safety of study treatments.  The impact of major protocol deviations 
on the efficacy results will be investigated by assessing the robustness of the study results and 
conclusions to the choice of analysis set, both including and excluding data potentially affected by 
major protocol deviations. 
Major protocol deviations and any action to be taken regarding the exclusion of participants or 
affected data from specific analyses are defined in the project-specific Protocol Deviation 
Specification. Final decisions made regarding the exclusion of participants and/or participants data 


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OTT166-201 
Statistical Analysis Plan 
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Project Document Version No. 3.0 
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Project Document Effective Date: 09-Feb-2024 
Related to:  SOP-GDO-WW-019 
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from analyses will be made prior to unmasking and will be documented and approved by OcuTerra 
Therapeutics, Inc. 
The number and percentage of participants with at least one major protocol deviation as well as major 
protocol deviation categories for the ITT Analysis Set by treatment and overall will be summarized.  
This summary will also include a summary of participants excluded from the PPS due to major 
protocol deviations by category. 
A by-participant listing of all protocol deviations will also be provided. 
4.5 
Demographics and Baseline Characteristics 
The following demographics and baseline characteristics will be summarized on ITT Analysis Set by 
treatment and overall: 
• Age (years) 
• Gender 
• Race 
• Ethnicity 
• Height (cm) at Baseline 
• Weight (kg) at Baseline 
• Body Mass Index (kg/m2) at Baseline 
• HbA1C at Baseline 
• Intraocular pressure at Baseline 
• DRSS steps at the Baseline Visit 
• ETDRS letter score at Baseline 
• Central Subfield Thickness (CST) at Baseline 
• Duration of Diabetes (years) defined as time from diagnosis to randomization 
• Diabetes Type (Type 1 and Type 2)  
• Diagnosis of systemic hypertension 
Additional demographic or baseline assessments may be added to the summary tables. 
A separate summary of subgroups on ITT Analysis Set will also be provided by treatment and overall: 
• Age (<65 years, ≥65 years)  
• BMI (Normal [<25 kg/m2], Overweight [≥25 to <30 kg/m2], Obese [≥30 kg/m2]) 
• HbA1C (≤7%, >7%) 
• Duration of Diabetes (<median, ≥median) 
• Baseline DRSS (47 or 53 or 61B) 
• Presence of fluid in the central subfield at Baseline (Y/N) 


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Statistical Analysis Plan 
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Project Document Effective Date: 09-Feb-2024 
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By-participant listing of demographic and other baseline characteristics as well as subgroups will also 
be provided. 
4.6 
Medical and Surgical History 
Medical and surgical history at screening will be collected under the Medical History form of the 
eCRF and will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 
24.1 or higher. Medical and surgical history will be summarized for the Safety Analysis Set by 
treatment and overall using system organ class (SOC) and preferred term (PT). 
A by-participant listing for medical and surgical history will be provided. 
4.7 
Prior and Concomitant Medications 
Prior medication is defined as any medications that started and stopped before the first dose of study 
drug. 
Concomitant medication is defined as any medications that started before the first dose of study drug 
and stops on or after the first dose of study drug, as well as any medications that started on or after 
the first dose of study drug. 
Medication start and stop dates will be compared to the date of first dose of study drug to allow 
medications to be classified as either prior or concomitant. Medications starting after the End of Study, 
as previously defined, will not be classified or summarized. 
Incomplete start and end date of the medications will be imputed as described in Section 4.2.1. 
Medications will be coded using the World Health Organization Drug (WHO-Drug) Global March 
2022 B3G. Prior and concomitant medications will be summarized on Safety Analysis Set by 
treatment and overall.  Participants with more than one medication in a given Anatomical Therapeutic 
Chemical (ATC) level 4 and preferred term will be counted only once. 
By-participant listings of both prior and concomitant medications will also be provided. 
4.8 
Rescue Therapy 
Participants meeting one or all the following criteria in the study eye would qualify for rescue with 
anti-VEGF therapy and/or PRP laser after consultation with the Medical Monitor: 
Objective Rescue Therapy Criteria: 
• Worsening DRSS level to 65 or higher as determined by the central reading center 
• Decrease in BCVA of ≥ 10 ETDRS letters from BL associated with presence of new fluid or 
an increase in fluid in the central subfield compared to baseline at any visit 
• Decrease in BCVA of 5 to 9 ETDRS letters from BL at two consecutive visits 4 weeks apart 
associated with presence of new fluid or an increase in fluid in the central subfield compared 
to baseline 
• Increase in CST of ≥ 75 microns from BL associated with presence of new fluid or an increase 
in fluid in the central subfield compared to baseline 
• Development of anterior segment neovascularization (ASNV) 
Subjective Rescue Therapy Criteria: 
• Any other condition that, in the clinical opinion of the investigator, warrants rescue therapy 
after consultation with the Medical Monitor 


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Summary tabulations of number and percentage of participants with rescue therapy, reasons for 
rescue and type of rescue therapy will be provided.  
A by-participant listing will be provided. 
The start date of rescue therapy in the study eye will be determined by the earliest concomitant 
medication in the study eye with ATC4CD=“SL01A” or the earliest ocular concomitant procedure 
confirmed by the clinical team to be rescue therapy.  This will be subset on the participants who have 
completed the “Rescue Therapy for Ocular Diabetic Complications” eCRF.  
4.9 
Treatment Exposure and Compliance 
4.9.1 Treatment Exposure  
Exposure to study drug will be summarized using the ITT Analysis Set and also the Safety Analysis 
Set. The total number of doses administered, and the duration of treatment will be summarized in a 
summary table by treatment group and overall. 
A by-participant listing of treatment exposure will be provided. 
4.9.2 Treatment Compliance  
Overall treatment compliance (%) will be calculated as: 
Total Number of Doses of Study Drug Administered
Total Number of Doses of Study Drug Planned
× 100% 
The total number of doses of study drug administered is the actual number of drops administered.  In 
the event a participant takes study drug after their EOS date, the total number of doses administered 
will not include any doses recorded after the EOS date. 
The total number of doses of study drug planned is calculated based on a participant’s duration in the 
study and the randomized treatment.  A participant randomized to BID treatment will have 2 times 
the (date of EOS – date of first dose + 1). A participant randomized to QID treatment will have 4 
times the (date of EOS – date of first dose + 1). 
For participants who take rescue therapy in the study eye during the study, the total number of doses 
of study drug planned is calculated based on a participant’s treatment duration prior to rescue and 
randomized treatment. A participant randomized to BID treatment will have 2 times the (date of EOT 
– date of first dose + 1). A participant randomized to QID treatment will have 4 times the (date of 
EOT – date of first dose + 1).  
A summary of the treatment compliance will be provided for the ITT Analysis Set and also the Safety 
Analysis Set by treatment and overall.  
Monthly (every 4 weeks) treatment compliance (%) will be calculated as: 
Total Number of Doses of Study Drug Administered each Month 
Total Number of Doses of Study Drug Planned for each month × 100% 
The total number of doses of study drug planned is calculated based on a participant’s duration in the 
study and the randomized treatment.  A participant randomized to BID treatment will have 2 times 
the minimum of 28 or the (date of EOS – date of first dose in month + 1). A participant randomized 
to QID treatment will have 4 times the minimum of 28 or the (date of EOS – date of first dose in 
month + 1). 


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For participants who take rescue therapy in the study eye during the study, the total number of doses 
of study drug planned is calculated based on a participant’s treatment duration prior to rescue and 
randomized treatment. A participant randomized to BID treatment will have 2 times the minimum of 
28 or the (date of EOT – date of first dose in month + 1). A participant randomized to QID treatment 
will have 4 times the minimum of 28 or the (date of EOT – date of first dose in month + 1). 
Number and percentage of participants with compliance in categories (<75%, 75-<90%, ≥90%) will 
be provided for overall and monthly treatment compliance.   
A by-participant listing of treatment compliance will be provided. 
4.10 Efficacy Evaluation 
4.10.1 Analysis and Data Conventions 
This study is designed to evaluate the superiority of two doses of OTT166 (5 mg/day and 10 mg/day) 
compared to vehicle control for the treatment of DR. For each dose within each endpoint, the null 
hypothesis is that there is no difference between OTT166 and vehicle control or the difference is in 
the direction of inferiority of OTT166, and the alternative hypothesis is that there is a difference 
between OTT166 and vehicle control in the direction of superiority of OTT166.  
All statistical tests will be one-sided and will be performed at the 5% level of significance, unless 
otherwise stated. The vehicle control group will be combined for all efficacy analyses and two-sided 
90% confidence intervals will be presented. A comparison between the two control groups will be 
performed for the primary endpoint to confirm the groups are comparable. 
4.10.1.1 Adjustments for Covariates 
The primary efficacy analysis will be adjusted for the randomization stratification factor, the 
Screening DRSS score (47 or 53 or 61B). 
4.10.1.2 Handling of Missing Data and Data After Intercurrent Events 
Primary Efficacy Analysis: 
Handling of missing DRSS response at Week 24 data in participants without ICEs: 
• Multiple imputation assuming missing at random (MAR).  
Handling of DRSS response at Week 24 data missing after ICEs: 
• Single imputation (non-response) when applying composite variable strategy. 
• Multiple imputation assuming MAR when applying hypothetical and treatment policy 
strategy.  
Handling of DRSS data response at Week 24 observed after ICEs: 
• Replaced by non-response (single imputation) in the analysis when applying composite 
variable strategy. 
• Replaced by MAR multiple imputation algorithm based on data from participants not 
affected by the respective ICE when applying hypothetical strategy. 
• Kept in the analysis when applying treatment policy strategy.   
If a participant experiences more than one ICE, ICE(s) with a composite variable strategy take 
priority over ICEs with hypothetical strategies, which take priority over ICEs with a treatment 
policy strategy. 


