Conditions: Nonproliferative Diabetic Retinopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 167
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of subcutaneously administered AKB-9778 15mg once daily or 15mg twice daily for 12 months in patients with moderate to severe non-proliferative diabetic retinopathy (NPDR).

Detailed description:

Arms:
arm 1: AKB-9778 15 mg (QD); To maintain masking, subjects will receive BID dosing with masked study medication administered as one dose of active and one dose of matching placebo arm 2: AKB-9778 15 mg (BID) arm 3: Placebo Group: SC Phosphate-Buffered-Saline (PBS) (BID)

Interventions: intervention 1: AKB-9778 intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous AKB-9778 15mg intervention 2: Subcutaneous Placebo

Protocol document:
SAP_002.pdf: 
Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
                                                                                  CONFIDENTIAL                                                          Page 1 of 19 
 
 STATISTICAL ANALYSIS PLAN 
 
AKB-9778-CI-5001 
 
PHASE 2 DOUBLE-MASKED, PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY AND 
EFFICACY OF SUBCUTANEOUSLY ADMINISTERED AKB-9778 15MG ONCE DAILY OR 15MG TWICE 
DAILY FOR 12 MONTHS IN PATIENTS WITH MODERATE TO SEVERE NON-PROLIFERATIVE 
DIABETIC RETINOPATHY 
Prepared for: 
Aerpio Therapeutics, Inc. 
Version and Author details: 
Version Date: 
27 February 2019 
Version  
Final 
Author: 
Jatinder Singh 
 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
                                                                                  CONFIDENTIAL                                                          Page 2 of 19 
 
SIGNATURES 
 
The undersigned have approved this Statistical Analysis Plan for use in this study. 
 
 
 
 
 
 
 
 
 
Jatinder Singh, Biostatistician, Trial Runners, LLC 
 
Date 
 
 
 
 
 
 
 
Steve Pakola, Chief Medical Officer, Aerpio Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
Mitchell Brigell, Vice-President of Clinical Development, Aerpio 
Therapeutics, Inc. 
 
Date 
 
 
 
 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
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Table of Contents 
1 
INTRODUCTION.................................................................................................................... 5 
1.1 
Change from Protocol .......................................................................................................... 5 
2 
STUDY OBJECTIVES .............................................................................................................. 5 
3 
STUDY DESIGNS ................................................................................................................... 5 
3.1 
Sample Size Considerations .................................................................................................. 6 
3.2 
Randomization .................................................................................................................... 6 
3.3 
Schedule of Evaluations and Analysis Visit Windows .............................................................. 6 
4 
ANALYSIS POPULATIONS ..................................................................................................... 7 
4.1 
Safety Population ................................................................................................................ 7 
4.2 
Modified Intent-to-Treat Population ...................................................................................... 8 
4.3 
Per Protocol Population ........................................................................................................ 8 
4.4 
Pharmacokinetic Population ................................................................................................. 8 
4.5 
Sub-Study Populations ......................................................................................................... 8 
5 
STUDY VARIABLES AND COVARIATES ................................................................................. 8 
5.1 
Primary Efficacy Endpoints ................................................................................................... 8 
5.2 
Secondary Efficacy Endpoints ............................................................................................... 8 
5.3 
Exploratory Efficacy Endpoints ............................................................................................. 9 
5.4 
Exploratory Efficacy Sub-Study Endpoints ............................................................................. 9 
5.5 
Safety Endpoints ................................................................................................................. 9 
6 
DATA PREPARATION ..........................................................................................................10 
7 
DATA CONVENTION ............................................................................................................11 
7.1 
Missing Data ..................................................................................................................... 11 
7.2 
Descriptive Statistics .......................................................................................................... 11 
7.3 
Study Days Relative to First Day of Treatment .................................................................... 12 
8 
DISPOSITION AND EXIT STATUS .......................................................................................12 
8.1 
Subject Disposition ............................................................................................................ 12 
8.2 
Extent of Study Drug Exposure ........................................................................................... 12 
8.3 
Protocol Deviations ............................................................................................................ 12 
8.4 
Exclusion from Analysis Populations .................................................................................... 12 
9 
BASELINE CHARACTERISTICS ............................................................................................13 
9.1 
Demographics and Baseline/Screening Characteristics ......................................................... 13 
9.2 
Prior and Concomitant Medications ..................................................................................... 13 
9.3 
Medical History .................................................................................................................. 13 
10 EFFICACY ANALYSIS ..........................................................................................................13 
10.1 Primary Efficacy Endpoint Analysis ...................................................................................... 14 
10.2 Secondary, Exploratory and Exploratory Sub-Study Efficacy Endpoint Analysis ...................... 14 
11 SAFETY ANALYSIS ..............................................................................................................14 
11.1 Safety Endpoint Analysis .................................................................................................... 15 
11.1.1 Adverse Events ........................................................................................................... 15 
11.1.2 Electrocardiogram (ECG) .............................................................................................. 15 
12 PHAMACOKINETIC ANALYSIS ............................................................................................15 
13 PHARMACODYNAMICS ANALYSIS ......................................................................................16 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
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14 EXPLORATORY GENETIC ANALYSIS ...................................................................................16 
15 VALIDATION .......................................................................................................................16 
16 APPENDIX 1 ........................................................................................................................17 
17 APPENDIX  2 GLOSSARY OF ABBREVIATIONS ...................................................................18 
 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Aerpio Therapeutic, Inc. Protocol AKB-9778-CI-5001.  
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol (amendment 5 integrated) dated 18 Sep 2017. The final 
approval of the SAP by Aerpio Therapeutic, Inc. and Trial Runners will occur prior to database lock.  
1.1 Change from Protocol 
Not applicable. 
2 
STUDY OBJECTIVES 
The primary objective is to assess the effects of AKB-9778 15 mg once daily (QD) or 15 mg twice daily 
(BID) for 48 weeks on severity of diabetic retinopathy (DR) in subjects with moderate to severe non-
proliferative DR (NPDR). 
Secondary objectives include: 
• 
To assess the safety and tolerability of AKB-9778 15 mg QD or 15 mg BID for 48 weeks in subjects 
with moderate to severe NPDR. 
• 
To determine the AKB-9778 systemic exposure based on sparse Pharmacokinetic (PK) sampling 
in subjects with NPDR. 
3 
STUDY DESIGNS 
This is a Phase 2 randomized, double-masked, placebo controlled, multi-center study, to evaluate the safety 
and efficacy of 48 weeks of subcutaneous AKB-9778 administered 15 mg QD or 15 mg BID in subjects with 
moderate to severe NPDR. Exploratory evaluations include pharmacokinetic assessments, as well as 
exploratory efficacy assessments (OCT-Angiography (OCT-A), Ultra Wide-Field (UWF) imaging and non-
invasive Electroretinography (ERG) at a subset of sites. Blood samples will be retained for biomarker and 
genetic analysis. 
Subjects will participate in the study for approximately 56 weeks (screening period up to 4 weeks, baseline 
and treatment periods for 48 weeks, and follow-up period for 4 weeks). The study will be conducted at 
approximately 50 investigative sites. Subjects will be randomized 1:1:1 to either AKB-9778 15mg QD, AKB-
9778 15mg BID, or placebo treatment groups. Fifty (50) subjects are planned per group. The treatment 
groups are as follows: 
• 
Active Group: SC AKB-9778 15 mg (QD); To maintain masking, subjects will receive BID dosing 
with masked study medication administered as one dose of active and one dose of matching 
placebo.  
• 
Active Group: SC AKB-9778 15 mg (BID) 
• 
Placebo Group: SC phosphate-Buffered-Saline (PBS) (BID) 
Subjects will self-administer study medication as subcutaneous (SC) injections in the abdomen (preferably) 
around the same time every morning and evening, if possible. The investigator, all study-site personnel, all 
Sponsor personnel (except for an unmasked CMC representative), Central Image Reading Center 
personnel, and subjects will be masked to treatment assignment during the entirety of the study. 
Randomization will be stratified by screening Early Treatment of Diabetic Retinopathy Study (ETDRS) 
Diabetic Retinopathy Severity Score (DRSS) (levels 4, 5 and 6 equally distributed among the treatment 
groups). 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
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Spot UACR and eGFR will be assessed at baseline, and thereafter every 12 weeks as exploratory 
assessments to evaluate for any potential effects on renal function. Plasma samples will be collected at 
specified times on Day 1 and Month 6 visit for PK assessments. These samples will be analyzed for AKB-
9778 using validated bioanalytical methods. 
A blood sample will be retained for exploratory genetic analysis that may provide insight into the role of the 
VE-PTP/Tie2 pathway in diabetic retinopathy and an individual subject's response to AKB-9778 treatment. 
Similarly, blood samples collected at baseline and week 48 End of Treatment (EOT) will be retained for 
exploratory analysis of biomarkers in plasma associated with VE-PTP inhibition and Tie2 activation. Once 
results of the study are known, the Sponsor will determine the value of conducting the genetic and 
biomarker assessments. 
3.1 Sample Size Considerations 
Estimates for sample size calculations are derived from published data from the analysis of the effect of 
ranibizumab (Lucentis®) and aflibercept (Eylea®) intravitreal administration regimens on DR severity score 
in the RISE/RIDE studies and VIVID/VISTA studies, respectively, in which at least 28-46% of subjects 
improved by ≥ 2 steps after 12 months of treatment. 
With 45 evaluable subjects per treatment group, the study has >85% power (based on Fisher’s Exact Test 
and a 2-sided alpha =0.05) to demonstrate a statistically significant improvement in percent of subjects 
improving by ≥ 2 steps on the ETDRS diabetic retinopathy severity scale, assuming underlying rates for 
active and placebo of 30% and 5%, respectively. Assuming 10% drop-out/nonevaluable rate, a sample size 
of 50 subjects per treatment arm (approximately 150 total) was selected. 
3.2  Randomization 
Approximately 150 subjects will be enrolled in the study. Subjects meeting all eligibility criteria will be 
randomized 1:1:1 to either AKB-9778 15 mg QD, AKB-9778 15 mg BID, or placebo treatment groups. Fifty 
(50) subjects are planned per group. The treatment groups are as follows: 
• 
Active Group: SC AKB-9778 15 mg (QD) 
• 
Active Group: SC AKB-9778 15 mg (BID) 
• 
Placebo Group: SC PBS (BID) 
Using a central IWRS randomization system, eligible subjects will be assigned in a double-masked fashion 
1:1:1 to one of the 3 treatment groups. To maintain balance between treatment groups with respect to DR 
severity, randomization will be stratified by screening ETDRS DRSS (levels 4, 5 and 6). 
3.3 Schedule of Evaluations and Analysis Visit Windows 
The schedule of visits and procedures are provided in the protocol. The study consists of 48 weeks of study 
treatment with 4 week of follow-up period. There is a screening visit (Day-28 to -1), baseline visit (Day 1), 
site visits at every 4 weeks and follow-up/exit visit at week 52. Tables 1-4 show the visit windows to be used 
for analyses: 
Table 1: Visit Windows (Data Collected at All Monthly Visits – BP/HR, BCVA, chemistry) 
Visit 
Target Day of the Visit 
Visit Window (Days) for Analyses 
Baseline 
1 
<= 1 
Week 4 
29 
15-42 
Week 8 
57 
43-70 
Week 12 
85 
71-98 
Week 16 
113 
99-126 
Week 20 
141 
127-154 
Week 24 
169 
155-182 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
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Week 28 
197 
183-210 
Week 32 
225 
211-238 
Week 36 
253 
239-266 
Week 40 
281 
267-294 
Week 44 
309 
295-322 
Week 48 
337 
323-350 
Note: All days are referenced to Day 1 
 
 
Table 2: Visit Windows (Data Collected at Months 3, 6, 9, 12 – Body System Assessments, Slit Lamp, IOP, Indirect Ophth, 
SD OCT, FP, OCT Angiography, ERG, Urinalysis, Fecal Occult Blood Test) 
Visit 
Target Day of the Visit 
Visit Window (Days) for Analyses 
Baseline 
1 
< = 1 
Week 12 
85 
82-126 
Week 24 
169 
127-210 
Week 36 
253 
211-294 
Week 48 
337 
295-378 
Note: All days are referenced to Day 1 
Note: Urinalysis was not collected at Week 12, so it should not have a Week 12 Window; all other visit windows are as shown in the 
table. 
 