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MAR imputation will be generated based on a regression model for DRSS levels with covariates for 
randomized treatment group and the randomization stratification variable. DRSS response will be 
derived based on the imputed values. A total of 100 imputations will be used, followed by the 
MIANALYZE procedure to combine the estimates. 
 
Secondary Efficacy Analysis: 
Secondary endpoints involving a proportion: 
Missing data for the secondary endpoints involving a proportion will be imputed using the same 
approach as described for the primary efficacy analysis (ICE handling and missing data imputation).  
MAR imputation for the secondary endpoints involving a proportion will be generated based on a 
regression model with covariates for treatment group and the randomization stratification variable.  
Where appropriate, the dichotomous variable will be derived based on the imputed data. 
Change from baseline secondary endpoints: 
Handling of missing data of change from baseline in participants without ICEs: 
• Multiple imputation of the value at Week 24 (for BCVA and CST) assuming missing at 
random (MAR).  
Handling of missing data of change from baseline after ICEs: 
• Single imputation using the worst value at each visit observed among all participants when 
applying composite variable strategy. 
• Multiple imputation assuming MAR when applying treatment policy or hypothetical strategy.  
Handling of data observed after ICEs: 
• The value will be replaced by a single imputation using the observed worst value at each 
visit among all participants when applying composite variable strategy. 
• Replaced by MAR multiple imputation algorithm based on the assumption that the 
intercurrent event would not have occurred when applying hypothetical strategy. 
• Kept in the analysis when applying treatment policy strategy. 
MAR imputation for the continuous secondary endpoints (BCVA and CST) will be generated based 
on a linear regression model adjusting for treatment group, the randomization strata, and BL score 
of the analyzed variable where applicable and then the change from baseline will be calculated.  A 
total of 100 imputations will be used followed by the MIANALYZE procedure to combine the 
estimates. 
Time to event secondary endpoints: 
• Missing data for the time to event of secondary endpoints will be considered as censored. 
Participants who receive rescue medication will be censored at the start of rescue 
medication. 
4.10.1.3 Multiple Comparisons/Multiplicity 
No multiplicity adjustment is planned for this study. 


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4.10.1.4 Examination of Subgroups 
The uniformity of the treatment effect for the primary efficacy variable will be examined for the 
following subgroups: 
• Age (<65 years, ≥65 years) 
• Gender (Male, Female) 
• Race (White, Black or African American, Asian, Other) 
• Ethnicity (Hispanic, Not Hispanic) 
• BMI (Normal [<25 kg/m2], Overweight [≥25 to <30 kg/m2], Obese [≥30 kg/m2]) 
• HbA1C (≤7%, >7%) 
• Diagnosis of systemic hypertension (Y/N) 
• Duration of Diabetes (<median, ≥median) 
• Randomization strata (Screening DRSS:47 or 53 or 61B) 
• Presence of fluid in the central subfield at Baseline (Y/N) 
A forest plot with overall treatment effect included at the top will be provided. 
4.10.2 Primary Efficacy Analysis 
The primary efficacy outcome measure of the study will be the proportion of participants who have 
improved by ≥2 steps from BL DRSS at Week 24. DRSS score levels will be recoded into 12 steps, 
provided by WRC.  
Comparison of the primary endpoint will be made between each dose group and the combined vehicle 
control group using Mantel-Haenszel (MH) test of the difference in two proportions stratified by the 
randomization stratification factor (BL DRSS score 47 or 53 or 61B). The estimated MH risk 
difference will be summarized along with the two-sided 90% CI using MH stratum weights and the 
Sato variance estimator.  
The primary efficacy analysis will be performed on the ITT Analysis Set, while the PPS will be 
used as a supplementary analysis. ICEs and missing data will be handled as described in Section 
4.10.1.2.  
In order to assess the robustness of the study conclusions to the choice of imputation method, the 
following sensitivity analyses will be performed on the ITT Analysis Set and PPS for the primary 
endpoint:   
• An observed case analysis where only observed responses will be used for analysis. 
Observed data after initiation of rescue medication will be set to missing. 
• A LOCF analysis where missing post-baseline responses will be imputed using the LOCF 
procedure. 
Measurements after rescue will be imputed using the last observation prior to rescue 
treatment; a non-response will be imputed if no post-baseline measurements are available. 


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A supplementary analysis will be performed on the ITT Analysis Set and PPS for the primary 
endpoint to assess the time to improvement of ≥2 steps improvement from BL in DRSS score. 
Analyses will be based on observed data, where participants who receive rescue medication will be 
censored at the start of rescue medication (unless improvement of ≥2 steps improvement from BL 
in DRSS score is achieved prior to starting rescue medication). This analysis will be presented based 
on the Kaplan-Meier method, along with a 90% confidence interval. A stratified log-rank test 
adjusting for the randomization stratification factor will be performed, to compare the combined 
vehicle control with each treatment group. Additionally, a stratified Cox proportional hazards model 
adjusting for the randomization stratification factor will be employed to estimate the hazards ratio 
between the combined vehicle control and each treatment group.  
The primary efficacy analysis will also be performed by Baseline subgroups in Section 4.10.1.4, to 
assess the consistency of the treatment effect.    
An additional sensitivity analysis may be performed to assess the proportion of participants with an 
improvement of ≥2 steps improvement from the Visit 2/Baseline visit in DRSS score if needed. 
4.10.3 Secondary Efficacy Analysis 
The secondary outcome measures are described in Section 3.2.3. All secondary endpoints analyses 
will be performed on the Intention-to-Treat Analysis Set.  The following secondary endpoint analyses 
will be repeated on the PPS: 
• Proportion of participants who develop ASNV determined by the investigator at Week 24. 
• Proportion of participants who develop CI-DME at Week 24. 
• Change in DRSS steps is defined as DR worsening or improving by 1, 2, or ≥3 steps.  
• Proportion of participants with mild PDR (DRSS score 61B) at baseline who regress to NPDR 
(DRSS score ≤ 53) by Week 24 
• Mean and median change in BCVA (ETDRS letters) from baseline to Week 24. 
• Lines gained/lost in BCVA (± 5, 10, and 15 ETDRS letters) at Week 24. 
• Mean and median change in CST from baseline to Week 24. 
• Proportion of participants who met the objective rescue criteria as defined in protocol section 
2.14.9. 
• Time to meet the objective rescue therapy criteria.  
• Proportion of participants who develop VTC at Week 24 
 
Continuous variable and changes from baseline will be summarized at each visit by treatment using 
descriptive statistics. Categorical variables will be summarized at each visit by treatment using 
frequencies and percentages. 
The secondary endpoints involving proportions of participants will be analyzed using the same 
approach (MH test) as described for the primary efficacy analysis and based on the ITT Analysis set.  
The categorical secondary endpoints will be compared using a proportional odds model with 
covariates for treatment group and the randomization stratification factor. If the assumption of 
proportional odds is rejected, a different analysis approach, such as a rank-based ANCOVA, will be 


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considered. The rank-based ANCOVA will be a two-sided test and a two-sided p-value will be 
presented. 
The time to event secondary endpoints will be defined as time to first development of an event and 
will be estimated based on the Kaplan-Meier method, along with a 90% confidence interval. Analyses 
will be based on observed data, where participants who receive rescue medication will be censored 
at the start of rescue medication. A stratified log-rank test adjusting for the randomization 
stratification factor will be performed, to compare the combined vehicle control with each treatment 
group. Additionally, a stratified Cox proportional hazards model adjusting for the randomization 
stratification factor will be employed to estimate the hazards ratio between the combined vehicle 
control and each treatment group. 
Continuous secondary endpoints involving change from BL to Week 24 will be analyzed using an 
analysis of covariance (ANCOVA) model with BL measurement of the variable as a covariate and 
treatment group and the randomization stratification factor as fixed factors. As a sensitivity analysis 
of the continuous secondary endpoints involving change from BL to Week 24, a rank-based 
ANCOVA model will be employed. The pair-wise comparisons of each OTT166 dose group versus 
combined vehicle control will be done in the ANCOVA model. Two-sided 90% confidence intervals 
for the difference of each OTT166 dose group minus combined vehicle control will be calculated.  
The specific reasons for meeting rescue criteria as described in protocol section 2.14.9 will also be 
summarized using number and percentage by treatment group.  
4.10.4 Exploratory Analysis 
Exploratory imaging outcome measures are described in Section 3.2.4. 
• All exploratory endpoint analyses will be performed on the Intention-to-Treat Analysis Set 
and will be based on observed data, where observed data after the initiation of rescue 
medication will be set to missing unless specified otherwise. The following exploratory 
endpoint analyses will be repeated on the PPS:  
• Change in MV from baseline to Week 24 for 1, 3, and 6 mm regions.  
• Change in area of retinal non-perfusion from baseline to Week 24 seen on widefield FA. 
• Proportion of participants with intact FAZ seen on widefield FA at Week 24. 
The exploratory endpoints involving proportions of participants will be analyzed using the same 
approach (MH test) as described for the primary efficacy analysis if not specified otherwise.  
The time to event exploratory endpoints will be estimated based on the Kaplan-Meier method, along 
with a 90% confidence interval. A stratified log-rank test adjusting for the randomization stratification 
factor will be performed, to compare the combined vehicle control with each treatment group. 
Additionally, a stratified Cox proportional hazards model adjusting for the randomization 
stratification factor will be employed to estimate the hazards ratio between the combined vehicle 
control and each treatment group. 
Continuous exploratory endpoints involving change from BL will be analyzed using an ANCOVA 
model with BL measurement of the variable as a covariate and treatment group and the randomization 
stratification factor as fixed factors. The pair-wise comparisons of each OTT166 dose group versus 
combined vehicle control will be done in the ANCOVA model. Two-sided 90% confidence intervals 
for the difference of each OTT166 dose group minus combined vehicle control will be calculated.  
 


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Within participant treatment effects will also be assessed for the primary endpoint (DRSS step change 
of ≥ 2 steps) and key secondary endpoints (BCVA change, CST change, and development of CI-
DME). Differences in outcomes from screening to Week 24 between eyes for participants in the two 
active treatment groups (OTT166 5 mg/day, OTT166 10 mg/day) will be compared using an 
appropriate paired data analysis: McNemar’s test for dichotomous data and either a paired t-test or a 
Wilcoxon signed-rank test for continuous outcome data (changes from baseline). Data for eyes that 
were treated with anti-VEGF and/or laser will be imputed with LOCF from the time of starting 
treatment with anti-VEGF and/or laser. The earliest concomitant medication in the fellow eye with 
ATC4CD=”SL01A” will be considered for anti-VEFG treatment in the fellow eye. Additionally, the 
first ocular concomitant procedure in the fellow eye will be considered for laser treatment.  The ocular 
concomitant procedures will be reviewed and confirmed by the clinical team.  
Associations between baseline covariates and compliance may be assessed graphically: monthly 
compliance may be presented as a series of boxplots for each baseline subgroup, by treatment group 
and overall, allowing for the observation of compliance trends within or between groups.   
4.11 Safety Evaluation 
All safety summaries and analyses will be based upon the Safety Analysis Set by treatment group 
(i.e., vehicle control doses (5% BID, 5% QID), vehicle control combined, active OTT166 doses (5% 
BID, 5% QID), and OTT166 combined). Safety summaries for age, gender, race and ethnicity 
subgroups will be provided. If any safety measurements are repeated at the same visit after dosing on 
Day 1, then the last (non-missing) value of any repeated measurements will be used in the descriptive 
statistics and in the calculation of changes from BL. No inferential statistics will be performed for 
safety variables. 
4.11.1 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 24.1 or higher. Intensity and causality of AE will be evaluated by the investigator.  The 
intensity of AE will be graded according to the criteria in Appendix 4 of the Protocol.   
Incomplete start and end date of the AEs will be imputed as described in Section 4.2.1. 
Participants with multiple incidents of events for a given preferred term (PT) and system organ 
class (SOC) will be counted only once. Similarly, if participants experience multiple incidents of 
events for a given PT and SOC, the worst intensity will be used in the summaries presenting 
intensity, and the worst causality to study drug will be used in the summaries presenting causality, 
respectively. 
Any missing intensity will be queried for completion and assessed by the Investigator based on AEs 
and serious AEs, as defined in Appendix 4 of the Protocol. 
Any missing causality will also be queried for completion, and any events that still have missing 
causality in the final data will be deemed as ‘Related’. 
Adverse events of special interest (AESI) are defined as: 
• Hypersensitivity reactions. Symptoms of hypersensitivity reactions (allergic reactions) 
include: 
• Rash 
• Wheezing and difficulty breathing 


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• Dizziness and fainting 
• Swelling around the mouth, throat or eyes  
• A fast pulse 
• Sweating 
Treatment-emergent adverse events (TEAEs) are defined as any adverse events occurring (onset 
date/time) at the time of or after dosing on Day 1. Where the AE start date is missing, AEs will be 
assumed to be treatment-emergent, unless there is clear evidence (through comparison of partial 
dates) to suggest that the adverse event started prior to the first dose of study treatment. 
Adverse event summaries will be sorted in terms of decreasing frequency for SOC, and PT within 
SOC, in the overall group, and then alphabetically for SOC, and PT within SOC if there are any ties 
in frequency. 
Analysis and reporting for adverse events will be based on TEAEs. An overall summary of TEAEs 
will include the number and percentage of participants in the following categories: 
• Number and percentage of participants with TEAEs 
• Number and percentage of participants with drug-related TEAEs 
• Number and percentage of participants with TEAEs leading to discontinuation of study drug 
• Number and percentage of participants with TEAEs leading to study discontinuation 
• Number and percentage of participants with treatment-emergent serious adverse event 
(TESAEs) 
• Number and percentage of participants with drug-related treatment-emergent serious 
adverse event (TESAEs) 
• Number and percentage of participants with TESAEs leading to discontinuation of study 
drug 
• Number and percentage of participants with TESAEs leading to study discontinuation 
• Number and percentage of participants by intensity of TEAEs (mild, moderate, severe) 
• Number and percentage of participants who experienced death from any cause 
• Number and percentage of participants with AESIs 
Summaries of TEAEs by treatment group, SOC, and PT will be presented for the following: 
• All TEAEs 
• Ocular TEAEs in the Study Eye 
• Ocular TEAEs in the Fellow Eye 
• Non-Ocular TEAEs 
• Drug-related TEAEs  
• TEAEs leading to discontinuation of study 
• TEAEs leading to discontinuation of study drug 


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• All TESAEs  
• Ocular TESAEs in the Study Eye 
• Ocular TESAEs in the Fellow Eye 
• Non-Ocular TESAEs 
• Drug-related TESAEs  
• TESAEs leading to discontinuation of study 
• TESAEs leading to discontinuation of study drug 
• TEAEs by intensity 
• AESIs 
• AESIs leading to discontinuation of study 
• AESIs leading to discontinuation of study drug 
By-participant listings of corresponding TEAE data will also be provided. Separate listings will be 
presented for TEAEs leading to discontinuation of study drug and treatment-emergent serious adverse 
events (TESAEs). Any AEs occurring between signing of ICF and dosing on Day 1 will be presented 
in a separate listing. All listings will be done by treatment group and participant, detailing verbatim, 
SOC, PT, start date, stop date (if resolved), intensity, seriousness, outcome, action taken with respect 
to study drug, and relationship to study drug. The AE onset will also be shown relative (in number of 
days) to the day of the first study drug administration. 
4.11.2 Clinical Laboratory Evaluation 
All laboratory values will be reported and summarized using standard international (SI) units. 
Continuous test results for each laboratory parameter and changes from baseline will be 
summarized at each visit by treatment using descriptive statistics.  Categorical test results for each 
parameter will be summarized at each visit by treatment using frequencies and percentages. 
The abnormal values will be flagged with ‘L’ for values below the lower limit of the clinical 
reference range and ‘H’ for values above the upper limit of the clinical reference range and included 
in the listings. A shift from baseline to out-of-normal range at each post-baseline visit will be 
summarized by treatment.  If a participant has both low and high out-of-normal post-baseline value, 
each low and high will be counted separately. By-participant listings of laboratory parameters will 
also be provided. 
Urinalysis results will be listed by participant and timepoint including changes from baseline for 
numeric variables, flags for any measurements that are outside the reference ranges and any 
repeated/unscheduled assessments.  
The results of pregnancy and HbA1c testing will be listed for each participant. 
4.11.3 Vital Signs 
Vital signs measurements will be listed by participant and timepoint including changes from BL and 
any repeated/unscheduled measurements. Descriptive statistics (n, mean, SD, minimum, median, 


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maximum) will be provided by treatment group and timepoint for both absolute values and changes 
from BL.  
4.11.4 Physical Examination 
A listing of physical examination data by participant will be provided.  
4.11.5 Data and Safety Monitoring Board (DSMB) 
No DSMB is planned. 
4.12 Planned Interim Analyses 
There are no interim analyses planned.  
4.13 Determination of Sample Size 
The study will enroll approximately 210 participants, 70 participants in each OTT166 treatment group 
and 35 participants per group into each matching vehicle control group and allowing for around 5% 
study attrition, this will ensure at least 66 participants per treatment group and combined vehicle 
control group. 
For the primary endpoint of improvement by at least 2 steps from baseline on the DRSS at Week 24, 
completing 66 participants per group (active treatment BID, active treatment QID, combined vehicle 
control) through Week 24 will yield at least 90% power to demonstrate that the active treatment is 
superior to placebo using a 1-sided alpha of 0.05, provided that the true treatment effect (active 
treatment efficacy rate minus control efficacy rate) is at least 0.20 and the control efficacy rate is at 
most 0.06.  
The sample size calculation was computed in nQuery 8.7 using a Chi square test for two proportions 
(continuity corrected). 
4.14 Changes in the Conduct of the Study or Planned Analysis 
• Analyses described in the SAP supersede the planned analyses in the study protocol.  
Similarly, planned analyses may be amended as a result of planned blinded data reviews.  
Changes will be finalized prior to the database lock. 
5 
REFERENCES 
[1] Mantel, N. and Haenszel, W., 1959. Statistical aspects of the analysis of data from retrospective 
studies of disease. Journal of the national cancer institute, 22(4), pp.719-748. 
[2] Sato, T., 1989. On the variance estimator for the Mantel-Haenszel risk difference. Biometrics, 
45(4), pp.1323-1324. 
[3] Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on 
Statistical Principles for Clinical Trials E9(R1) Final version (Step 4), Adopted on 20 November 
2019. (https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf) 
[4] Staurenghi, G., Feltgen, N., Arnold, J.J., Katz, T.A., Metzig, C., Lu, C. and Holz, F.G., 2018. 
Impact of baseline Diabetic Retinopathy Severity Scale scores on visual outcomes in the VIVID-
DME and VISTA-DME studies. British Journal of Ophthalmology, 102(7), pp.954-958.  
[5] Friedman, S. M., Almukhtar, T. H., Baker, C. W., Glassman, A. R., Elman, M. J., Bressler, N. M., 
Maker, M.P., Jampol, L.M., Melia, M. & Diabetic Retinopathy Clinical Research Network. (2015). 