 
Table 3: Visit Windows (Data Collected at Months 6 and 12 – Height, Weight, Temperature, FA) 
Visit 
Target Day of the Visit 
Visit Window (Days) for Analyses 
Baseline 
1 
< = 1 
Week 24 
169 
85-252 
Week 48 
337 
253-420 
Note: All days are referenced to Day 1 
 
Table 4: Visit Windows (Data Collected at Months 2, 4, 6, 8, 10, 12 – Hematology) 
Visit 
Target Day of the Visit 
Visit Window (Days) for Analyses 
Baseline 
1 
<= 1 
Week 8 
57 
29-84 
Week 16 
113 
85-140 
Week 24 
169 
141-196 
Week 32 
225 
197-252 
Week 40 
281 
253-308 
Week 48 
337 
309-364 
Note: All days are referenced to Day 1 
 
When multiple observations are captured in a visit window, use the scheduled visit that matches the visit 
window in the analysis (e.g., if week 24 scheduled visit is in the week 24 window, use this visit for Week 24 
analysis visit).  If there is no scheduled visit that matches the visit window, the one closest to the target date 
of the visit will be used to represent the window.  If two observations are equidistant from the target date, 
then the observation that is closer to the upper end of the window visit will be used. 
4 
ANALYSIS POPULATIONS 
4.1 Safety Population 
The safety population will include all enrolled subjects who receive at least one dose of study medication. 
Group assignment will follow actual treatment received. All safety analyses will be conducted using the 
safety population. 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
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4.2 Modified Intent-to-Treat Population 
The modified intent-to-treat (MITT) population will include all enrolled subjects who receive at least one 
dose of study medication. Group assignment will follow treatment group assigned at randomization. The 
primary efficacy analysis will be conducted using the MITT population. 
4.3 Per Protocol Population 
The per protocol (PP) population will consist of all subjects in the MITT population who do not have major 
protocol deviations considered to affect the primary efficacy variable DRSS, have completed their 48-week 
visit on treatment, and have been at least 70% compliant. The rules for determining exclusion from the per-
protocol population will be made and implemented prior to unmasking. Sensitivity analyses of the primary 
efficacy variables will be conducted using the PP population. 
4.4 Pharmacokinetic Population 
The pharmacokinetic population will consist of all subjects with at least one plasma sample collected for 
AKB-9778 analysis. 
4.5 Sub-Study Populations 
Sub-study populations include those subjects who participated in the UWF- FA, UWF- Photography, OCT-
A, and ERG sub-studies, respectively.  
5 
STUDY VARIABLES AND COVARIATES   
5.1 Primary Efficacy Endpoints  
The primary efficacy endpoint is the percentage of subjects with an improvement in study eye severity of 
diabetic retinopathy (DR) (ETDRS DRSS) of ≥ 2 steps at week 48 compared to baseline.   
5.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
• 
Proportion of subjects with a worsening in the study eye DRSS of ≥ 2 steps at week 48 
• 
Mean change from baseline in DRSS in the study eye at week 48 
• 
Proportion of subjects with an improvement or worsening in the study eye DRSS of ≥ 3 steps at 
week 48. 
• 
Subjects with criterion step improvement in DRSS at week 48 (≥2 steps improvement in the study 
eye for patients with non-qualified fellow eye and ≥3 steps improvement on the Person scale for 
patients with qualified fellow eyes) 
• 
Subjects with criterion step improvement in DRSS at week 48 (≥2 steps improvement in the study 
eye for patients with non-qualified fellow eye and ≥3 steps improvement on the Binocular scale for 
patients with qualified fellow eyes) 
• 
Proportion of patients developing center-involved Diabetic Macular Edema (DME) or Proliferative 
Diabetic Retinopathy (PDR) or PDR-related outcomes during treatment period based on Clinical 
Data. Due to variation in clinician criteria for reporting DME and PDR adverse events, all events 
will be reviewed and AEs that were not treated and were not validated in FPRC interpretation of 
imaging data will be censored from the results. 
• 
Proportion of patients developing center-involved DME or PDR or worsening of ≥2 steps DRSS at 
week 48 based on Central Image Reading Center Evaluation 
• 
Primary and secondary assessments in qualified fellow eyes and all qualified eyes (study eyes and 
qualified fellow eyes). 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
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• 
Primary and secondary endpoints assessed at week 12, 24 and 36. 
5.3 Exploratory Efficacy Endpoints 
Change from baseline in urine-albumin-to-creatinine ratio (UACR) and estimated glomerular (eGFR) at 
week 12, 24, 36 and 48 in the overall MITT population and in the subgroup of subjects with renal 
insufficiency at baseline (UACR >30 µg/mg for UACR analysis; eGFR <90 mL/min/1.73m2 for the eGFR 
analysis) is the exploratory efficacy endpoint used to investigate renal function.  
For urine albumin values below the lower limit of quantitation, UACRs will be calculated using the 0.5xLLQ 
value.  Due to the positive skewness, UACR data will be log transformed prior to analysis. The primary 
outcome will be percent change in geometric mean.  
5.4 Exploratory Efficacy Sub-Study Endpoints 
Exploratory efficacy sub-study endpoints include: 
• 
Mean change from baseline in ERG parameters (LKC Composite Score; Implicit Time (ms) in 16 
Td’s; Amplitude Value (µV) in 16 TD’s) at week 48.  
• 
Mean change from baseline in Retinal Capillary Dropout 3x3, Retinal Capillary Dropout 6x6, FAZ 
Area (mmsq), Vessel Density (%), Vessel Skeleton Density 6x6 (%), Total Vessel Length 6x6 (mm) 
and Non-Perfusion Area 6x6 (mmsq) measured by OCT- A at week 48.  
• 
Mean change from baseline in Ischemia Disc (%), Ischemia Macula (%), Leakage Disc (%), 
Leakage Macula (%) and Microaneurysm Count Macula in the regions ROI 1 and ROI 2 measured 
by UWF-FA at week 48.  
• 
Subjects (Eyes) with criterion step change in DRSS on UWF-photography (Worsening ≥3, ≥2, 
Improvement ≥2, ≥3) at week 48 
A more detailed presentation of the variables to be analyzed for these sub-studies is provided in the 
appended sub-study analysis plans. 
5.5 Safety Endpoints 
Safety endpoints include: 
• 
Incidence and severity of systemic and ocular AEs  
• 
Ocular AEs at Study eyes, all qualified eyes and unqualified fellow eyes during treatment period. 
• 
Shift from baseline in body system assessments for the parameters general appearance, HEENT 
(Head, Ears, Eyes, Nose and Throat), cardiovascular, respiratory, abdomen/gastrointestinal, 
musculoskeletal, and dermatologic at week 12, 24, 36, 48. 
• 
Change from baseline in vital sign measurements (SBP, DBP, HR, BMI, Weight and Temperature) 
at every 4 weeks. 
• 
Change from baseline in ECG parameters (HR, PR, QRS and QTcF) at week 24, 48. 
• 
Change from baseline in clinical laboratory assay results (blood chemistry (at every 4 weeks), 
hematology (at every 8 weeks), fecal occult blood test (at week 24, 36, 48), and urinalysis (at week 
24, 36, 48).  
• 
Mean change from baseline in ETDRS Best Corrected Visual Acuity (BCVA) letter score in the 
study eyes, all qualified eyes and unqualified fellow eyes at every 4 weeks.  
• 
Proportion of subjects with a loss of ≥15 letters, loss of ≥10 letters and loss of ≥5 letters in BCVA 
compared to baseline at week 48.  
• 
Mean change from baseline in Spectral Domain Optical Coherence Tomography (SD OCT): Central 
Subfield Thickness (CST) in the study eyes, all qualified eyes and unqualified fellow eyes at week 
12, 24, 36, 48.  


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
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• 
Proportion of subjects with increase of ≥100 µm and increase of ≥50 µm SD OCT: CST in the study 
eyes, all qualified eyes and unqualified fellow eyes at week 48. 
• 
Change from baseline in Intraocular Pressure (IOP), with additional sub-group analysis with 
baseline IOP <16 mmHg and baseline IOP ≥ 16 mmHg in the study eyes and fellow eyes at week 
12, 24, 36, 48. 
• 
Shift from baseline in Slit Lamp Biomicroscopy examination for the parameters Eyelids, Cornea, 
Conjunctiva, Anterior Chamber, Iris/Pupil and Lens in all qualified eyes and unqualified fellow eyes 
at week 12, 24, 36, 48.  
• 
Shift from baseline in Dilated Indirect Ophthalmoscopy examination for the parameters Vitreous, 
Macula, Optic Nerve, and Peripheral Retina in all qualified eyes and unqualified fellow eyes at week 
12, 24, 36 and 48.   
• 
Change from baseline in Fluorescein Angiogram (FA) for the parameters total area of capillary non-
perfusion, and leakage within ETDRS grid, change in fluorescein leakage from screening, NVD and 
NVE within 7 standard field in all qualified eyes and unqualified fellow eyes at week 24, 48. 
• 
Shift from baseline in Fundus Photograph (FP) for the parameters clinically significant ME 
(ETDRS), hard exudate presence within grid, and hemorrhages and/or microaneurysms within grid 
in all qualified eyes and unqualified fellow eyes at 12, 24, 36, 48.   
6 
DATA PREPARATION 
Except for the laboratory data (clinical laboratory assays, PK and biomarker data) and imaging data, all 
reported study data will be recorded on the eCRFs supplied by TrialRunners (TR) using iMedNet Electronic 
Data Capture (RDC),.  Only the Principal Investigator and authorized study staff according to the Delegation 
of Responsibilities log are entitled to make entries on the eCRF.  Data from source documents will be 
entered into RDC by site personnel.  The laboratory and imaging data will be incorporated into the study 
database electronically.  The details of the laboratory data transfer can be found in the Data Transfer 
Agreements (DTAs) and TR’s Standard Operating Procedure (SOP) on electronic data importation. 
All ocular image data (fundus photographs, FA and SD-OCT) will be transmitted to the Eyekor Excelsior 
data platform. The Wisconsin Fundus Photograph Reading Center (FPRC) will assess all screening images 
to confirm subject eligibility. The FPRC will also grade all 7-field or 4-field wide color fundus photographs 
for DRSS, FA data, and SD-OCT data. Details are contained in the FPRC image grading charter. Ultra-
wide field fluorescein angiography data will be graded by the Campane Center for Advanced Imaging at 
the Cole Eye Institute (CCAI) using their custom software. Details are contained in the CCAI UWF-FA 
charter. Electroretinographic data will be evaluated by LKC Technologies using their custom software. The 
FPRC, CCAI and LKC Technologies will store graded data in Excelsior and this data will be transferred to 
TR per the DTA and incorporated into the study database electronically.  OCT-A and UWF-color 
photographs will be graded by the Boston Image Reading Center (BIRC) using their custom software. Data 
will be stored at BIRC and transferred TR per the DTA and incorporated into the study database 
electronically. Source raw images will be stored at study sites. Image grading source data will be stored at 
the reading centers. 
All analyses outlined in this document will be carried out after the following has occurred: 
• 
All data management requirements are met according to TR standard operating procedures, 
including data entry, performance of edit and validation checks, documentation and resolution of 
data queries, and database lock with written authorization provided by appropriate TR and Sponsor 
personnel; 
• 
Protocol deviations have been identified and status defined (major/minor deviations);  
• 
Analysis populations have been determined, and 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
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• 
Randomized treatment codes have been unmasked. 
7 
DATA CONVENTION 
All data analysis will be performed by Trial Runners, LLC after the study is completed and database has 
been locked and released for unmasking.  Statistical programming and analyses will be performed using 
SAS® Version 9.4 or higher.  Output will be provided in RTF format for tables and PDF format for tables, 
listings, and figures using landscape orientation.  All study data will be listed by subject, treatment, and 
visit (as applicable), based on all enrolled subjects. 
 
7.1 Missing Data  
Efficacy data related to eye anatomy or visual function that is collected after rescue treatment (i.e., 
treatment for DME or PDR other than study medication) will be treated as missing data. Unless, otherwise 
stated, missing data will be handled using the following approach: 
• 
For start date, partial dates will have first day of the month imputed if day is missing, and January 
of that year will be imputed if month is missing. If both day and month are missing, January 01 will 
be imputed.  
• 
For end date, partial dates will have last day of the month imputed if day is missing, and December 
of that year will be imputed if month is missing. If both day and month are missing, December 31 
will be imputed.  
• 
Missing data are imputed using Last Observation Carried Forward (LOCF) for all visits except 
screening/baseline; screening/baseline values are not carried forward.  
• 
For vision related efficacy measurements (Tables 14.2.1.x, 14.2.2.x, 14.2.3.x, 14.2.4.x, 14.2.5.x, 
14.2.6.x, 14.2.7.x,14.2.8.x, 14.2.10.x, 24.2.11.x, 14.2.12.x, 14.2.13, 14.3.12.3, 14.3.13.3, 
14.3.14.2x, 14.3.14.5) subjects receiving rescue treatment will be handled differently to reflect their 
status as a treatment failure and to avoid confounding of the effects of rescue treatment with the 
effects of study drug. Specifically, last pre-rescue data are carried forward for LOCF analysis. If 
rescue and DRSS occur on the same day, DRSS from that day is carried forward. For Observed 
Case (OC) analyses, results post-rescue are omitted, and last pre-rescue data are carried forward. 
Note that for DRSS scales involving both eyes (Person and Binocular scale) the carry forward rules 
apply only to the rescued eye in calculation of the combined score. 
• 
Where severity or relationship is missing for adverse events, most conservative imputation will be 
made.  
7.2 Descriptive Statistics   
For continuous variables, descriptive statistics will include the number of subjects (n), mean, standard 
deviation (SD), median, minimum and maximum. Categorical variables will be summarized using absolute 
and relative frequencies (i.e., counts and percentages). For categorical analyses, eyes that receive rescue 
therapy will be considered as treatment failures. Safety and PK data will be analyzed as collected. 
 
All efficacy data will be summarized by treatment groups and overall using appropriate descriptive statistics. 
Summaries will be presented for both the MITT and PP populations, where applicable. Due to the small 
number of subjects t enrolled at each center, all summaries and analyses will be performed using data 
pooled across centers. Unscheduled data, such as information from unscheduled visits or investigator 
comments, will be included in the data listings.  In general, these data will be excluded from the summary 
tables unless otherwise specified.  
 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
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7.3 Study Days Relative to First Day of Treatment 
Baseline results will be those recorded just prior to dosing. In cases where more than one pre-dose 
observation has been recorded, the last recording will be identified as the baseline result. Study days will 
be numbered relative to the first day of dosing. The start of study (Day 1) will be defined as the date on 
which a subject takes the first dose of any study medication, as recorded on the CRF. Relative to study 
start, days will be numbered ...,-2, -1, 1, 2, ... with Day 1 data collected on the first day of dosing prior to 
the start of study medication (Pre-Dose). Recorded data will be assigned to evaluation/assessment 
windows. 
8 
DISPOSITION AND EXIT STATUS 
8.1 Subject Disposition 
Subjects who are enrolled, complete the study, discontinue study medication, or withdraw from the study 
including reasons for study medication discontinuation or study withdrawal will be summarized along with 
the number and percentage of subjects in each of the analysis populations (safety, PP, PK and sub-study) 
in tabular format by treatment group and for all subjects. The number and percentage of subjects who 
completed 1-month follow-up visit will be summarized in the Safety population. The reasons for active 
treatment period discontinuation that will be summarized include: adverse events, treatment for PDR or 
DME, subject withdrew consent, lost to follow-up, protocol deviation, termination of study and other.  
Individual subject disposition data will be listed.  
8.2 Extent of Study Drug Exposure 
Exposure to treatment and treatment compliance will be summarized by treatment group and for all 
subjects. A listing will present all product accountability details. Duration of exposure is determined from 
the dispensed and return date information. Treatment compliance is determined as the number of actual 
doses received over the number of expected doses multiplied by 100. Expected subcutaneous study 
medication doses is twice the date of the last date of dosing minus the date of the Day 1 visit plus 1 (minus 
allowed days of non-dosing, i.e., days on which subject was intentionally not dosing per Investigator 
instruction/allowance, due to safety/tolerability or concomitant illness/procedure/hospitalization). The 
number and percentage of subjects who are at least 70% compliant will be summarized. 
8.3 Protocol Deviations 
The number and percentage of subjects with major protocol deviations will be summarized by treatment 
groups and for all subjects for the safety population.  The protocol deviations that will be summarized 
include:  informed consent, inclusion/exclusion and randomization, study drug administration and 
assignment at site, improper protocol procedures at site (missed, repeated, not per protocol), site’s failure 
to report SAE/AE, visit out of window (missed, early, late), subject’s non-compliance with subcutaneous 
study drug (<70% of expected doses administered), subject’s use of prohibited concomitant medication, 
subject’s failure to follow instructions and other.   A subject listing will be provided that includes the date of 
the deviation, the deviation description and the classification of whether the deviation was judged to be 
major or minor. 
8.4 Exclusion from Analysis Populations 
The number and percentage of subjects that are excluded from Per Protocol Population due to protocol 
deviations, did not complete study and non-compliant will be summarized for the MITT population by 
treatment groups and for all subjects. The number of subjects with percentage excluded from 
pharmacokinetic population because of non-evaluable data will also be presented for MITT population by 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
CONFIDENTIAL 
      Page 13 of 19 
 
 
treatment groups and for all subjects. A listing for the subjects excluded from MITT population will be 
generated.   
 
9 
BASELINE CHARACTERISTICS  
9.1 Demographics and Baseline/Screening Characteristics 
All demographic and baseline data will be summarized per treatment group and overall. These will be 
presented for the safety population and MITT population separately.  The demography presentation will 
include Age (years), Sex, Ethnicity, Race, and BMI (kg/m^2). Summary statistics of duration of diabetics 
(years), and the types of diabetics will be presented. The duration of NPDR (years), DRSS and BCVA will 
be summarized for the study eye.  Number and percentage of subjects with right eye (OD) and left eye 
(OS), and prior treatment of PDR or DME in study eye will also be summarized. Additionally, the number 
and percentage of subjects who were taking insulin and ACEi/ARB will be presented by the treatment group 
and for all subjects.  
9.2 Prior and Concomitant Medications 
Prior and concomitant medications will be presented for each subject coded per the World Health 
Organization (WHO) Anatomical Therapeutics Chemical (ATC) Drug dictionary. Prior medication are those 
medications that were started anytime and were stopped within 30 days prior to visit 1. Concomitant 
medications are those medications that were started anytime after visit 1 and before the last study visit or 
started anytime before visit 1 and were ongoing on or after visit 1. The data will be summarized by ATC 
dictionary (WHO DDE B2 September 1, 2017) drug class and generic name and classified as non-ocular 
and ocular prior and concomitant medications. Further, ocular prior and concomitant medications are 
presented for study eyes, qualified fellow eyes and unqualified fellow eyes. Descending sorting order by 
the frequency of ATC drug classification, and within that descending order by the frequency of generic 
name will be followed. A separate listing for both non-ocular and ocular prior and concomitant medication 
will present be presented.  
Medications with partial dates that do not allow determination of whether prior or concomitant will be 
considered concomitant. Prior and concomitant medications are presented for safety population.  
9.3 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1 
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment groups and for all subjects by System Organ Class (SOC) and Preferred Term (PT) using safety 
population.  Ocular medical history will be similarly summarized by treatment groups and for all subjects for 
the study eyes, qualified fellow eyes, and unqualified fellow eyes separately. Subjects with multiple medical 
histories in the same SOC or PT will be counted only once for the respective SOC or PT. Subject listings 
of medical history will be generated separately for ocular and non-ocular data.  
10 EFFICACY ANALYSIS 
Efficacy analysis will be performed after the last patient has completed the study. Data to be included in 
this analysis include Subject Disposition, Extent of Drug Exposure, Demographic and Baseline 
Characteristics, Primary Outcome (MITT & PP population, LOCF & OC), all secondary efficacy endpoints 
(MITT, LOCF), OCT-A (MITT, LOCF & OC), UACR (MITT & PP population, LOCF & OC), eGFR (MITT & 
PP population, LOCF & OC), ERG (MITT, LOCF & OC), and UWF-FA (MITT, LOCF & OC). The primary 
efficacy analysis will only contain data on events that occurred at timepoints up to and including the EOT 
visit (week 48).  


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
CONFIDENTIAL 
      Page 14 of 19 
 
 
10.1 Primary Efficacy Endpoint Analysis 
The primary hypotheses to be tested is that AKB-9778 15 mg twice daily and AKB-9778 15 mg once daily 
will be superior to placebo in the improvement of DR as measured by the ETDRS severity scale change 
from baseline at 48 weeks. Specifically, the primary endpoint is the percentage of subjects with an 
improvement in study eye severity of DR (ETDRS DRSS) of ≥ 2 steps at 48 weeks without need for 
treatment of PDR or DME (by IVT, laser, or vitrectomy) in the study eye. DRSS scores used for all analyses 
will be obtained from final adjudicated grading by the central reading center (Fundus Photograph Reading 
Center for the standard field images).  
The primary hypotheses will be tested in the MITT population using a Fisher’s Exact Test with a 2-sided 
5% significance level. AKB-9778 15 mg twice daily will be tested first. If this is found to be statistically 
significant, then AKB-9778 15 mg once daily will be tested for statistical significance, at the same 
significance level. Cochran-Mantel-Haenszel (CMH) test stratified for baseline ETDRS DRSS (levels 4, 5 
and 6) will also be used for testing primary hypothesis in the MITT population.  Missing data will be imputed 
using LOCF; baseline values will not be carried forward.   
As a sensitivity analysis, primary hypothesis will be tested using Fisher’s Exact test, and CMH test stratified 
for baseline ETDRS DRSS (levels 4, 5 and 6) on OC in the PP population.  
 
10.2 Secondary, Exploratory and Exploratory Sub-Study Efficacy Endpoint Analysis 
Secondary efficacy endpoints are summarized in Section 5.2, and involve alternative analyses of DRSS 
results, showing the proportion of patients who develop sight-threatening complications of DR (DME & 
PDR). Measures of kidney function (UACR and eGFR) are exploratory efficacy endpoints. Exploratory sub-
study endpoints are derived from OCT-Angiography, Ultra-wide field fluorescein angiography, Ultra-wide 
field color photographs, and electroretinography. Details of these variables and their analysis are contained 
in separate SAPs.  
Normality assumption will be tested for any endpoint of continuous nature. If normality assumption is 
violated, appropriate transformation and/or non-parametric analysis will be employed. Otherwise, all 
secondary, exploratory and exploratory sub-study endpoints of continuous nature will be analyzed using 
ANCOVA model, and all inferential analyses will use a 2-sided 5% significance level. For the exploratory 
efficacy endpoints UACR and eGFR, for internal decision-making purposes, a 1-sided 10% significance 
level will be used. Whenever possible, a mixed model repeated measures (MMRM) model will be utilized 
to analyze this data. The model will include change from baseline as the dependent variable. The p-value 
and 95% CI from the model is baseline parameter adjusted.  
For MMRM, visit will be treated as the repeated variable within a subject. Within-subject error, an 
unstructured variance-covariance will be applied; in case of non-convergence, compound symmetry will be 
used. MMRM model for UACR and eGFR is adjusted by the baseline HbA1c, Baseline Systolic BP, log-
transformed Baseline UACR, and ACEi/ARB use.  
Secondary, exploratory and exploratory sub-study endpoints of a dichotomous nature will be analyzed using 
the same approach as outlined for the primary efficacy endpoint.  
11 SAFETY ANALYSIS 
The safety and tolerability of AKB-9778 will be determined by incidence and severity of treatment emergent 
AEs and changes from baseline in ECG, vital sign measurements, clinical laboratory assay results (blood 
chemistry, hematology, fecal occult blood, and urinalysis), BCVA, IOP, slit lamp examinations, funduscopic 
examinations and FA. Continuous and qualitative variables will be summarized indicating change from 
baseline and shift tables, where appropriate. Some data will be summarized through treatment period as 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
CONFIDENTIAL 
      Page 15 of 19 
 
 
well as throughout the study (treatment period plus follow-up period). Also, individual subject safety data 
will be listed. 
11.1 Safety Endpoint Analysis 
11.1.1 Adverse Events 
All AEs reported during the study and follow-up period will be recorded and coded using MedDRA version 
20.1 terminology. An AE will be considered as treatment-emergent if it has an onset during the treatment 
period or is pre-existing and worsens after the first dose of study medication is administered. When the 
date of AE is same as date of randomization, the site will be queried to ensure timing of AE start relative to 
first dose is determined.  
The incidence of all reported treatment-emergent adverse events (TEAEs) will be summarized using system 
organ class and preferred term by treatment group and overall, using counts and percentages. All adverse 
events will also be presented by relationship and severity. Further, serious adverse events and adverse 
events leading to discontinuation will also be presented. 
Separate analyses will be performed for ocular and non-ocular TEAEs. For ocular TEAEs, the subject will 
be considered to have had the TEAE if at least one eye had the TEAE. Ocular TEAEs will be summarized 
separately for all eyes, study eyes, all qualified eyes (study eyes and qualified fellow eyes) and unqualified 
fellow eyes.  
Subjects may have more than one AE per system organ class and preferred term. At each level of subject 
summarization, a subject will be counted once if they reported 1 or more events and will be reported with 
the highest severity. In cases where severity or relationship is missing, the most conservative approach will 
be taken (i.e. highest severity and assumed to be related). 
A listing of TEAEs will be generated showing adverse event location (OD, OS or non-ocular), duration of 
TEAEs with onset date, severity, relationship with study medication and change in status of ongoing event. 
Also, listing for serious adverse events, and adverse events leading to discontinuation will be generated.  
11.1.2 Electrocardiogram (ECG) 
Change from baseline for ECG parameters will be presented along with their associated 95% confidence 
intervals.  Potentially clinically significant findings will also be presented based on the following categories:  
• 
The proportion of patients obtaining treatment-emergent absolute QTcF values > 450 ms and ≤ 
480 ms; > 480 ms and ≤ 500 ms; and > 500 ms. 
• 
The proportion of patients obtaining a QTcF increase from baseline values >30 and ≤60 ms; and > 
60 ms. 
• 
The proportion of patients obtaining a QRS change from baseline > 25% resulting in QRS > 120 
ms 
• 
The proportion of patients obtaining a PR interval change from baseline >25% reaching a value 
>220 ms 
• 
The proportion of patients obtaining a heart rate change from baseline > 25% decrease resulting 
in a heart rate < 50 beats per minute (bpm) and heart rate change from baseline > 25% increase 
resulting in a heart rate > 100 bpm 
12 PHAMACOKINETIC ANALYSIS 
AKB-9778 plasma concentrations will be summarized by treatment group and nominal sampling time using 
descriptive statistics. Individual subject pharmacokinetic data will be listed. Additional analyses including 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
CONFIDENTIAL 
      Page 16 of 19 
 
 
the potential relationship of plasma concentration and selected safety and efficacy parameters and/or 
subject demographic variables may be performed. 
13 PHARMACODYNAMICS ANALYSIS 
Blood samples collected at baseline and Month 12 End of Treatment (EOT) will be retained for exploratory 
analysis of biomarkers in plasma. Once results of the study are known, the Sponsor will determine the value 
of conducting these analyses. 
14 EXPLORATORY GENETIC ANALYSIS 
For subjects who have provided consent for genetic sampling, a blood sample will be retained for 
exploratory genetic analysis that may provide insight into the role of Tie2 in diabetic retinopathy and an 
individual subject's response to AKB-9778 treatment. Once results of the study are known, the Sponsor will 
determine the value of conducting these analyses. 
15 VALIDATION 
Derived datasets will be independently reprogrammed by a second programmer. The separate datasets 
produced by the two programmers must match 100%. Tables will be independently reprogrammed by a 
second programmer for numeric results. Statisticians will be involved in the process of programming and 
validating tables that include inferential statistical results. Figures will be checked for consistency against 
corresponding tables and listings, or independently reprogrammed if there are no corresponding tables or 
listings.  
 