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Topical nepafenec in eyes with non-central diabetic macular edema. Retina (Philadelphia, Pa.), 35(5), 
944. 


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6 
APPENDIX 
6.1 
Schedule of Activities 
Study Procedure  
Screening 
Visit 1  
Baseline 
(BL) Visit 2 Visit 3  
Visit 4  Visit 5  Visit 6  
Visit 7 
Visit 8a  
Week  
-- 
0 
4 
8 
12 
16 
20 
24 
Day (visit window)  
-21 to -1  
1 
29 ± 7 
days  
57 ± 7 
days  
85 ± 7 
days  
113 ± 7 
days  141 ± 7 days 169 ± 7 days 
Screening/Baseline (BL):  
  
  
  
  
  
  
  
  
Informed consent  
X  
 
 
 
 
 
 
  
Inclusion/exclusion  
X  
X  
 
 
 
 
 
  
Medical and ophthalmic 
history  
X  
 
 
 
 
 
 
  
Demographics  
X  
 
 
 
 
 
 
  
Randomization  
 
X  
 
 
 
 
 
  
Interval Medical Review:  
  
  
  
  
  
  
  
  
Review of concomitant 
medications  
X  
X  
X  
X  
X  
X  
X 
X  
Continue study treatmentb  
 
X  
X  
X  
X  
X  
X 
X  
Ocular Assessments:  
  
  
  
  
  
  
  
  
Refraction and BCVA 
(ETDRS) 
OU  
OU  
OU  
OU  
OU  
OU  
OU 
OU  
Slit lamp examination  
OU  
OU  
OU  
OU  
OU  
OU  
OU 
OU  
Assessment of corneac 
OU  
OU  
OU  
OU 
OU 
OU 
OU 
OU 
Intraocular pressured  
OU  
OU  
OU  
OU  
OU  
OU  
OU 
OU  
Indirect ophthalmoscopy 
OU  
OU  
OU  
OU  
OU  
OU  
OU 
OU  


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4-wide or 7-field color 
fundus photography 
(mandatory)e 
OU  
OU  
SE  
SE 
OU 
SE  
SE 
OU 
SD-OCT (widefield if 
available) 
OU  
OU  
SE  
SE  
OU  
SE  
SE 
OU 
OCTA (if available) 
OU  
 
 
 
 
 
 
OU 
Wide field Fluorescein 
Angiographym 
OU 
 
 
 
 
 
 
OU 
Gonioscopy 
OU 
 
 
 
 
 
 
OU 
Non-Ocular Assessments:  
  
  
  
  
  
  
  
  
Physical examinationf  
X  
  
Vital signsg  
X  
X  
X  
X  
X  
X  
X 
X  
Adverse eventsh  
X  
X  
X  
X  
X  
X  
X 
X  
IP adherence reviewn 
 
 
X 
X 
X 
X 
X 
X 
Laboratory Testing:i 
  
  
  
  
  
  
  
  
Hematology, blood 
chemistry, urinalysis, and 
HbA1cj,l  
X  
 
 
 
 
 
 
X 
Pregnancy test, women of 
childbearing potentialk  
serum  
urine  
urine  
urine  
urine  
urine  
urine 
urine  
Abbreviations: BCVA: best corrected visual acuity; BL: baseline; ETDRS: Early Treatment Diabetic Retinopathy Study; HbA1c: glycosylated hemoglobin; 
OCTA: optical coherence tomography – angiography; OU: both eyes; SD-OCT: spectral-domain optical coherence tomography; SE: study eye; 
a 
Participants who are withdrawn from the study before Week 24/Visit 8 will be asked to return to the clinic to complete the Visit 8 assessments.  
b 
Participants will continue to receive study treatment based on exam findings, AE review, and verification that rescue criteria are not met. 
c 
Cornea health assessment following instillation of fluorescein stain, including epithelium and endothelium, for signs of toxicity.  
d 
Intraocular pressure should be measured at approximately the same time of day from visit to visit, if possible. 
e 
An FP and FA must be performed once a participant has been diagnosed with worse than mild PDR, ASNV, or new onset or worsening CI-DME in the study 
eye, and before rescue treatment is given.  
f 
May be performed at Visit 1 or Visit 2, Including height, weight, and body temperature. 


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g 
Vital signs (blood pressure and heart rate) will be measured after the participant has been sitting for 5 minutes at the screening visit. From baseline through 
end of study only blood pressure and heart rate will be measured. 
h 
AEs will be collected from the time the ICF is signed until early termination or the end of study visit. If a participant withdraws from the study, ongoing AEs 
will be followed to the end of study visit or until the participant withdraws consent. 
i 
All samples collected for laboratory assessments will be obtained prior to administration of study drug. 
j 
At visits at which FA is performed, urinalysis samples will be collected before FA in order to avoid false elevations in urine protein values.  
k 
For women of childbearing potential, a negative screening serum pregnancy test at Visit 1 is required before randomization. All women of childbearing 
potential will have a urine pregnancy test at each treatment visit starting at Visit 2 (Day 1); a negative urine pregnancy test is required before treatment is 
continued (randomized treatment, rescue treatment). 
l 
Refer to Appendix 3.3 in protocol for clinical laboratory test details. 
m 
 Screening Fluorescein angiography is valid for 3 months. Participants undergoing rescreen do not need IVFA repeated within 3 months of original 
angiogram. 
n 
Cornea should be assessed at the beginning before dilation. 
o 
Adherence to the dosing regimen should be monitored continuously and discussed with the participant at each visit. Sites are expected to intervene if there is 
suboptimal adherence or absence of data transfer and document the intervention in the patient dashboard. 
 


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6.2 
ETDRS Final Diabetic Retinopathy Severity Scale (For Individual Eye) 
 
Level  Severity  
Definition  
10  
DR absent  
Microaneurysms and other characteristics absent  
12٭ 
 Non-DR abnormalities  
 
14٭ 
DR questionable  
14A HE definite; microaneurysms absent  
 
 
14B SE definite; microaneurysms absent  
 
 
14C IRMA definite; microaneurysms absent  
 
 
14Z     Venous loops >D/1; microaneurysms absent  
15٭ 
DR questionable  
Hemorrhage(s) definite; microaneurysms absent  
20  
Microaneurysms only  
Microaneurysms definite, other characteristics absent  
35†  
Mild NPDR  
35A Venous loops ≥ D/1  
 
 
35B SE, IRMA, or VB = Q  
 
 
 
 
 
35D HE ≥ D/1 ( < STD 3 in any field )  
 
 
35E HE ≥ M/1 ( ≥ STD 3 in any field )  
 
 
35F SE ≥ D/1 ( any definite )  
43  
Moderate NPDR  
43A H/Ma = M/4-5 (> STD 1(4+ fields) -OR- ≥ STD 
2A (1 field) )  
 
 
43B IRMA = D1-3  (any definite  < STD 8A )  
47  
Moderately Severe NPDR  
47A Both L43 characteristics  
 
 
47B IRMA = D/4-5  ( < STD 8A )  
 
 
47C H/Ma = S/2-3  ( < STD 2B )  
 
 
47D VB = D/1   
53  
Severe NPDR  
53A ≥ 2 of the L47 characteristics  
 
 
53B H/Ma ≥ S/4-5 (≥ STD 2A in 4+ fields or ≥ 2B in 
any field )  
 
 
53C IRMA ≥ M/1 ( ≥ STD 8A )  
 
 
53D VB ≥ D/2-3 or S1 (≥ STD 6 in 2+ fields or ≥ 6B 
in any field)  
53E  
Very Severe NPDR  
53E ≥ 2 of 53B, 53C, and 53D  
60  
Inactive PDR  
60 Scatter or Local Rx  
61  
Mild PDR  
61A FPD and/or FPE only (regressed PDR)  
 
 
61B NVE < ½ DA in ≥ 1 field  
65  
Moderate PDR  
65A NVE ≥ M/1 ( ≥ ½ DA in ≥ 1 field)  
 
 
65B NVD = D ( < STD 10A ) ; and VH and PRH = A 
or Q  
 
 
65C VH or PRH = D ( < 1 DA) and NVE < M (< ½ 
DA ) and NVD absent  


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71/75  High-risk PDR  
71A VH or PRH ≥ M/1 ( ≥ 1 DA )  
 
 
71B NVE ≥ M/1 ( ≥ ½ DA 1 field ) and VH or PRH ≥ 
D/1 ( any )  
 
 
71C NVD = D ( < STD 10A )  and VH or PRH ≥ D/1 
( any )  
 
 
71D NVD ≥ M ( ≥ STD 10A )  
 
 
75 NVD ≥ M ( ≥ STD 10A) and VH or PRH ≥ D/1 
(any)  
81  
Advanced PDR: fundus 
partially obscured, center of 
macula attached  
NVD = cannot grade, or NVD < D and NVE = cannot 
grade in ≥ 1 field and absent in all others; and retinal 
detachment at center of macula < D  
85  
Advanced PDR: posterior 
fundus obscured, or center of 
macula detached  
85A VH = VS (obscuring) in Field 1 or 2 85B Retinal 
detachment at center of macula = D (present)  
90  
Cannot grade, even for 81 or 
85  
 
Abbreviations:  DR = diabetic retinopathy; NPDR = nonproliferative DR; PDR = proliferative DR; HE = hard exudates; SE = soft 
exudates; IRMA = intraretinal microvascular abnormalities; VB = venous beading; H/Ma = hemorrhages/microaneurysms; NVE = new 
vessels elsewhere; NVD = new vessels on or adjacent to optic disc; VH = vitreous hemorrhage; PRH = preretinal hemorrhage 
Severity categories are of the form (maximum severity/extent), where maximum severity can be absent (A), questionable (Q), definitely 
present (D), moderate (M), severe (S), or very severe (VS), and extent is the number of photographic fields at that severity level.  For 
example, M/2-3 means there are two or three fields from fields 3 to 7 with moderate severity, and none with higher severity. 
٭  Levels 12, 14, and 15 are not considered separate steps in the scale, but are pooled with level 10 or 20 (or excluded). 
†   NPDR levels 35 and above all require presence of microaneurysms. 
 