 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
CONFIDENTIAL 
      Page 17 of 19 
 
 
 
16 APPENDIX 1 
 
Person level 
Level worse eye 
Level better eye 
1 
1 
1 
2 
2 
1 
3 
2 
2 
4 
3 
<3 
5 
3 
3 
6 
4 
<4 
7 
4 
4 
8 
5 
<5 
9 
5 
5 
10 
6 
<6 
11 
6 
6 
12 
7 
<7 
13 
7 
7 
14 
8 
<8 
15 
8 
8 
16 
>8 
<8 
17 
>8 
>8 
 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
CONFIDENTIAL 
      Page 18 of 19 
 
 
17 APPENDIX  2 
GLOSSARY OF ABBREVIATIONS 
 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutics Chemical 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice Daily 
BIRC 
Boston Image Reading Center 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats Per Minute 
CCAI 
Campane Center for Advanced Imaging 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CST 
Central Sub-Field Thickness 
DTA 
Data Transfer Agreement 
DBP 
Diastolic Blood Pressure 
DME 
Diabetic Macular Edema 
DR 
Diabetic Retinopathy 
DRSS 
Diabetic Retinopathy Severity Score 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EOT 
End of Treatment 
ERG 
Electroretinogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein Angiography 
FP 
Fundus Photograph 
FPRC 
Fundus Photograph Reading Center 
HR 
Heart Rate 
IOP 
Intra-ocular Pressure 
IVT 
Intra-Vitreal Therapy 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent-to-Treat 
MMRM 
Mixed Model Repeated Measures 
NPDR 
Non-proliferative Diabetic Retinopathy 
OC 
Observed Cases 
OCT-A 
Optical Coherence Tomography Angiography 
OD 
Right Eye 
OS 
Left Eye 
PBS 
Phosphate Buffered Saline  
PDR 
Proliferative Diabetic Retinopathy 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
QD 
Once Daily 
RDC 
Remote Data Capture 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 


Aerpio Therapeutics, Inc.                                                                                                             Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 27 February 2019 
 
CONFIDENTIAL 
      Page 19 of 19 
 
 
SBP 
Systolic Blood Pressure 
SC 
Subcutaneous 
SD 
Standard Deviation 
SD OCT 
Spectral Domain Optical Coherence Tomography 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
TR 
Trial Runners 
Td’s 
Troland Seconds 
UACR 
Urine-albumin-to-creatinine Ratio 
UWF 
Ultra-wide Field 
WHO 
World Health Organization 
 


Tri*i".,, ,:'i",..
Note to Flle
Clinical Study ProtocolAKB-9778{F5001: PHASE 2 DOUBLE-MASKED, PLACEBO-CONTROLLED STUDY
TO ASSESS THE SAFETY AND EFFICACY OF SUBCUTANEOUSLY ADMINISTERED AKB 9778 15MG ONCE
DAILY OR 15MG TWICE DAILY FOR 12 MONTHS IN PATIENTS WITH MODERATE TO SEVERE NON-
PROLI FERATIVE DIABETIC RETI NOPATHY
To: 
Statistical Analysis Plan, Final Version 27Feb2079
Date: 03-Mar-2019
Re: 
Criteria used to define Progression to Vision-Threatening Complications (DME and/or PDR)
Criteria used to define Proqression to Vision-Threatening Complications (DME and/or PDR):
Qualified eyes were included as progressors if one or more of the following conditions occurred during
the trial:
1. An AE of DME was entered that was either treated or was confirmed by the reading center as
having eithercenter involved retinalcyst, center involved retinaledema, center involved subretinal
fluid, or central subfield thickness >300 microns.
2. An AE of PDR, NVE, NVD, orvitreous hemorrhage
3. lW with anti-VEGF therapy or corticosteroid with indication for treatment documented as either
DME or PDR
4. PRP, Grid laser, orfocal laserwith indication fortreatment documented as either DME or PDR
5. An increase in central subfield thickness of 220o/o at last observation
6. DRSS score of >53, indicating PDR, at last observation
DATE


Aerpio Therapeutics, Inc.                                                                                               OCT-A Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 28 February 2019 
 
 
                                                               CONFIDENTIAL                                                                               Page 1 of 5 
 
Statistical Analysis Plan 
OCT-Angiography Efficacy Sub-study 
Study AKB-9778-CI-5001 
PHASE 2 DOUBLE-MASKED, PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY AND 
EFFICACY OF SUBCUTANEOUSLY ADMINISTERED AKB-9778 15MG ONCE DAILY OR 15MG TWICE 
DAILY FOR 12 MONTHS IN PATIENTS WITH MODERATE TO SEVERE NON-PROLIFERATIVE 
DIABETIC RETINOPATHY 
Prepared for: 
Aerpio Therapeutics, Inc. 
Version and Author details: 
Version Date: 
28 February 2019 
Version Number 
1.0 
Author: 
Jatinder Singh 
 


Aerpio Therapeutics, Inc.                                                                                               OCT-A Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 28 February 2019 
 
 
                                                               CONFIDENTIAL                                                                               Page 2 of 5 
 
SIGNATURES 
 
The undersigned have approved this Statistical Analysis Plan for use in this study. 
 
 
 
 
 
 
 
 
 
Jatinder Singh, Biostatistician, Trial Runners, LLC 
 
Date 
 
 
 
 
 
 
 
Steve Pakola, Chief Medical Officer, Aerpio Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
Mitchell Brigell, Vice-President of Clinical Development, Aerpio 
Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 


Aerpio Therapeutics, Inc.                                                                                               OCT-A Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                          Version Date: 28 February 2019 
 
 
                                                               CONFIDENTIAL                                                                               Page 3 of 5 
 
OCT-Angiography (OCT-A) images were obtained in study AKB-9778-CI-5001 as an exploratory sub-study. 
Images (3mm x 3mm and 6mm x 6mm images, centered on the fovea) from study and fellow eyes were 
obtained at pretreatment Baseline, Week 12, Week 24, Week 36 and Week 48/EOT visits. Data acquisition 
and transmission protocols were specified in study manuals for Optovue, Zeiss, and Topcon systems. All 
images were uploaded to the Eyekor Excelsior platform. Images were graded by the Boston Image Reading 
Center (BIRC) using their custom software. Parameters graded are shown in Table 1. Outcome variables 
of primary interest are FAZ area, % vessel density, % vessel skeleton density, total vessel length, and non-
perfusion area. 
Continuous sub-study endpoints of interest will be analyzed using an ANCOVA model, and all inferential 
analyses will use a 2-sided 5% significance level. Whenever possible, a mixed model repeated measures 
(MMRM) model will be utilized to analyze this data. The model will include change from baseline as the 
dependent variable. The p-value and 95% CI from the model is baseline parameter adjusted.  For MMRM, 
visit will be treated as the repeated variable within a subject. Within-subject error, an unstructured variance-
covariance will be applied; in case of non-convergence, compound symmetry will be used. 
Categorical variables will be tested using a Fisher’s Exact Test with a 2-sided 5% significance level. AKB-
9778 15mg twice daily will be tested first. If this is found to be statistically significant, then AKB- 9778 15mg 
once daily will be tested for statistical significance, at the same significance level. Cochran-Mantel-Haenszel 
(CMH) test stratified for baseline values will also be used for testing.  Missing data will be imputed using 
Last Observation Carried Forward (LOCF); baseline values will not be carried forward. 
The relation between change in DRSS from baseline to Week 48/EOT visit and baseline FAZ Area, baseline 
Vessel Skeleton Density (6x6), baseline Total Vessel Length (6x6), and baseline Non-perfusion Area (6x6) 
will also be calculated.


Aerpio Therapeutics, Inc.                                                                                                OCT-A Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                             Version Date: 4 January 2019 
 
 
                                                                               CONFIDENTIAL                                                              Page 4 of 5 
 
TABLE: OCT-A Parameters. Parameters of primary interest are noted in red. 
 Parameter 
Unit 
Picklist or  
Numerical Value 
Picklist or Numerical Value 
(addtl) 
OCTA_FAZ Area 
mmsq 
Numerical Value 
XXX.XXX 
OCTA_FAZ Perimeter 
mm 
Numerical Value 
XXX.XXX 
OCTA_Acircularity 
Index 
score 
Numerical Score 
XXX.XXX 
OCTA_FAZ 
Remodeling 3x3 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_Microaneurysm 
3x3 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_Microaneurysm 
6x6 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_Vascular 
Tortuosity 3x3 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_Vascular 
Tortuosity 6x6 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_IRMA 3x3 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_IRMA 6x6 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_Retinal 
Capillary Dropout 3x3 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_Retinal 
Capillary Dropout 6x6 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_Retinal 
Neovascularization 
3x3 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_Retinal 
Neovascularization 
6x6 
- 
Yes/No/Can't Grade 
If YES, Select Sector: 
superotemporal, superonasal, 
inferotemporal, inferonasal 
OCTA_Vessel Density 
3x3 
percent 
Numerical Value 
XXX.XXX 
OCTA_Vessel Density 
6x6 
percent 
Numerical Value 
XXX.XXX 
OCTA_Vessel 
Skeleton Density 3x3 
percent 
Numerical Value 
XXX.XXX 


Aerpio Therapeutics, Inc.                                                                                                OCT-A Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                             Version Date: 4 January 2019 
 
 
                                                                               CONFIDENTIAL                                                              Page 5 of 5 
 
OCTA_Vessel 
Skeleton Density 6x6 
percent 
Numerical Value 
XXX.XXX 
OCTA_Total Vessel 
Length 3x3 
mm 
Numerical Value 
XXX.XXX 
OCTA_Total Vessel 
Length 6x6 
mm 
Numerical Value 
XXX.XXX 
OCTA_Non-perfusion 
Area 3x3 
mmsq 
Numerical Value 
XXX.XXX 
OCTA_Non-perfusion 
Area 6x6 
mmsq 
Numerical Value 
XXX.XXX 
  
  
  
  
Evolutive Assessment 
  
  
  
OCTA_Retinal 
Capillary Dropout 3x3 
- 
Better/Worse/Unchanged/Can't 
Grade 
  
OCTA_Retinal 
Capillary Dropout 6x6 
- 
Better/Worse/Unchanged/Can't 
Grade 
  
 


Aerpio Therapeutics, Inc.                                                                                                    ERG Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                         Version Date:  28 February 2019 
 
 
                                                                         CONFIDENTIAL                                                                     Page 1 of 7 
 
Statistical Analysis Plan 
Electroretinogram Efficacy Sub-study 
Study AKB-9778-CI-5001 
PHASE 2 DOUBLE-MASKED, PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY AND 
EFFICACY OF SUBCUTANEOUSLY ADMINISTERED AKB-9778 15MG ONCE DAILY OR 15MG TWICE 
DAILY FOR 12 MONTHS IN PATIENTS WITH MODERATE TO SEVERE NON-PROLIFERATIVE 
DIABETIC RETINOPATHY 
Prepared for: 
Aerpio Therapeutics, Inc. 
Version and Author details: 
Version Date: 
28 February 2019 
Version Number 
1.0 
Author: 
Jatinder Singh 
 


Aerpio Therapeutics, Inc.                                                                                                    ERG Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                         Version Date:  28 February 2019 
 
 
                                                                         CONFIDENTIAL                                                                     Page 2 of 7 
 
SIGNATURES 
 
The undersigned have approved this Statistical Analysis Plan for use in this study. 
 
 
 
 
 
 
 
 
 
Jatinder Singh, Biostatistician, Trial Runners, LLC 
 
Date 
 
 
 
 
 
 
 
Steve Pakola, Chief Medical Officer, Aerpio Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
Mitchell Brigell, Vice-President of Clinical Development, Aerpio 
Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 


Aerpio Therapeutics, Inc.                                                                                                    ERG Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                         Version Date:  28 February 2019 
 
 
                                                                         CONFIDENTIAL                                                                     Page 3 of 7 
 
Electroretinograms were obtained in study AKB-9778-CI-5001 as an exploratory efficacy sub-study. Light-
adapted flicker responses and pupillary responses were obtained to 3 stimulus strengths, from the study 
and fellow eyes, at pretreatment Baseline, Week 12, Week 24, Week 36, and Week 48/EOT visits, using 
the LKC RETeval system. Data acquisition and transmission protocols were specified in a study manual. 
All responses were uploaded to the Eyekor Excelsior platform. Responses were graded by LKC 
Technologies (Gaithersburg, MD). Parameters graded are shown in Table 1. Outcome measures of primary 
interest are LKC Composite score, age adjusted pupil area ratio, age adjusted fundamental implicit time for 
stimulus strengths 4, 16 and 32 Troland-seconds (Td’s), age adjusted Fundamental amplitude for stimulus 
strengths 4, 16 and 32 Td’s. Given the multitude of variables, inferential statistics will not be performed on 
non-age adjusted parameters. Non-Age adjusted parameters will be summarized by descriptive statistics 
only. 
Sub-study ERG endpoints of interest will be analyzed using an ANCOVA model without adjustment for 
multiplicity, and all inferential analyses will use a 2-sided 5% significance level. Whenever possible, a mixed 
model repeated measures (MMRM) model will be utilized to analyze this data. The model will include 
change from baseline as the dependent variable. The p-value and 95% CI from the model is baseline 
parameter adjusted.  For MMRM, visit will be treated as the repeated variable within a subject. Within-
subject error, an unstructured variance-covariance will be applied; in case of non-convergence, compound 
symmetry will be used. 
Categorical variables will be tested using a Fisher’s Exact Test with a 2-sided 5% significance level. AKB-
9778 15mg twice daily will be tested first. If this is found to be statistically significant, then AKB- 9778 15mg 
once daily will be tested for statistical significance, at the same significance level. Cochran-Mantel-Haenszel 
(CMH) test stratified for baseline values will also be used for testing.  Missing data will be imputed using 
Last Observation Carried Forward (LOCF); baseline values will not be carried forward. 
The relation between change in DRSS from baseline to Week 48/EOT visit and baseline Pupil Area Ratio, 
LKC Composite Score, and baseline Fundamental Implicit Time and Fundamental Amplitude for each 
stimulus strength will also be calculated. 
 
 


Aerpio Therapeutics, Inc.                                                                                                    ERG Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                         Version Date:  28 February 2019 
 
 
                                                                         CONFIDENTIAL                                                                     Page 4 of 7 
 
Table: ERG Parameters. Those of primary interest are noted in red. 
Parameter 
Picklist or Numeric Value 
Field Description 
Derived measures 
Pupil Area Ratio Value Not Age 
Adjusted 
Number (populated by .json 
import) 
Ratio of the pupil area between 
the 4 Td-s stimulus and the 32 
Td-s stimulus.  Unit: none 
Pupil Area Ratio Value Age Adjusted 
Number (populated by .json 
import) 
Ratio of the pupil area between 
the 4 Td-s stimulus and the 32 
Td-s stimulus.  Unit: none 
LKC Composite score 
 
Number (populated by .json 
import) 
Combined measure of vision-
threatening diabetic retinopathy.  
Scores above 20 have increased 
risk of VTDR.  Unit: none 
Stimulus Strength 32 
32 Fundamental Implicit Time Value 
Not Age Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of best-
fitting sine wave (fundamental). 
Unit: ms. Stimulus: 32 Td-s flicker 
with no background 
32 Fundamental Implicit Time Value 
Age Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of best-
fitting sine wave (fundamental). 
Unit: ms. Stimulus: 32 Td-s flicker 
with no background 
32 Fundamental Amplitude Value Not 
Age Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
best-fitting sine wave 
(fundamental). Unit: µV. Stimulus: 
32 Td-s flicker with no 
background 
32 Fundamental Amplitude Value Age 
Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
best-fitting sine wave 
(fundamental). Unit: µV. Stimulus: 
32 Td-s flicker with no 
background 
32 Harmonic Implicit Time Value Not 
Age Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of 
waveform. Unit: ms. Stimulus: 32 
Td-s flicker with no background 
32 Harmonic Implicit Time Value Age 
Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of 
waveform. Unit: ms. Stimulus: 32 
Td-s flicker with no background 
32 Harmonic Amplitude Value Not Age 
Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
waveform. Unit: µV. Stimulus: 32 
Td-s flicker with no background 


Aerpio Therapeutics, Inc.                                                                                                    ERG Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                         Version Date:  28 February 2019 
 
 
                                                                         CONFIDENTIAL                                                                     Page 5 of 7 
 
Parameter 
Picklist or Numeric Value 
Field Description 
32 Harmonic Amplitude Value Age 
Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
waveform. Unit: µV. Stimulus: 32 
Td-s flicker with no background 
32 Pupil Diameter 
Number (populated by .json 
import) 
Steady-state pupil diameter for 
the 32 Td-s stimulus.  Unit: mm 
Stimulus Strength: 16 
16 Fundamental Implicit Time Value 
Not Age Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of best-
fitting sine wave (fundamental). 
Unit: ms. Stimulus: 16 Td-s flicker 
with no background 
16 Fundamental Implicit Time Value 
Age Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of best-
fitting sine wave (fundamental). 
Unit: ms. Stimulus: 16 Td-s flicker 
with no background 
16  Fundamental Amplitude Value Not 
Age Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
best-fitting sine wave 
(fundamental). Unit: µV. Stimulus: 
16 Td-s flicker with no 
background 
16  Fundamental Amplitude Value Age 
Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
best-fitting sine wave 
(fundamental). Unit: µV. Stimulus: 
16 Td-s flicker with no 
background 
16 Harmonic Implicit Time Value Not 
Age Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of 
waveform. Unit: ms. Stimulus: 16 
Td-s flicker with no background 
16 Harmonic Implicit Time Value Age 
Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of 
waveform. Unit: ms. Stimulus: 16 
Td-s flicker with no background 
16  Harmonic Amplitude Value Not 
Age Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
waveform. Unit: µV. Stimulus: 16 
Td-s flicker with no background 


Aerpio Therapeutics, Inc.                                                                                                    ERG Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                         Version Date:  28 February 2019 
 
 
                                                                         CONFIDENTIAL                                                                     Page 6 of 7 
 
Parameter 
Picklist or Numeric Value 
Field Description 
16  Harmonic Amplitude Value Age 
Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
waveform. Unit: µV. Stimulus: 16 
Td-s flicker with no background 
16 Pupil Diameter 
Number (populated by .json 
import) 
Steady-state pupil diameter for 
the 16 Td-s stimulus.  Unit: mm 
Stimulus strength: 4 
4 Fundamental Implicit Time Value Not 
Age Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of best-
fitting sine wave (fundamental). 
Unit: ms. Stimulus: 4 Td-s flicker 
with no background 
4 Fundamental Implicit Time Value 
Age Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of best-
fitting sine wave (fundamental). 
Unit: ms. Stimulus: 4 Td-s flicker 
with no background 
4  Fundamental Amplitude Value Not 
Age Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
best-fitting sine wave 
(fundamental). Unit: µV. Stimulus: 
4 Td-s flicker with no background 
4  Fundamental Amplitude Value Age 
Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
best-fitting sine wave 
(fundamental). Unit: µV. Stimulus: 
4 Td-s flicker with no background 
4 Harmonic Implicit Time Value Not 
Age Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of 
waveform. Unit: ms. Stimulus: 4 
Td-s flicker with no background 
4 Harmonic Implicit Time Value Age 
Adjusted 
Number (populated by .json 
import) 
Time from flash to peak of 
waveform. Unit: ms. Stimulus: 4 
Td-s flicker with no background 
4  Harmonic Amplitude Value Not Age 
Adjusted 
Number (populated by .json 
import) 
 
Peak to peak amplitude of the 
waveform. Unit: µV. Stimulus: 4 
Td-s flicker with no background 


Aerpio Therapeutics, Inc.                                                                                                    ERG Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                         Version Date:  28 February 2019 
 
 
                                                                         CONFIDENTIAL                                                                     Page 7 of 7 
 
Parameter 
Picklist or Numeric Value 
Field Description 
 
4  Harmonic Amplitude Value Age 
Adjusted 
Number (populated by .json 
import) 
Peak to peak amplitude of the 
waveform. Unit: µV. Stimulus: 4 
Td-s flicker with no background 
4 Pupil Diameter 
Number (populated by .json 
import) 
Steady-state pupil diameter for 
the 4 Td-s stimulus.  Unit: mm 
 


Aerpio Therapeutics, Inc.                                                                                                UWF-C Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                           Version Date 28 February 2019 
 
 
                                                                   CONFIDENTIAL                                                                          Page 1 of 3 
 
Statistical Analysis Plan 
Ultra-Wide Field Color Photograph Efficacy Sub-study 
Study AKB-9778-CI-5001 
PHASE 2 DOUBLE-MASKED, PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY AND 
EFFICACY OF SUBCUTANEOUSLY ADMINISTERED AKB-9778 15MG ONCE DAILY OR 15MG TWICE 
DAILY FOR 12 MONTHS IN PATIENTS WITH MODERATE TO SEVERE NON-PROLIFERATIVE 
DIABETIC RETINOPATHY 
Prepared for: 
Aerpio Therapeutics, Inc. 
Version and Author details: 
Version Date: 
28 February 2019 
Version Number 
1.0 
Author: 
Jatinder Singh 
 


Aerpio Therapeutics, Inc.                                                                                                UWF-C Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                           Version Date 28 February 2019 
 
 
                                                                   CONFIDENTIAL                                                                          Page 2 of 3 
 
SIGNATURES 
 
The undersigned have approved this Statistical Analysis Plan for use in this study. 
 
 
 
 
 
 
 
 
 
Jatinder Singh, Biostatistician, Trial Runners, LLC 
 
Date 
 
 
 
 
 
 
 
Steve Pakola, Chief Medical Officer, Aerpio Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
Mitchell Brigell, Vice-President of Clinical Development, Aerpio 
Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 


Aerpio Therapeutics, Inc.                                                                                                UWF-C Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                           Version Date 28 February 2019 
 
 
                                                                   CONFIDENTIAL                                                                          Page 3 of 3 
 
Ultra-wide field Color Photographs were obtained in study AKB-9778-CI-5001 as an exploratory sub-study. 
Images were obtained from both eyes, at pretreatment Baseline, Week 24, and Week 48/EOT visits, using 
either an Optos 200Tx or Optos California system. Data acquisition and transmission protocols were 
specified in a study manual. All images were uploaded to the Eyekor Excelsior platform. Images were 
graded by the Boston Image Reading Center using their custom software. Grading will follow ETDRS DRSS 
criteria, but the analysis area will include the entire ultra-wide field rather than be limited to the central 7-
fields. DRSS grades ranging from 10-85 will be converted to an ordinal score ranging from 1-11. Monocular 
scores will be converted to Person and Binocular scores in subjects with qualified fellow eyes as is specified 
for the primary DRSS outcome.   
The primary endpoint of this substudy is the percentage of subjects with an improvement in study eye 
severity of DR (ETDRS DR Severity Score or DRSS) of ≥ 2 steps at 48 weeks without need for treatment 
of PDR or DME (by IVT, laser, or vitrectomy) in the study eye. 
The primary hypotheses will be tested in the MITT population using a Fisher’s Exact Test with a 2-sided 
5% significance level. AKB-9778 15mg twice daily will be tested first. If this is found to be statistically 
significant, then AKB- 9778 15mg once daily will be tested for statistical significance, at the same 
significance level. Cochran-Mantel-Haenszel (CMH) test stratified for baseline ETDRS DRSS (levels 4, 5 
and 6) will also be used for testing primary hypothesis in the MITT population.  Missing data will be imputed 
using Last Observation Carried Forward (LOCF); baseline values will not be carried forward. For rescued 
eyes the last observation pre-rescue will be carried forward. 
As a sensitivity analysis, Fisher’s Exact test and CMH test stratified for baseline ETDRS DRSS (levels 4, 5 
and 6) on Observed Cases (OC carrying forward pre-rescue values) in the Per Protocol (PP) population 
will also be performed. Secondary analyses will be performed on study eyes and all qualified eyes on 
derived DRSS Person and Binocular scales. 
 