 
 
6.3 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) 
Rationale for the amendment 
This statistical analysis plan has been amended to incorporate changes made in the current protocol 
amendment v5.0 of 10 October 2023 as well as additional changes not in the current protocol. 
Changes below that are not shown in the current version of the protocol should supersede any analysis 
described in the current protocol v5.0.  
 
6.3.1 Amendment 1 
 
Change # 1 
List of Abbreviations 
The following abbreviations have been added or updated: 
• IRMA: Intraretinal microvascular abnormality was added 
• TMV: Total Macular Volume has been changed to MV: Macular Volume  
 
Change # 2 


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Section 2 STUDY OBJECTIVES AND ENDPOINTS  
• Section 2.1, 2.2, and 2.3 have been combined as Section 2 and updated to present all the study 
objectives and endpoints in a table format for clarity  
• The following endpoint has been updated (the text in bold has been added): 
o Proportion of participants who develop ASNV determined by the investigator at 
Week 24 
• The following secondary endpoint has been deleted from this section and throughout the SAP 
o Mean and median step change in DRSS step from baseline to Week 24  
 
Change# 3 
Section 3.1 Overall Study Design and Plan: 
• The following changes in bold have been made in this section 
o The study population will be participants with Type 1 or Type 2 diabetes under 
adequate control as evidenced by glycosylated hemoglobin (HbA1c≤12.0%), who 
show typical fundus alterations and have been diagnosed with moderately severe to 
severe NPDR or mild PDR, as defined by the DRSS Steps 47, 53 and 61B (Appendix 
6.2). Participants may have fluid in the macula with BCVA of ≥69 Early Treatment 
Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent 20/40) and Central 
Subfield Thickness (CST) of ≤ 325 µm, and a normal foveal contour, which needs 
to be confirmed by an independent central reading center, in at least 1 eye. 
 
Change# 4 
Section 3.2.1 Primary Endpoint – Safety  
• The Primary Endpoint - Safety section has been updated to only include the primary endpoint 
for safety shown in bold below and remove all other secondary safety endpoints: 
o The primary safety outcome measure of the study will be the proportion of 
participants who develop TEAEs through Week 24.  
 
Change# 5 
Section 3.2.2 Primary Efficacy Endpoint and Estimand  
• The following changes (text shown in bold below) have been made in this section: 
o The primary clinical question of interest is to determine the effectiveness of different 
doses of OCT166 versus vehicle control on ≥2 steps improvement from BL in DRSS 
score at Week 24 without requiring rescue treatment if the study drug is not 
discontinued prior to Week 24. This will support the dose selection for subsequent 
pivotal studies of OTT166. The estimand for the primary efficacy analysis is defined 
as follows, 
• Participant population attribute of the primary Estimand has been updated: 
o DR participants with Type 1 or Type 2 diabetes under adequate control (HbA1c 
≤12.0%) who show typical fundus alterations and have been diagnosed with 
moderately severe to severe NPDR or mild PDR as defined by the DRSS Steps 
47, 53, and 61B, with BCVA ≥ 69 ETDRS letters, CST of ≤ 325 µm, and a 
normal foveal contour.  
• The following ICE strategies have been changed: 
• ICE b) has been changed from “Death due to DR” to “Death”, and strategy has been changed 
from Composite strategy (non-response) to Hypothetical.  


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• ICE c) Strategy has been changed from Hypothetical to Composite strategy (non-response).  
• ICE e) Strategy has been changed from Hypothetical to Treatment policy.  
• ICE e) and f) compliance evaluation time range has been changed from every 4 weeks 
through Week 24 
• ICE f) upper bound of compliance has been changed from 100% to 90%  
 
• The following paragraph (in bold) has been moved from this Section to Section 4.10.1.2: 
o If a participant experiences more than one ICE, ICE(s) with a composite variable 
strategy take priority over ICEs with other strategies. And ICEs with a 
hypothetical strategy take priority over ICEs with treatment policy strategy. 
 
• The Supplemental Estimand description was moved from Section 4.10.1.2 to this Section and 
the strategy was changed from treatment policy for ICEs c) through f) to having ICEs c) and 
e) use Hypothetical strategy as described below in bold: 
o A Supplemental Estimand will be defined and analyzed where the ICEs defined 
above will be handled using alternative strategies as follows: c, and e would be 
changed to Hypothetical strategy. 
 
Change# 6 
Section 3.2.3 Secondary Endpoints    
• The following secondary endpoint has been deleted from this section: 
o Mean and median change in DRSS step from baseline to Week 24. 
• The following changes (text in bold) have been made to the following secondary endpoints:  
o Proportion of participants who develop ASNV determined by the investigator at Week 
24. 
o Proportion of participants who develop CI-DME at Week 24. 
o CI-DME is defined as the presence of any fluid within the central subfield in 
participants who have no fluid at baseline or CST> 325 µm. 
o Proportion of participants who met the objective rescue criteria as defined in protocol 
section 2.14.9. 
o Time to meet the objective rescue therapy criteria as defined in protocol section 2.14.9 
 
Change # 7 
Section 3.2.4 Exploratory Endpoints 
The following changes in bold have been made: 
• Change in Total Macular Volume (TMV) from baseline to Week 24 for 1, 3, and 6 mm regions 
endpoint has been updated to Change in Macular Volume (MV) and moved from the bottom 
of this section to the top; the definition has also been updated (see in bold below):  
o Change in Macular Volume (MV) from baseline to Week 24 for 1, 3, and 6 mm 
regions.  
▪ MV for the 1 mm region is the central 1 subfield, for the 3 mm region is 
the middle 5 subfields and for the 6 mm region is all 9 subfields as 
provided by the imaging center 
• The following endpoints have been deleted: 


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o Proportion of participants who do not have non-CI-DME at baseline that develop 
non-CI-DME at Week 24. 
▪ Non-CI-DME is defined as central subfield thickness below the threshold 
defined in Friedman et. al. (2015) for Zeiss Cirrus and meeting one of the 
following: 1) At least 2 non-central subfields with thickness values above 
threshold; or 2) At least 1 non-central subfield with thickness value more 
than 15 μm above threshold. 
o Time to development of non-CI-DME (in those participants who do not have non-
CI-DME at baseline). 
o Time to resolve non-CI-DME (in those participants who do have non-CI-DME at 
baseline). 
o Optical Coherence Tomography (OCT) endpoints:  
o Proportion of participants with appearance or disappearance of subretinal 
fluid or cysts in the 9 subfields at Week 24 
Change# 8 
Section 4.4.1 Analysis Sets 
• The following changes in bold have been made to the definition of the ITT Analysis Set: 
o All randomized participants who received at least one dose of the study drug. 
Participants will be included into the analysis as randomized. This corresponds to 
what is referred to in ICH E9 as the Full Analysis Set. 
• FAS definition and references throughout the SAP have been deleted 
• The following changes in bold have been made to this section: 
o The ITT Analysis Set will be used for all efficacy analyses and BL analyses except 
participant disposition which will be shown for the ITT Analysis Set and for the 
Safety Analysis Set if the two analysis sets differ. The PP set will be determined 
prior to database lock and will be used as a supplementary analysis of the primary 
endpoint.  
o The number and percentage of participants in each analysis set by treatment group will 
be summarized for the ES. Inclusion in the PP set will be indicated in the listing of 
participant disposition for the ITT Analysis Set. 
o Unless otherwise specified, participant disposition, demographics, and baseline 
characteristics will be summarized by the randomized treatment group (i.e., 
vehicle control doses (5% BID, 5% QID), vehicle control combined, active 
OTT166 doses (5% BID, 5% QID)), and overall. 
 
Change # 9 
Section 4.4.2 Disposition of Participants 
• The following change in bold has been made: 
o Participant disposition will be summarized for the ITT Analysis Set by treatment and 
overall, for: 
• The following participant disposition characteristics in bold have been deleted: 
o Number of participants screened 
o Number of participants with screen failure 
• The following paragraph in bold has been added: 


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o Participant disposition for participants who were screen failures (defined as 
participants in the Enrolled Set who were not randomized and are not included 
in the ITT Analysis Set) will be summarized and will include the reason for screen 
failure. 
 
Change# 10  
Section 4.4.3 Protocol Deviations 
• The following changes in bold have been made: 
o The number and percentage of participants with at least one major protocol deviation 
as well as major protocol deviation categories for the ITT Analysis Set by treatment 
and overall will be summarized.   
 