Aerpio Therapeutics, Inc.                                                                                              UWF-FA Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                           Version Date:28 February 2019 
 
                                                                      CONFIDENTIAL                                                                       Page 1 of 4 
 
Statistical Analysis Plan 
Ultra-wide Field Fluorescein Angiography Efficacy Sub-study 
Study AKB-9778-CI-5001 
PHASE 2 DOUBLE-MASKED, PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY AND 
EFFICACY OF SUBCUTANEOUSLY ADMINISTERED AKB-9778 15MG ONCE DAILY OR 15MG TWICE 
DAILY FOR 12 MONTHS IN PATIENTS WITH MODERATE TO SEVERE NON-PROLIFERATIVE 
DIABETIC RETINOPATHY 
Prepared for: 
Aerpio Therapeutics, Inc. 
Version and Author details: 
Version Date: 
28 February 2019 
Version Number 
1.0 
Author: 
Jatinder Singh 
 


Aerpio Therapeutics, Inc.                                                                                              UWF-FA Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                           Version Date:28 February 2019 
 
                                                                      CONFIDENTIAL                                                                       Page 2 of 4 
 
SIGNATURES 
 
The undersigned have approved this Statistical Analysis Plan for use in this study. 
 
 
 
 
 
 
 
 
 
Jatinder Singh, Biostatistician, Trial Runners, LLC 
 
Date 
 
 
 
 
 
 
 
Steve Pakola, Chief Medical Officer, Aerpio Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
Mitchell Brigell, Vice-President of Clinical Development, Aerpio 
Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 


Aerpio Therapeutics, Inc.                                                                                              UWF-FA Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                           Version Date:28 February 2019 
 
                                                                      CONFIDENTIAL                                                                       Page 3 of 4 
 
Ultra-wide field fluorescein angiography was obtain6ed in study AKB-9778-CI-5001 as an 
exploratory sub-study. Time-series Images were obtained from the study eye, at pretreatment 
Baseline, Week 24, and Week 48/EOT visits, using either an Optos 200Tx or Optos California 
system. Data acquisition and transmission protocols were specified in a study manual. All images 
were uploaded to the Eyekor Excelsior platform. Images were graded by the Campane Center for 
Advanced Imaging at the Cole Eye Institute (CCAI) using their custom software. Parameters 
graded are shown in Table 1. Outcome variables of primary interest are Ischemic index in macula 
centered ROI 1 (Region of Interest 1) and ROI 2, Leakage index in macula centered ROI 1 and ROI 
2, and Microaneurysm counts in macula centered ROI 1 and ROI 2.   
Continuous sub-study endpoints of interest will be analyzed using an ANCOVA model, and all 
inferential analyses will use a 2-sided 5% significance level. Whenever possible, a mixed model 
repeated measures (MMRM) model will be utilized to analyze this data. The model will include 
change from baseline as the dependent variable. The p-value and 95% CI from the model is 
baseline parameter adjusted.  For MMRM, visit will be treated as the repeated variable within a 
subject. Within-subject error, an unstructured variance-covariance will be applied; in case of non-
convergence, compound symmetry will be used. 
Categorical variables will be tested using a Fisher’s Exact Test with a 2-sided 5% significance level. 
Cochran-Mantel-Haenszel (CMH) test stratified for baseline values will also be used for testing.  
Missing data will be imputed using Last Observation Carried Forward (LOCF); baseline values will 
not be carried forward. 
The relation between change in DRSS from baseline to Week 48/EOT visit and baseline Ischemia 
%, baseline Total Leakage Index, and total Aneurysms will also be calculated.


Aerpio Therapeutics, Inc.                                                                                              UWF-FA Statistical Analysis Plan 
Protocol: AKB-9778-CI-5001                                                                                             Version Date: 4 January 2019 
 
 
                                                                      CONFIDENTIAL                                                                       Page 4 of 4 
 
 
Table: UWF-FA Parameters. Those of primary interest are noted in red. 
Parameter 
Unit 
Ischemia % 
%, 2 decimals 
Ischemia Disc Centered ROI 1 Ischemia Index 
%, 2 decimals 
Ischemia Disc Centered ROI 2 Ischemia Index 
%, 2 decimals 
Ischemia Disc Centered ROI 3 Ischemia Index 
%, 2 decimals 
Ischemia Disc Centered ROI 1+2 Ischemia Index (Derived) 
%, 2 decimals 
Ischemia Macula Centered ROI 1 Ischemia Index 
%, 2 decimals 
Ischemia Macula Centered ROI 2 Ischemia Index 
%, 2 decimals 
Ischemia Macula Centered ROI 3 Ischemia Index 
%, 2 decimals 
Ischemia Macula Centered ROI 1+2 Ischemia Index (Derived) 
%, 2 decimals 
Leakage Total Leakage Index 
%, 2 decimals 
Leakage Disc Centered ROI 1 Leakage Index 
%, 2 decimals 
Leakage Disc Centered ROI 2 Leakage Index 
%, 2 decimals 
Leakage Disc Centered ROI 3 Leakage Index 
%, 2 decimals 
Leakage Disc Centered ROI 1+2 Leakage Index (Derived) 
%, 2 decimals 
Leakage Macula Centered ROI 1 Leakage Index 
%, 2 decimals 
Leakage Macula Centered ROI 2 Leakage Index 
%, 2 decimals 
Leakage Macula Centered ROI 3 Leakage Index 
%, 2 decimals 
Leakage Macula Centered ROI 1+2 Leakage Index (Derived) 
%, 2 decimals 
Total Aneurysms 
Number 
MA Disc Centered ROI  I  
Number 
MA Disc Centered ROI 2 
Number 
MA Disc Centered ROI 3  
Number 
MA Disc Centered Aneurysms ROI 1 + ROI 2 (Derived) 
Number 
MA Macula Centered ROI 1 
Number 
MA Macula Centered ROI 2  
Number 
MA Macula Centered ROI 3 
Number 
MA Macula Centered Aneurysms ROI 1 + ROI 2 (Derived) 
Number 
 
 

Prot_001.pdf: 
Protocol No. AKB-9778-CI-5001 
 
18September2017 
Amendment #5 Integrated 
 
 
 
 
Aerpio — Company Confidential 
Page 1 of 72 
 
 
 
 
CLINICAL PROTOCOL 
 
PHASE 2 DOUBLE-MASKED, PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY AND 
EFFICACY OF SUBCUTANEOUSLY ADMINISTERED AKB-9778 15MG ONCE DAILY OR 15MG TWICE 
DAILY FOR 12 MONTHS IN PATIENTS WITH MODERATE TO SEVERE NON-PROLIFERATIVE 
DIABETIC RETINOPATHY 
 
 
Compound: 
AKB-9778 
US IND Number: 
113,322 
Protocol Number: 
AKB-9778-CI-5001 
Phase: 
Phase 2 
Date: 
Final Version        16 Sept 2016 
Amendment #1     01 Dec 2016 
Amendment #2     05 Jan 2017 
Amendment #3     06 March 2017 
Amendment #4     11 April 2017 
Amendment #5  18 Sept 2017 
 
 
Sponsor: 
Aerpio Therapeutics LLC 
9987 Carver Road 
Suite 420 
Cincinnati, OH 45242 
 
This document contains information that is confidential and proprietary to the Sponsor, Aerpio Therapeutics 
LLC.  This information is being provided to you solely for the purpose of evaluating and/or conducting a clinical 
trial for the Sponsor.  You may disclose the contents of this document only to study personnel under your 
supervision, the Institutional Review Board, the United States Food and Drug Administration, or duly authorized 
representatives of regulatory agencies for this purpose under the condition that they maintain confidentiality.  The 
contents of this document may not be used in any other clinical trial, disclosed to any other person or entity, 
and/or published without the prior written permission of the Sponsor.  The foregoing shall not apply to disclosure 
required by any regulations; however, you will give prompt notice to the Sponsor of any such disclosure. 


Protocol No. AKB-9778-CI-5001 
 
18September2017 
Amendment #5 Integrated 
 
 
 
 
Aerpio — Company Confidential 
Page 2 of 72 
 
1 STUDY CONTACTS 
 
For study related and administrative questions, please contact: 
Laura Gambino, BS 
Director, Project Management 
Aerpio Therapeutics LLC 
9987 Carver Road, Suite 420 
Cincinnati, OH  45242 
Mobile Telephone:  (513) 253-9411 
Email:  lgambino@aerpio.com 
 
For clinical and subject related issues or questions, please contact: 
Barbara Withers, PhD 
Senior Director, Clinical Operations 
Aerpio Therapeutics LLC 
9987 Carver Road, Suite 420 
Cincinnati, OH  45242 
Mobile Telephone:  (513) 256-3592 
Email:  bwithers@aerpio.com 
 
Steve Pakola, MD 
Chief Medical Officer  
Aerpio Therapeutics LLC 
9987 Carver Road, Suite 420 
Cincinnati, OH  45242 
Mobile Telephone:  (914) 309-3406 
Email:  spakola@aerpio.com  
 
Mitchell Brigell, PhD 
Vice President, Clinical Development 
Aerpio Therapeutics LLC 
9987 Carver Road, Suite 420 
Cincinnati, OH  45242 
Mobile Telephone:  (513) 432-7790 
Email:  mbrigell@aerpio.com  
 
 
 
 


Protocol No. AKB-9778-CI-5001 
Amendment #5 Integrated 
1.1 Protocol Approval 
itchell Brigell, hD 
Date 
Vice President, Clinical Development 
Aerpio Therapeutics LLC 
~{J!1vt 
Barbara Withers, PhD 
Senior Director, Clinical Operations 
Aerpio Therapeutics LLC 
Steve 
ola, MD 
Chief Medical Officer 
Aerpio Ther euti 
LLC 
Aerpio -
Company Confidential 
Page 3 of72 
I 8 September20 I 7 
Date 


Protocol No. AKB-9778-CI-5001 
 
18September2017 
Amendment #5 Integrated 
 
 
 
 
Aerpio — Company Confidential 
Page 4 of 72 
 
1.2 Investigator Agreement 
I confirm that I have read and that I understand this protocol, the Investigator Brochure, and other 
product information provided by the Sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also protect the rights, safety, privacy, and well-being of study 
subjects in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Conference on Harmonization Guidance for Industry, Good Clinical Practice 
E6. 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• 
Regulatory requirements for reporting serious adverse events defined in this protocol. 
• 
Terms outlined in the Clinical Trial Agreement. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Name of Facility 
Location of Facility (City, State) 
 
 


Protocol No. AKB-9778-CI-5001 
 
18September2017 
Amendment #5 Integrated 
 
 
 
 
Aerpio — Company Confidential 
Page 5 of 72 
 
TABLE OF CONTENTS   
1 
STUDY CONTACTS ................................................................................................... 2 
1.1 
Protocol Approval .................................................................................................... 3 
1.2 
Investigator Agreement ............................................................................................ 4 
2 
PROTOCOL SUMMARY ............................................................................................ 9 
3 
LIST OF ABBREVIATIONS ..................................................................................... 13 
4 
BACKGROUND INFORMATION ........................................................................... 16 
4.1 
Rationale ................................................................................................................. 17 
4.2 
Summary of Nonclinical Experience ..................................................................... 18 
4.3 
Summary of AKB-9778 Clinical Experience ......................................................... 20 
4.4 
Potential Benefits and Risks ................................................................................... 22 
4.4.1 
Potential Benefits and Risks of AKB-9778 ....................................................... 22 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 24 
5.1 
Primary Objective .................................................................................................. 24 
5.2 
Secondary Objective .............................................................................................. 24 
5.3 
Exploratory Objectives ........................................................................................... 24 
5.4 
Exploratory Efficacy Sub-Study Objectives (To be conducted at a subset of sites)24 
5.5 
Primary Efficacy Endpoints ................................................................................... 25 
5.6 
Secondary Efficacy Endpoints ............................................................................... 25 
5.6.1 
Exploratory Efficacy Endpoints: ....................................................................... 25 
5.6.2 
Exploratory Efficacy Sub-Study Endpoints ...................................................... 25 
5.6.3 
Safety Endpoints: ............................................................................................... 25 
6 
STUDY DESIGN ........................................................................................................ 26 
6.1 
Study Design .......................................................................................................... 26 
6.2 
Rationale for Study Design .................................................................................... 28 
6.3 
AKB-9778 Dose Justification ................................................................................ 28 
6.4 
Oversight of Safety ................................................................................................. 28 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 28 
7.1 
General Criteria ...................................................................................................... 28 
7.2 
Subject Eligibility Criteria ..................................................................................... 29 
7.2.1 
Subject-Level Inclusion Criteria ........................................................................ 29 
7.2.2 
Subject-Level Exclusion Criteria: ..................................................................... 29 
7.3 
Ocular Eligibility Criteria ....................................................................................... 31 
7.3.1 
Study Eye / Qualified Fellow Eye Inclusion Criteria: ....................................... 31 
7.3.2 
Study Eye /Qualified Fellow Eye Exclusion Criteria ........................................ 31 
7.4 
Waivers ................................................................................................................... 32 
7.5 
Replacement of Subjects ........................................................................................ 32 


Protocol No. AKB-9778-CI-5001 
 
18September2017 
Amendment #5 Integrated 
 
 
 
 
Aerpio — Company Confidential 
Page 6 of 72 
 
7.6 
Discontinuation of Study Medication/Withdrawal of Subjects .............................. 32 
8 
STUDY PRODUCT AND TREATMENT OF SUBJECTS ....................................... 33 
8.1 
Study Medication, Supplies and Storage ................................................................ 33 
8.1.1 
Storage and Handling of Study Medication ...................................................... 34 
8.2 
Dispensing Procedures ........................................................................................... 34 
8.3 
Treatment of Subjects ............................................................................................. 34 
8.3.1 
Treatment Group Assignments .......................................................................... 34 
8.3.2 
Randomization and Allocation to Treatment Group ......................................... 34 
8.3.3 
Masking in the Study ......................................................................................... 35 
8.3.4 
Unmasking ......................................................................................................... 35 
8.3.5 
Study Drug Administration ............................................................................... 35 
8.4 
Prior and Concomitant Therapy ............................................................................. 36 
8.4.1 
General .............................................................................................................. 36 
8.4.2 
Investigational Medications ............................................................................... 36 
8.4.3 
Treatment of PDR or DME ............................................................................... 37 
8.5 
Product Accountability and Destruction ................................................................ 37 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 38 
9.1 
Administrative Procedures ..................................................................................... 39 
9.1.1 
Informed Consent Procedure ............................................................................. 39 
9.1.2 
Documentation of Screen Failures .................................................................... 39 
9.1.3 
Contraception and Pregnancy Avoidance Measures ......................................... 39 
9.1.4 
Diet, Fluid and Activity Control ........................................................................ 40 
9.1.5 
Laboratory Accreditation and Reference Ranges .............................................. 40 
9.2 
Study Procedures and Evaluations ......................................................................... 40 
9.2.1 
Clinical Evaluations ........................................................................................... 41 
9.2.2 
Laboratory Evaluations: .................................................................................... 43 
9.3 
Schedule of Activities ............................................................................................ 45 
9.3.1 
Visit Windows ................................................................................................... 46 
9.3.2 
Activities to be conducted at the Study Site ...................................................... 46 
9.3.3 
Activities to be conducted at the Homecare nurse visit .................................... 53 
10 
ADVERSE EVENTS .................................................................................................. 54 
10.1 
Definitions .............................................................................................................. 54 
10.1.1 
Adverse Events (AEs) ....................................................................................... 54 
10.1.2 
Serious Adverse Events (SAEs) ........................................................................ 55 
10.1.3 
Severity .............................................................................................................. 56 
10.2 
Eliciting Adverse Event Information ..................................................................... 56 
10.3 
Reporting ................................................................................................................ 56 


Protocol No. AKB-9778-CI-5001 
 
18September2017 
Amendment #5 Integrated 
 
 
 
 
Aerpio — Company Confidential 
Page 7 of 72 
 
10.3.1 
Reporting Period ................................................................................................ 56 
10.3.2 
Reporting AEs ................................................................................................... 56 
10.3.3 
Reporting SAEs ................................................................................................. 57 
10.3.4 
Relationship to Study Medication ..................................................................... 57 
10.3.5 
Follow-Up of Unresolved Events ...................................................................... 58 
10.4 
Exposure In Utero .................................................................................................. 58 
11 
DATA ANALYSIS ..................................................................................................... 59 
11.1 
Sample Size Determination .................................................................................... 59 
11.2 
Study Populations ................................................................................................... 59 
11.2.1 
Safety Populations ............................................................................................. 59 
11.2.2 
Efficacy Populations .......................................................................................... 59 
11.3 
Analysis of Demographics and Baseline Variables ............................................... 59 
11.4 
Disposition of Subjects ........................................................................................... 60 
11.5 
Study Days and Assessment Windows .................................................................. 60 
11.6 
Safety Analysis ....................................................................................................... 60 
11.7 
Efficacy Analyses ................................................................................................... 60 
11.8 
Pharmacokinetic Analyses ..................................................................................... 61 
11.9 
Pharmacodynamic Analyses .................................................................................. 61 
11.10 
Exploratory Genetic Analyses ................................................................................ 61 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 61 
12.1 
Case Report Forms (CRFs) .................................................................................... 61 
12.2 
Record Retention .................................................................................................... 62 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ....................... 62 
13.1 
Study Site Monitoring Visits .................................................................................. 62 
13.2 
Protocol Deviations ................................................................................................ 63 
14 
TRIAL DISCONTINUATION/INVESTIGATIVE SITE TERMINATION ............. 63 
14.1 
Criteria for Premature Termination or Suspension of the Study ............................ 63 
14.2 
Criteria for Premature Termination or Suspension of Investigational Sites .......... 63 
14.3 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Site(s) ............................................................................................. 63 
15 
ETHICS ....................................................................................................................... 64 
15.1 
Ethical Conduct of the Study ................................................................................. 64 
15.2 
Institutional Review Board (IRB) .......................................................................... 64 
15.3 
Subject Information and Consent ........................................................................... 64 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 64 
15.5 
Subject Confidentiality ........................................................................................... 65 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 65 
17 
REFERENCES ............................................................................................................ 66 


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18 
APPENDICES ............................................................................................................ 68 
18.1 
Appendix A: Schedule of Activities ....................................................................... 68 
18.2 
Appendix B: Criteria for Treatment of PDR or DME in the Study Eye or Qualified 
Fellow Eye During the Study ................................................................................. 71 
 
 
 
 


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2 PROTOCOL SUMMARY  
Protocol Number:  AKB-9778-CI-5001   
Protocol Title: Phase 2 Double-masked, Placebo-Controlled Study To Assess The Safety And Efficacy Of 
Subcutaneously Administered AKB-9778 15mg Once Daily Or 15mg Twice Daily For 12 Months In Patients With 
Moderate To Severe Non-Proliferative Diabetic Retinopathy 
 
 
Study 
Objectives: 
Primary Objective:   
1. To assess the effects of AKB-9778 15mg once daily or 15mg twice daily for 12 months 
on severity of diabetic retinopathy in subjects with moderate to severe non-proliferative 
diabetic retinopathy (NPDR)  
Secondary Objective: 
1. To assess the safety and tolerability of AKB-9778 15mg once daily or 15mg twice daily 
for 12 months in subjects with moderate to severe NPDR  
2. To determine the AKB-9778 systemic exposure based on sparse PK sampling in subjects 
with NPDR 
 
Exploratory Objectives: 
1. To explore the potential benefit of AKB-9778 on renal function in subjects with NPDR 
2. To explore the relationship between AKB-9778 systemic exposure and efficacy and 
safety in subjects with NPDR 
 
Exploratory Efficacy Sub Study Objectives (To be conducted at a subset of sites) 
1. To explore the effects of AKB-9778 on optical coherence tomography angiography 
(OCT-A) in subjects with NPDR 
2. To explore the effects of AKB-9778 on retinal function as measured by 
electroretinogram (ERG) assessment in subjects with NPDR 
3. To explore the effects of AKB-9778 on peripheral retinal abnormalities using ultra-wide 
field (UWF) fundus photography and UWF fluorescein angiography 
 
Study 
Endpoints: 
Primary Efficacy Endpoint 
1. Percentage of subjects with an improvement in study eye severity of diabetic retinopathy 
(DR) (Early Treatment Diabetic Retinopathy Study (ETDRS) DR Severity Score or 
DRSS) of ≥ 2 steps at Month 12 
Secondary Efficacy Endpoints  
1. Mean change from baseline in DRSS in the study eye at Month 12  
2. Patient level (binocular) change from baseline in DRSS (according to methods of Klein 
et al, 2001) at Month 12  
3. Proportion of subjects with a worsening in the study eye DRSS of ≥ 2 steps at Month 12  
4. Proportion of subjects with an improvement or worsening in the study eye DRSS of ≥ 3 
steps at Month 12  
5. Proportion of patients developing center-involved DME or PDR or PDR-related 
outcomes during study  
6. Primary and secondary endpoints (1 through 4) assessed at Months 3, 6 and 9 
7. Primary and secondary assessments in all fellow eyes, fellow eyes that meet all 
eligibility criteria (qualified fellow eyes), and either eyes (i.e. best response)  


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Exploratory Efficacy Endpoints: 
1. Change from baseline in urine-albumin-to-creatinine ratio (UACR) and estimated 
glomerular filtration rate (eGFR) at Month 12 
Exploratory Efficacy Sub-Study Endpoints:  
1. Mean change from baseline in ERG parameters at Month 12 
2. Mean change from baseline in indices of macular perfusion, as measured by OCT-A, at 
Month 12 
3. Mean change from baseline in area of peripheral non-perfusion, peripheral leakage, and 
peripheral retinopathy using UWF imaging, at Month 12 
Safety Endpoints:   
1. Incidence and severity of systemic and ocular adverse events (AEs) 
2. Change from baseline in body system assessments 
3. Change from baseline in vital sign measurements 
4. Change from baseline in ECG parameters 
5. Change from baseline in clinical laboratory assay results (blood chemistry, hematology, 
fecal occult blood and urinalysis)  
6. Change from baseline in intraocular pressure (IOP) 
7. Change from baseline in slit lamp examination parameters 
8. Change from baseline in dilated funduscopic examination parameters 
9. Change from baseline in fluorescein angiogram (FA) parameters 
10. Mean change from baseline in ETDRS Best Corrected Visual Acuity (BCVA) letter 
score in the study eye at Month 12  
11. Proportion of subjects with a decrease of ≥15 letters in ETDRS BCVA at Month 12 
(compared to baseline)  
 
Study 
Population: 
Subjects with moderate to severe NPDR (ETDRS Level 43 – 53 inclusive), 18 through 80 
years of age (inclusive), no evidence of central involved DME and ETDRS BCVA letter 
score ≥ 70 (Snellen 20/40 or better).  
Study Design: 
Phase 2 randomized, double-masked, placebo controlled, multi-center study, to evaluate the 
safety and efficacy of 12 months of subcutaneous AKB-9778 administered either 15 mg QD 
or 15 mg BID in subjects with moderate to severe NPDR. Pharmacokinetic assessments are 
included as an exploratory endpoint. Exploratory efficacy assessments (OCT-A, UWF 
imaging and non-invasive ERG) will also be included at a subset of sites.  Blood samples will 
be retained for biomarker and genetic analysis.    
General 
Statistical 
Methods and 
Types of 
Analyses: 
Analysis Populations 
Safety Population 
The safety population will include all enrolled subjects who receive at least one dose of study 
medication. All safety analyses will be conducted using the safety population. 
Modified Intent-to-Treat Population 
The modified intent-to-treat (MITT) population will include all enrolled subjects who receive 
at least one dose of study medication. The primary efficacy analysis will be conducted using 
the MITT population. 
 
Per Protocol Population 


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The per protocol (PP) population will consist of all subjects in the MITT population who do 
not have major protocol deviations considered to affect the primary efficacy variable DRSS, 
have completed a minimum of 12 months of treatment and have been at least 70% compliant. 
Sensitivity analyses of the primary efficacy variables will be conducted using the PP 
population. 
Sample Size 
Estimates for sample size calculations are derived from published data from the analysis of 
the effect of ranibizumab (Lucentis®) and aflibercept (Eylea®) intravitreal administration 
regimens on DR severity score in the RISE/RIDE studies and VIVID/VISTA studies, 
respectively, in which 28-46% of subjects improved by ≥ 2 steps after 12 months of 
treatment.    
With 45 evaluable subjects per treatment group, the study has > 85% power (based on 
Fisher’s Exact Test and a 2-sided alpha =0.05) to demonstrate a statistically significant 
improvement in proportion of subjects improving by ≥ 2 steps on the ETDRS severity scale, 
assuming underlying rates for active and placebo of 30% and 5%, respectively. Assuming 
10% drop-out/non-evaluable rate, a sample size of 50 subjects per treatment arm 
(approximately 150 total) has been selected.  
Efficacy Analyses 
All efficacy data will be summarized by treatment group and time point using appropriate 
descriptive statistics. Summaries will be presented for both the MITT and PP populations.  
The primary hypotheses to be tested is that AKB-9778 15mg twice daily and AKB-9778 
15mg once daily will be superior to placebo in the improvement of DR as measured by the 
ETDRS severity scale change from baseline at 12 months.  The primary hypotheses will be 
tested in the MITT population using a Fisher’s Exact Test with a 2-sided 5% significance 
level. To adjust for multiplicity, a pre-specified testing order will be used. AKB-9778 15mg 
twice daily will be tested first, and AKB-9778 15mg once daily will be tested second.  
Secondary and exploratory endpoints will be analyzed without adjustment for multiplicity.  
Continuous variables will be analyzed using ANCOVA models and dichotomous variables 
will be analyzed using the same approach as outlined for the primary endpoint.  Additional 
exploratory analyses will be conducted to understand the relationship between exposure and 
response. 
Interim Safety Analyses 
On an ongoing basis throughout the conduct of the study, multiple layers of planned safety 
monitoring will be conducted. These include weekly masked reviews by the Aerpio Medical 
Monitor, monthly masked reviews by the Aerpio Clinical Safety Review Team (CSRT), and 
quarterly masked reviews by the Safety Assessment Committee These reviews are detailed in 
a separate document (AKB-9778 Safety Surveillance Plan). 
Study 
Medication:  
Subcutaneous treatments: 
• 
15 mg AKB-9778 (in 100 mg/mL Hydroxypropyl-Beta-Cyclodextrin [HPβCD]) 
subcutaneous injection: To be provided as sterile pre-filled ready-to-inject syringes  
• 
Placebo (Phosphate-Buffered Saline) subcutaneous injection: To be provided as 
sterile pre-filled ready-to-inject syringes  
Duration of 
Treatment: 
48 weeks  
Duration of 
Participation: 
Screening period: up to 4 weeks; Baseline and Treatment period: 48 weeks; Post-treatment 
Follow-up period: 4 weeks. The Screening, Baseline, Treatment, and Follow-up periods will 
require subject participation for approximately 56 weeks. 
Number of 
Subjects: 
Approximately 150 subjects (50 per treatment group) 


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Number of 
Study 
Centers: 
Approximately 50 sites  
Volume of 
Blood Drawn: 
Hematology (8 X 4 mL) 
Chemistry (14 X 3.5 mL) 
Serum Pregnancy (1 X 2.5 mL) 
Pharmacokinetic Samples (4 X 6 mL) 
Exploratory Biomarker (2 X 3 mL) 
Genetic Sample (1 X 8.5 mL) 
Total volume blood drawn for entire study: Approximately 134 mL per subject.   
 