Change# 10 
Section 4.5 Demographics and Baseline Characteristics 
• The following changes in bold have been made: 
o Central Subfield Thickness (CST) at Baseline 
o HbA1C (≤7%, >7%) 
• The following subgroup has been added:  
o Presence of fluid in the central subfield at Baseline (Y/N) 
 
Change# 11 
Section 4.8 Rescue Therapy 
• The following changes in bold have been made in this section: 
o Participants meeting one or all the following criteria would qualify for rescue with 
anti-VEGF therapy and/or PRP laser after consultation with the Medical Monitor: 
Objective Rescue Therapy Criteria: 
▪ Worsening DRSS level to 65 or higher as determined by the central reading 
center 
▪ Decrease in BCVA of ≥ 10 ETDRS letters from BL associated with presence 
of new fluid or an increase in fluid in the central subfield compared to 
baseline at any visit 
▪ Decrease in BCVA of 5 to 9 ETDRS letters from BL at two consecutive visits 
4 weeks apart associated with presence of new fluid or an increase in fluid 
in the central subfield compared to baseline 
▪ Increase in CST of ≥ 75 microns from BL associated with presence of new 
fluid or an increase in fluid in the central subfield compared to baseline 
Subjective Rescue Therapy Criteria: 
▪ Any other condition that, in the clinical opinion of the investigator, warrants 
rescue therapy after consultation with the Medical Monitor 
 
Change# 12 
Section 6.1.1 Treatment Exposure  
The following changes in bold have been made in this section: 
• Exposure to study drug will be summarized using the ITT Analysis Set and also the Safety 
Analysis Set. The total number of doses administered, and the duration of treatment will be 
summarized in a summary table by treatment group and overall. 
 


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Change# 13 
Section 4.9.2 Treatment Compliance 
• The following changes and monthly compliance in bold have been added: 
o A summary of the treatment compliance will be provided for the ITT Analysis Set and 
also the Safety Analysis Set by treatment and overall.  
o Monthly (every 4 weeks) treatment compliance (%) will be calculated as: 
o 
𝐓𝐨𝐭𝐚𝐥 𝐍𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐃𝐨𝐬𝐞𝐬 𝐨𝐟 𝐒𝐭𝐮𝐝𝐲 𝐃𝐫𝐮𝐠 𝐀𝐝𝐦𝐢𝐧𝐢𝐬𝐭𝐞𝐫𝐞𝐝 𝐞𝐚𝐜𝐡 𝐌𝐨𝐧𝐭𝐡 
𝐓𝐨𝐭𝐚𝐥 𝐍𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐃𝐨𝐬𝐞𝐬 𝐨𝐟 𝐒𝐭𝐮𝐝𝐲 𝐃𝐫𝐮𝐠 𝐏𝐥𝐚𝐧𝐧𝐞𝐝 𝐟𝐨𝐫 𝐞𝐚𝐜𝐡 𝐦𝐨𝐧𝐭𝐡 
 
Change# 14 
Section 4.10.1 Analysis and Data Conventions 
The following changes in bold have been made in this section: 
• This study is designed to evaluate the superiority of two doses of OTT166 (5 mg/day and 10 
mg/day) compared to vehicle control for the treatment of DR. For each dose within each 
endpoint, the null hypothesis is that there is no difference between OTT166 and vehicle 
control or the difference is in the direction of inferiority of OTT166; the alternative 
hypothesis is that there is a difference between OTT166 and vehicle control in the direction 
of superiority of OTT166.  
 
Change# 15 
Section 4.10.1.2 Handling of Dropouts or Missing Data 
• Section was renamed to Handling of Missing Data and Data After Intercurrent Events 
• Supplemental estimand description was moved to section 3.2.2 above 
• BL HbA1C has been deleted from the MAR imputation model description in this section 
• Primary Efficacy Analysis: was added as the subheading just under the section heading to 
distinguish methods used for the primary efficacy analysis compared to the secondary efficacy 
analysis which also had a subheading added 
The following changes in bold have been made in this section: 
• Handling of DRSS response at Week 24 data missing after ICEs: 
o Single imputation (non-response) when applying composite variable strategy. 
o Multiple imputation assuming MAR when applying hypothetical and treatment policy 
strategy. For hypothetical strategy, data up until the ICE occurred will be used in 
the imputation; for treatment policy strategy, all available data will be used in 
the imputation.  
The following paragraph has been moved from Section 3.2.2 to this section: 
• If a participant experiences more than one ICE, ICE(s) with a composite variable 
strategy take priority over ICEs with hypothetical strategies, which take priority over 
ICEs with a treatment policy strategy 
The following changes in bold have been made in this section:  
MAR imputation will be generated based on a logistic regression model for DRSS response 
(Y/N) with covariates for randomized treatment group and the randomization stratification 
variable. A total of 100 imputations will be used, followed by the MIANALYZE procedure 
to combine the estimates. 
Secondary Efficacy Analysis: 
Secondary endpoints involving a proportion: 


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Missing data for the secondary endpoints involving a proportion will be imputed using the 
same approach as described for the primary efficacy analysis (ICE handling and missing data 
imputation).  
MAR imputation for the secondary endpoints involving a proportion will be generated based 
on a regression model with covariates for treatment group and the randomization stratification 
variable.   
Change from baseline secondary endpoints: 
Handling of missing data of change from baseline in participants without ICEs: 
• Multiple imputation of the value at Week 24 (for BCVA and CST) assuming missing at 
random (MAR).  
Handling of missing data of change from baseline after ICEs: 
• Single imputation using the worst value at Week 24 observed among all participants 
when applying composite variable strategy. 
• Multiple imputation assuming MAR when applying treatment policy or hypothetical strategy.  
Handling of data observed after ICEs: 
• The value will be replaced by a single imputation using the worst value at Week 24 
observed among all participants when applying composite variable strategy. 
• Replaced by MAR multiple imputation algorithm based on the assumption that the 
intercurrent event would not have occurred when applying hypothetical strategy. 
• Kept in the analysis when applying treatment policy strategy. 
MAR imputation for the continuous secondary endpoints (BCVA and CST) will be generated 
based on a linear regression model adjusting for treatment group, the randomization strata, and 
BL score of the analyzed variable where applicable, and then the change from baseline will 
be calculated. A total of 100 imputations will be used followed by the MIANALYZE 
procedure to combine the estimates. 
Time to event secondary endpoints: 
• Missing data for the time to event of secondary endpoints will be considered as censored. 
 
Change# 16 
Section 4.10.1.4 Examination of Subgroups 
The following changes in bold has been added: 
• Age (<65 years, ≥65 years) 
• Gender (Male, Female) 
• Race (White, Black or African American, Asian, Other) 
• Ethnicity (Hispanic, Not Hispanic) 
• BMI (Normal [<25 kg/m2], Overweight [≥25 to <30 kg/m2], Obese [≥30 kg/m2]) 
• Diagnosis of systemic hypertension (Y/N) 
• HbA1C (≤7%, >7%) 
 
The following subgroup in bold has been added: 
• Presence of fluid in the central subfield at Baseline (Y/N) 
 


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Change# 17 
Section 4.10.2 Primary Efficacy Analysis 
The following changes in bold have been made: 
• The primary efficacy analysis will be performed on the ITT Analysis Set, while the PPS will 
be used as a supplementary analysis. ICEs and missing data will be handled as described in 
Section 4.10.1.2.  
• In order to assess the robustness of the study conclusions to the choice of imputation 
method, the following sensitivity analyses will be performed for the primary endpoint:   
o An observed case analysis where only observed responses will be used for 
analysis 
o A last observation carried forward (LOCF) analysis where missing post-
baseline responses will be imputed using the LOCF procedure 
o Measurements after rescue will be imputed using the last observation prior to 
rescue treatment; a non-response will be imputed if no post-baseline 
measurements are available. 
 
Change# 18 
Section 4.10.3 Secondary Efficacy Analysis 
The following changes have been made in this section: 
The specific reasons for meeting rescue criteria as described in protocol section 2.14.9 will also be 
summarized using number and percentage by treatment group.  
 
Change# 19 
Section 4.10.4  Exploratory Analysis 
The following paragraphs in bold have been deleted from this section: 
• The proportion of participants who have non-CI-DME at baseline that is resolved (no 
non-CI-DME) by Week 24 and the proportion of participants who do not have non-CI-
DME at baseline that develop non-CI-DME by Week 24 will be summarized using a shift 
table. 
• The normality assumption will be visualized based on the histogram of the residuals, 
and if the data are skewed, then a rank-based ANCOVA will be performed. 
 
The following changes in bold have been made in this section: 
• Within participant treatment effects will also be assessed for the primary endpoint (DRSS 
step change of ≥ 2 steps) and key secondary endpoints (BCVA change, CST change, 
and development of CI-DME). 
 
The following paragraph in bold has been added to this section: 
• Associations between baseline covariates and compliance will be assessed graphically: 
monthly compliance will be presented as a series of boxplots for each baseline subgroup, 
by treatment group and overall, allowing for the observation of compliance trends 
within or between groups. 
 
Change# 20 
Section 4.11 Safety Evaluation 
The following changes in bold have been made in this paragraph: 


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• All safety summaries and analyses will be based upon the Safety Analysis Set by treatment 
group (i.e., vehicle control doses (5% BID, 5% QID), vehicle control combined, active 
OTT166 doses (5% BID, 5% QID), and OTT166 combined. Safety summaries for age, 
gender, race and ethnicity subgroups will be provided. If any safety measurements are 
repeated after dosing on Day 1, then the last (non-missing) value of any repeated 
measurements will be used in the descriptive statistics and in the calculation of changes from 
BL. No inferential statistics will be performed for safety variables. 
 
Change# 21 
Section 4.11.1 Adverse Events 
The following AESI definition has been updated to match the definition in the amended protocol 
section: 
• Adverse events of special interest (AESI) are defined as: 
Hypersensitivity reactions. Symptoms of hypersensitivity reactions (allergic reactions) 
include: 
o Rash 
o Wheezing and difficulty breathing 
o Dizziness and fainting 
o Swelling around the mouth, throat or eyes  
o A fast pulse 
o Sweating 
 
Number and percentage of participants with TEAEs leading to death has been deleted and replaced 
with the Number and percentage of participants who experienced death from any cause 
 
The following analyses in bold have been added: 
• Number and percentage of participants with TEAEs leading to discontinuation of 
study 
• Number and percentage of participants with TESAEs leading to discontinuation of 
study 
• Number and percentage of participants with AESIs leading to discontinuation of study 
drug 
 
Change# 22 
Section 4.14 Changes in the Conduct of the Study or Planned Analysis 
The following changes in bold have been made in this section: 
• Analyses described in the SAP supersede the planned analyses in the study protocol.  
Similarly, planned analyses may be amended as a result of planned blinded data reviews.  
Changes will be finalized prior to the database lock. 
Change# 23  
Appendix 6.2 ETDRS Final Diabetic Retinopathy Severity Scale (For Individual Eye) 
• ETDRS Final Diabetic Retinopathy Severity Scale has been updated with a new table that 
shows the subcategories and definitions within each DRSS level. 
 


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6.3.2 Amendment 2 
Rationale for the amendment 
This statistical analysis plan has been amended to incorporate changes made in the current protocol 
amendment v5.0 of 10 October 2023 as well as additional changes not in the current protocol. 
 
Change # 1 
Section 1 INTRODUCTION 
The protocol version was updated: 
• Study Protocol Version 5.0 dated October 10, 2023. 
 
Change # 2 
Section 2 STUDY OBJECTIVES AND ENDPOINTS  
• The following objectives and endpoints have been updated (the text in bold has been added): 
Secondary Objectives: 
Secondary Endpoints: 
To determine if topical OTT166 will prevent 
or delay the occurrence of visually 
threatening complications (VTC), defined as 
PDR worse than mild and/or anterior segment 
neovascularization (ASNV) determined by 
the investigator and/or CI-DME (defined 
below) 
 
 
• Proportion of participants developing 
worse than mild PDR (DRSS 65 and 
above) at Week 24 
• Time to development of PDR worse than 
mild (DRSS 65 and above)  
• Proportion of participants who develop 
ASNV determined by the investigator at 
Week 24 
• Proportion of participants who develop 
VTC at Week 24 
• Time to development of PDR worse 
than mild (DRSS 65 and above) or CI-
DME 
To determine if topical OTT166 will prevent 
or delay the occurrence of CI-DME (CI-DME 
is defined as the presence of fluid in the 
central subfield in participants who have no 
fluid at baseline or CST> 325 µm) 
• Proportion of participants who develop 
CI-DME at Week 24 
• Time to development of CI-DME 
 
 
 
Change# 3 
Section 3.1 Overall Study Design and Plan: 
• The following changes in bold have been made in this section 
o Approximately 210 participants diagnosed with moderately severe to severe NPDR or 
mild PDR and who are treatment naïve (i.e., no prior anti-Vascular Endothelial Growth 
Factor [VEGF] or laser (focal, grid, Pan-Retinal Photocoagulation [PRP]) 
administered) will be randomized 2:2:1:1 into the following groups: OTT166 5% BID, 
OTT166 5% QID, vehicle control 5% BID, vehicle control 5% QID. Randomization 
will be stratified by Screening DRSS score (47 or 53 or 61B). 
Change# 4 


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Section 3.2.2 Primary Efficacy Endpoint and Estimand  
• The Primary Estimand table has been updated to clarify the intercurrent events and 
intercurrent event handling (changes in bold): 
 
Primary Estimand 
Treatment 
conditions of 
interest 
OTT166 5 mg/day, OTT166 10 mg/day and matching vehicle control 
Participant 
Population 
DR participants with Type 1 or Type 2 diabetes under adequate control 
(HbA1c ≤12.0%) who show typical fundus alterations and have been 
diagnosed with moderately severe to severe NPDR or mild PDR as defined 
by the DRSS Steps 47, 53, and 61B, with BCVA ≥ 69 ETDRS letters, CST 
of ≤ 325 µm, and a normal foveal contour.   
Endpoint 
≥2 steps improvement from BL in DRSS score at Week 24 
Population level 
summary 
Difference in proportion of participants achieving ≥2 steps improvement 
from BL in DRSS score at Week 24 between each OTT166 treatment group 
and the combined vehicle control group. 
Intercurrent events 
(ICEs) and 
strategies to handle 
ICEs 
g) Rescue treatment in the study eye due to worsening DRSS level to 65 
or higher prior to assessment of DRSS at Week 24 
Composite strategy (non-response)  
h) Death prior to DRSS assessment at Week 24   
Hypothetical strategy 
i) Use of rescue treatment in the study eye for any other reason prior 
to DRSS assessment at Week 24 
Composite strategy (non-response) 
j) Premature discontinuation of study drug for any reason prior to 
DRSS assessment at Week 24 
Hypothetical strategy  
k) Study drug compliance <75% through Week 24 
Treatment policy strategy  
l) Study drug compliance between 75% to <90% through Week 24  
Treatment policy strategy  
 
 
ICE(s) with a composite variable strategy take priority over ICEs 
with other strategies. And ICEs with a hypothetical strategy take 
priority over ICEs with treatment policy strategy. 
 
Change# 5 


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Section 3.2.3 Secondary Endpoints  
• The following endpoints were added: 
o Proportion of participants who develop VTC at Week 24 
o Time to development of PDR worse than mild (DRSS 65 and above) or CI-DME 
 
Change# 6 
Section 4.2 
General Presentation Considerations    
• The Baseline definition was updated (changes in bold): 
o ‘Baseline’ is defined as the last available pre-treatment assessment for safety 
assessments. For DRSS score Baseline data, the Baseline value is defined as the 
Screening/Visit 1 result.  Pre-treatment values for DRSS were collected at the 
Screening/Visit 1 using fluorescein angiography in addition to fundus 
photography whereas Baseline/Visit 2 used fundus photography only. 
Participants were enrolled into the study and randomized to the study treatment 
based on the Screening/Visit 1 DRSS result. All other efficacy analyses that do 
not use DRSS score will use the last available pre-treatment assessment as 
Baseline. This is considered acceptable as this measurement is still the best 
representation of the Baseline value of the given assessment since it is highly 
unlikely that the study drug could have an impact on any measurement in a short 
period of time. 
• The following sentence was added: 
o Time to event analyses will be calculated from Study Day 1, including time to DRSS-
related endpoints comparing to the Baseline value.  These analyses will consider only 
post-Baseline assessments. The Visit 2/Baseline visit will not be considered. 
Change # 7 
Section 4.4.1 Analysis Sets 
The following changes in bold have been made: 
• The ITT Analysis Set will be used for all efficacy analyses and BL data analyses except 
participant disposition which will be shown for the ITT Analysis Set and for the Safety 
Analysis Set if the two analysis sets differ. All randomized participants are expected to be 
dosed and any exceptions will be described in the CSR. The PP set will be determined prior 
to database lock and will be used as a supplementary analysis of the primary endpoint.  
For analyses based on the SS, participants randomized to a control treatment group who 
receive any dose of active OTT166 treatment will be analyzed in the corresponding 
OTT166 treatment group (BID or QID).   
Change# 8 
Section 4.4.3 Protocol Deviations 
• The following sentence was added: 
o This summary will also include a summary of participants excluded from the PPS due 
to major protocol deviations by category.  
Change # 9 
Section 4.5 
Demographics and Baseline Characteristics 
• The following change in bold has been made: 
o DRSS steps at the Baseline Visit 
 
Change# 10  
Section 4.8 
Rescue Therapy 


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• The following change in bold has been made: 
o Participants meeting one or all the following criteria in the study eye would qualify 
for rescue with anti-VEGF therapy and/or PRP laser after consultation with the 
Medical Monitor 
• The following objective rescue criteria was added: 
o Development of anterior segment neovascularization (ASNV) 
• The following text was added: 
o The start date of rescue therapy in the study eye will be determined by the earliest 
concomitant medication in the study eye with ATC4CD=“SL01A” or the earliest 
ocular concomitant procedure confirmed by the clinical team to be rescue therapy.  
This will be subset on the participants who have completed the “Rescue Therapy for 
Ocular Diabetic Complications” eCRF.  
 
Change# 11 
Section 4.9.2 Treatment Compliance 
• The following text has been added (additions in bold): 
The total number of doses of study drug administered is the actual number of drops 
administered.  In the event a participant takes study drug after their EOS date, the total 
number of doses administered will not include any doses recorded after the EOS date. 
The total number of doses of study drug planned is calculated based on a participant’s 
duration in the study and the randomized treatment.  A participant randomized to BID 
treatment will have 2 times the (date of EOS – date of first dose + 1). A participant 
randomized to QID treatment will have 4 times the (date of EOS – date of first dose + 
1). 
For participants who take rescue therapy in the study eye during the study, the total 
number of doses of study drug planned is calculated based on a participant’s treatment 
duration prior to rescue and randomized treatment. A participant randomized to BID 
treatment will have 2 times the (date of EOT – date of first dose + 1). A participant 
randomized to QID treatment will have 4 times the (date of EOT – date of first dose + 
1).  
A summary of the treatment compliance will be provided for the ITT Analysis Set and also 
the Safety Analysis Set by treatment and overall.  
Monthly (every 4 weeks) treatment compliance (%) will be calculated as: 
Total Number of Doses of Study Drug Administered each Month 
Total Number of Doses of Study Drug Planned for each month × 100% 
The total number of doses of study drug planned is calculated based on a participant’s 
duration in the study and the randomized treatment.  A participant randomized to BID 
treatment will have 2 times the minimum of 28 or the (date of EOS – date of first dose 
in month + 1). A participant randomized to QID treatment will have 4 times the 
minimum of 28 or the (date of EOS – date of first dose in month + 1). 
For participants who take rescue therapy in the study eye during the study, the total 
number of doses of study drug planned is calculated based on a participant’s treatment 
duration prior to rescue and randomized treatment. A participant randomized to BID 


Parexel International 
OcuTerra Therapeutics, Inc. 
OTT166-201 
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: 09-Feb-2024 
Related to:  SOP-GDO-WW-019 
Page 50 of 53 
treatment will have 2 times the minimum of 28 or the (date of EOT – date of first dose 
in month + 1). A participant randomized to QID treatment will have 4 times the 
minimum of 28 or the (date of EOT – date of first dose in month + 1). 
Number and percentage of participants with compliance in categories (<75%, 75-<90%, 
≥90%) will be provided for overall and monthly treatment compliance.   
 
Change# 12 
Section 4.10.1  Analysis and Data Conventions 
• The following changes in bold have been made in this section: 
o For each dose within each endpoint, the null hypothesis is that there is no difference 
between OTT166 and vehicle control or the difference is in the direction of inferiority 
of OTT166, and the alternative hypothesis is that there is a difference between 
OTT166 and vehicle control in the direction of superiority of OTT166.  
o The vehicle control group will be combined for all efficacy analyses and two-sided 
90% confidence intervals will be presented. A comparison between the two control 
groups will be performed for the primary endpoint to confirm the groups are 
comparable. 
 
Change# 13 
Section 4.10.1.1 Adjustments for Covariates  
The following changes in bold have been made in this section: 
• The primary efficacy analysis will be adjusted for the randomization stratification factor, the 
Screening DRSS score (47 or 53 or 61B). 
 
Change# 14 
Section 4.10.1.2 
Handling of Missing Data and Data After Intercurrent Events 
• The following changes have been made (changes in bold): 
o Primary Efficacy Analysis: MAR imputation will be generated based on a logistic 
regression model for DRSS response (Y/N) levels with covariates for randomized 
treatment group and the randomization stratification variable. DRSS response will be 
derived based on the imputed values. A total of 100 imputations will be used, followed 
by the MIANALYZE procedure to combine the estimates. 
o Secondary Efficacy Analysis:  
o Secondary endpoints involving a proportion: MAR imputation for the secondary 
endpoints involving a proportion will be generated based on a logistic regression 
model with covariates for treatment group and the randomization stratification 
variable.  Where appropriate, the dichotomous variable will be derived based 
on the imputed data. 
o Change from baseline secondary endpoints:  
Handling of missing data of change from baseline after ICEs: 
• Single imputation using the worst value at each visit Week 24 observed 
among all participants when applying composite variable strategy. 
• Multiple imputation assuming MAR when applying treatment policy or 
hypothetical strategy.  
Handling of data observed after ICEs: 


Parexel International 
OcuTerra Therapeutics, Inc. 
OTT166-201 
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: 09-Feb-2024 
Related to:  SOP-GDO-WW-019 
Page 51 of 53 
• The value will be replaced by a single imputation using the observed worst 
value at each visit Week 24 among all participants when applying composite 
variable strategy. 
• Time to Event secondary endpoints: Missing data for the time to event of 
secondary endpoints will be considered as censored. Participants who receive 
rescue medication will be censored at the start of rescue medication. 
 
Change# 15 
Section 4.10.1.4 
Examination of Subgroups 
The following subgroup was updated:  
• Baseline Randomization strata (Screening DRSS:47 or 53 or 61B) 
 
Change# 16 
Section 4.10.2 Primary Efficacy Analysis 
• The following text was added (in bold) 
o In order to assess the robustness of the study conclusions to the choice of imputation 
method, the following sensitivity analyses will be performed on the ITT Analysis 
Set and PPS for the primary endpoint:   
▪ An observed case analysis where only observed responses will be used for 
analysis. Observed data after initiation of rescue medication will be set to 
missing. 
o A supplementary analysis will be performed on the ITT Analysis Set and PPS for 
the primary endpoint to assess the time to improvement of ≥2 steps improvement 
from BL in DRSS score. Analyses will be based on observed data, where 
participants who receive rescue medication will be censored at the start of 
rescue medication (unless improvement of ≥2 steps improvement from BL in 
DRSS score is achieved prior to starting rescue medication). 
o An additional sensitivity analysis may be performed to assess the proportion of 
participants with an improvement of ≥2 steps improvement from the Visit 
2/Baseline visit in DRSS score if needed. 
 
Change# 17 
Section 4.10.3 Secondary Efficacy Analysis 
The following text has been added: 
The following secondary endpoint analyses will be repeated on the PPS: 
• Proportion of participants who develop ASNV determined by the investigator at Week 24. 
• Proportion of participants who develop CI-DME at Week 24. 
• Change in DRSS steps is defined as DR worsening or improving by 1, 2, or ≥3 steps.  
• Proportion of participants with mild PDR (DRSS score 61B) at baseline who regress to NPDR 
(DRSS score ≤ 53) by Week 24 
• Mean and median change in BCVA (ETDRS letters) from baseline to Week 24. 
• Lines gained/lost in BCVA (± 5, 10, and 15 ETDRS letters) at Week 24. 


Parexel International 
OcuTerra Therapeutics, Inc. 
OTT166-201 
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: 09-Feb-2024 
Related to:  SOP-GDO-WW-019 
Page 52 of 53 
• Mean and median change in CST from baseline to Week 24. 
• Proportion of participants who met the objective rescue criteria as defined in protocol section 
2.14.9. 
• Time to meet the objective rescue therapy criteria.  
• Proportion of participants who develop VTC at Week 24 
 
The following text in bold has been added: 
The categorical secondary endpoints will be compared using a proportional odds model with 
covariates for treatment group and the randomization stratification factor. If the assumption of 
proportional odds is rejected, a different analysis approach, such as a rank-based ANCOVA, will be 
considered. The rank-based ANCOVA will be a two-sided test and a two-sided p-value will be 
presented. 
The time to event secondary endpoints will be defined as time to first development of an event and 
will be estimated based on the Kaplan-Meier method, along with a 90% confidence interval. Analyses 
will be based on observed data, where participants who receive rescue medication will be 
censored at the start of rescue medication. A stratified log-rank test adjusting for the randomization 
stratification factor will be performed, to compare the combined vehicle control with each treatment 
group. 
 
The following text has been deleted: 
Continuous secondary endpoints involving change from BL to Week 24 will be analyzed using an 
analysis of covariance (ANCOVA) model with BL measurement of the variable as a covariate and 
treatment group and the randomization stratification factor as fixed factors. The normality assumption 
will be visualized based on the histogram of residuals. 
 
Change# 18 
Section 4.10.4 Exploratory Analysis 
The following changes in bold have been made: 
All exploratory endpoint analyses will be performed on the Intention-to-Treat Analysis Set and will 
be based on observed data, where observed data after the initiation of rescue medication will be 
set to missing unless specified otherwise. The following exploratory endpoint analyses will be 
repeated on the PPS:  
• Change in MV from baseline to Week 24 for 1, 3, and 6 mm regions.  
• Change in area of retinal non-perfusion from baseline to Week 24 seen on widefield FA. 
• Proportion of participants with intact FAZ seen on widefield FA at Week 24. 
 
The following text was updated (changes in bold): 
Data for eyes that were treated with anti-VEGF and/or laser will be imputed with LOCF from the 
time of starting treatment with anti-VEGF and/or laser. Concomitant medications in the fellow eye 
with ATC4CD=”SL01A” will be considered for anti-VEFG treatment in the fellow eye. 
Additionally, ocular concomitant procedures in the fellow eye will be considered for laser 
treatment.  The ocular concomitant procedures will be reviewed and confirmed by the clinical 


Parexel International 
OcuTerra Therapeutics, Inc. 
OTT166-201 
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: 09-Feb-2024 
Related to:  SOP-GDO-WW-019 
Page 53 of 53 
team. The earliest date among the anti-VEGF and laser treatments will be considered the time 
of starting treatment for LOCF. 
Associations between baseline covariates and compliance will may be assessed graphically: monthly 
compliance will may be presented as a series of boxplots for each baseline subgroup, by treatment 
group and overall, allowing for the observation of compliance trends within or between groups.   
 
Change# 19 
Section 4.10.3 Secondary Efficacy Analysis 
The following changes have been made in this section: 
The specific reasons for meeting rescue criteria as described in protocol section 2.14.9 will also be 
summarized using number and percentage by treatment group.  
 
Change# 20 
Section 4.11.1  Adverse Events 
The following summaries were added (changes in bold): 
• Ocular TEAEs in the Study Eye 
• Ocular TEAEs in the Fellow Eye 
• Non-Ocular TEAEs 
• Drug-related TEAEs  
• TEAEs leading to discontinuation of study 
• TEAEs leading to discontinuation of study drug 
• All TESAEs  
• Ocular TESAEs in the Study Eye 
• Ocular TESAEs in the Fellow Eye 
• Non-Ocular TESAEs 
Change# 21 
Section 6.1 Schedule of Activities 
The following changes have been made: 
• IP adherence review was added to non-ocular assessments 
• Footnotes were added:  
o 
Cornea should be assessed at the beginning before dilation. 
o 
Adherence to the dosing regimen should be monitored continuously and discussed with the participant 
at each visit. Sites are expected to intervene if there is suboptimal adherence or absence of data 
transfer and document the intervention in the patient dashboard. 
 


Approval Signatures
Document Name:
Statistical Analysis Plan 11 Feb 2024 OTT166-201
Document Number:
VV-TMF-6342212
Parexel Version Number:
System Version Number:
2
. 0
Document Approvals
Reason for signing: Approved
Name: Kathleen Russell
Role: Biostatistics
Date of signature: 10-Feb-2024 02:39:39 GMT+0000
Reason for signing: Approved
Name: David Tanzer
Role: Sponsor
Date of signature: 12-Feb-2024 04:31:19 GMT+0000