 


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3 LIST OF ABBREVIATIONS 
 
ADA 
American Diabetes Association 
AE 
Adverse event 
ALT 
Alanine transaminase (SGPT) 
Ang1 
Angiopoietin 1 
Ang2 
Angiopoietin 2 
AST 
Aspartate transaminase (SGOT) 
AUC 
Area under the curve  
BA 
Benzyl alcohol 
BCVA 
Best corrected visual acuity 
BID 
Twice daily  
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
Cmax 
Maximum plasma drug concentration  
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CSRT 
Clinical Safety Review Team 
CST 
Central Subfield Thickness 
CYP 
Cytochrome 
CV 
Cardiovascular 
dL 
deciliter 
DME 
Diabetic macular edema 
DR 
Diabetic retinopathy 
DRSS 
Diabetic retinopathy severity score 
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ENT 
Ears, nose and throat 
eNOS 
Endothelial nitric oxide synthase 
EOT 
End of treatment 
ERG 
Electroretinogram 
FA 
Fluorescein angiograms 
FDA 
Food and Drug Administration 
FOBT 
Fecal Occult Blood Test 
g 
gram 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
HbA1C 
Hemoglobin A1c 
HEENT 
Head, ears, eyes, nose and throat 
Hgb 
Hemoglobin 
HPβCD 
Hydroxypropyl Beta Cyclodextrin 
HPTPβ 
Human Protein Tyrosine Phosphatase β 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation  


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IND 
Investigational New Drug 
IOP 
Intra-ocular pressure 
IRB 
Institutional Review Board 
IRMA 
Intra-retinal microvascular abnormalities 
IVT 
Intravitreal 
IWRS  
Interactive web response system 
kg 
kilogram 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LFTs 
Liver function tests 
MAD 
Multiple-ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular (cell) volume 
MedDRA 
Medical Dictionary for Regulatory Activities  
µL 
microliter 
µm 
micrometer 
mg 
milligram 
mL 
milliliter 
ms 
millisecond 
MITT 
Modified intent-to-treat 
MTD 
Maximum tolerated dose 
MPV 
Mean platelet volume 
MDRD  
Modification of Diet in Renal Disease  
NF 
National Formulary 
NPDR 
Non-proliferative diabetic retinopathy 
NVE 
Neovascularization elsewhere 
OCT 
Optical coherence tomography 
OCT-A 
Optical coherence tomography angiography 
PBS 
Phosphate-Buffered-Saline 
PD 
Pharmacodynamic 
PDR 
Proliferative Diabetic Retinopathy 
PK 
Pharmacokinetic 
POC 
Proof of Concept 
PP 
Per protocol 
PRN 
as needed 
PRP 
Panretinal scatter photocoagulation 
QA 
Quality Assurance 
QC 
Quality Control 
QD 
Once daily 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
RVO 
Retinal vein occlusion 
SAC 
Safety Assessment Committee 
SAD 
Single ascending dose 
SAE 
Serious adverse event  
SC 
Subcutaneous 
SD 
Standard deviation 
SD OCT 
Spectral domain optical coherence tomography 
SDH 
Sorbitol dehydrogenase 


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SHR 
spontaneously hypertensive rats 
SSP 
Safety Surveillance Plan 
TEAE 
Treatment emergent adverse event 
TIBC 
Total Iron Binding Capacity 
Tie2 
Tyrosine kinase with immune globulin-like and EGF-like domains2 
Tmax 
Time to Cmax 
TSAT 
Trasnferrin Saturation 
t1/2 
Half-life 
UACR 
Urine-albumin-to-creatinine ratio 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
UWF 
Ultra-wide field 
VEGF 
Vascular endothelial growth factor 
VE-PTP  
Vascular endothelial-protein tyrosine phosphatase 
WHO 
World Health Organization 
WBC 
White blood cell 
WKY 
Wistar-Kyoto  
 


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4 BACKGROUND INFORMATION 
Diabetes is estimated to affect 8.3% of the adult population, 382 million people worldwide, and 
this number is expected to rise to 592 million people by 2035 (Guariguata et al., 2014). Diabetic 
retinopathy (DR) is a frequent complication of diabetes that may result in blindness. The 
incidence of DR increases with duration of diabetes. The prevalence of DR in the diabetic 
population is approximately 33%, with approximately 10% having vision threatening conditions 
of macular edema or proliferative retinopathy (Yau et al., 2012). By 20 years after disease 
diagnosis, nearly 100% of type 1 diabetics and 60% of type 2 diabetics develop DR (Fong et al., 
2004a,b). In the Wisconsin Epidemiologic Study of Retinopathy, the 25-year cumulative rate of 
retinopathy progression in Type 1 diabetics was 83%, with 43% of this population progressing to 
proliferative retinopathy (Klein et al., 2008) and 29% progressing to macular edema (Klein et al., 
2009). Based on these data, it is clear that diabetic retinopathy will increase as a public health 
problem, with both aging of the US population and increasing prevalence of diabetes over time. 
The severity of DR has been standardized using the Early Treatment Diabetic Retinopathy Study 
(ETDRS) grading of standard 7-field fundus photographs. There is extensive evidence to show 
that as DR severity increases, the likelihood of development of macular edema or high-risk 
proliferative diabetic retinopathy (PDR) increases (Davis et al., 1998; Klein et al., 2001). Thus, 
early detection and treatment of DR would dramatically reduce both visual disability associated 
with diabetes as well as the impact of this visual loss on health economics. 
In pivotal trials of intravitreal anti-VEGF (vascular endothelial growth factor) effects on diabetic 
macular edema (DME), it was observed that treatment also had beneficial effects on DR. After 1 
year of treatment with Eylea®, 33.5% of subjects treated monthly and 28.4% of subjects treated 
bi-monthly improved by ≥ 2 steps on the ETDRS severity scale, compared to 10.9% in the laser 
treatment group (Korobelnik et al., 2014).  Similarly, in the RISE and RIDE trials with 
Lucentis®, 46.9% of subjects treated with 0.3 mg monthly and 46.8% of subjects treated with 
0.5 mg monthly for 2 years had a ≥ 2 step improvement in DR, compared to 6.8% of subjects 
treated with sham injections (Ip et al., 2012). There was also a decrease in the percent of subjects 
who worsened by ≥ 2 steps after 2 years of treatment (2.5%, 2.0%, and 12.4% in the 0.3 mg 
Lucentis, 0.5 mg Lucentis, and sham groups, respectively). On the basis of these data, Lucentis 
and Eylea have been approved for the treatment of DR in patients with DME. However, the 
efficacy of anti-VEGF therapy for the treatment of DR in patients without center-involved DME 
is unproven. Two trials have recently been initiated to test the efficacy of Eylea in this 
population (the PANORAMA study - NCT02718326 sponsored by Regeneron; and Protocol W - 
NCT02634333 sponsored by DRCR.net). However, it is important to note that eyes with non-
proliferative diabetic retinopathy (NPDR) and no DME have little visual dysfunction and thus 
the burden of multiple binocular intravitreal anti-VEGF injections may be unacceptable in this 
population. The objective of the present study is to examine the efficacy of AKB-9778 
subcutaneous administration in the treatment of NPDR in patients without DME. 
AKB-9778 is a first-in-class molecule in development for the treatment of diabetic eye disease, 
including DME and DR. AKB-9778 is a small molecule Tie2 (tyrosine kinase with 
immunoglobulin-like and EGF-like domains 2) activator that works through inhibition of VE-
PTP (vascular endothelial-protein tyrosine phosphatase), otherwise known as HPTPβ (human 
protein tyrosine phosphatase β), enhancing Tie2 activation and signaling.  Tie2 is a receptor 


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tyrosine kinase that is expressed principally in vascular endothelial cells and serves as the 
receptor for the angiopoietin family of secreted polypeptides.  Over the last decade, the 
Tie2/angiopoietin pathway has been identified as a key modulator of endothelial function and 
vascular stability (Augustin et al., 2009; Milner et al., 2009; Brindle et al., 2006; Fiedler et al., 
2006; Peters et al., 2004).  Members of the angiopoietin family are ligands for Tie2; angiopoietin 
1 (Ang1) is an agonist and angiopoietin 2 (Ang2) functions as a context dependent antagonist.  
The bulk of evidence indicates that Ang1/Tie2 signaling promotes normal vascular integrity.  
Conversely, in settings where Ang2 is upregulated, as in patients with diabetic retinopathy, Tie2 
signaling is blunted and the vasculature is destabilized promoting vascular leak and enabling 
pathologic angiogenesis.   
VE-PTP is an endothelial tyrosine phosphatase that dephosphorylates Tie2, further reducing Tie2 
signaling.  Inhibition of VE-PTP with AKB-9778 overrides Ang2 and restores Tie2 signaling. 
Importantly, AKB-9778-mediated Tie2 activation results in activation of the PI3 
kinase/Akt/endothelial nitric oxide synthase (eNOS) pathway, a critical pathway in maintaining 
endothelial function and vascular integrity. Thus, AKB-9778 promotes vascular stability through 
enhanced Tie2 activation resulting in improved endothelial function, reduced vascular leak and 
inflammation, and resistance to pathologic angiogenesis.  
In multiple preclinical vascular disease models, vascular stabilizing effects of AKB-9778 
resulted in decreased vascular leak and/or suppression of pathologic neovascularization.  In 
models of retinopathy, AKB-9778 dramatically reduced VEGF-driven retinal edema and 
neovascularization and prevented retinal detachment (Shen et al., 2014).  The vascular stabilizing 
properties of AKB-9778 may be beneficial in the treatment and prevention of a broad range of 
retinal pathology including nonproliferative and proliferative diabetic retinopathy, diabetic 
macular edema, neovascular age-related macular degeneration, and retinal vein occlusion, for 
which current therapy is not optimal.  
4.1  Rationale 
Please see the AKB-9778 Investigator Brochure for additional discussion and information for 
the following section. 
AKB-9778 is a small molecule that inhibits VE-PTP. This inhibition selectively increases the 
phosphorylation of Tie2 and augments Ang-1 signaling pathways through Tie2 that lead to 
vascular stabilization and protection against vascular leak and pathologic angiogenesis.  
Two clinical studies in subjects with DME have been performed with AKB-9778, evaluating 
respectively 1 month and 3 months of treatment (Campochiaro et al., 2015, 2016). AKB-9778 
was well tolerated in these studies with no safety issues identified. The completed TIME-2 Proof 
of Concept study (Campochiaro, 2016) has shown that SC dosing of AKB-9778 15 mg twice 
daily (BID) may be of value in the treatment of DME when used in conjunction with Standard of 
Care anti-VEGF therapy and that AKB-9778 monotherapy may be effective in the treatment of 
NPDR. 
In the present study, the efficacy of AKB-9778 will be further evaluated in subjects with 
moderate to severe NPDR and no center-involved macular edema. 
 


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4.2 Summary of Nonclinical Experience 
Please see the AKB-9778 Investigator Brochure for additional discussion and information for 
the following section. 
A comprehensive nonclinical program has been conducted with AKB-9778 including evaluation 
in multiple retinopathy models, safety pharmacology studies, pharmacokinetic (PK) and 
metabolism studies, toxicology studies in rats, dogs, and monkeys, embryo-fetal development 
studies in rats and rabbits, and genotoxicity studies.  The nonclinical program conducted to date 
supports evaluation of the intended 15 mg QD and BID AKB-9778 hydroxypropyl-beta-
cyclodextrin (HPβCD) dose formulation regimens for a duration of 12 months in the current 
clinical study.  Please see the AKB-9778 Investigator Brochure for additional information.  
AKB-9778 has excellent SC bioavailability and demonstrates linear, dose-dependent increases in 
exposure following SC administration in rats, dogs and monkeys.  
In the Good Laboratory Practices (GLP) nonclinical safety studies, AKB-9778 formulated as a 
solution in 10% HPβCD demonstrated an excellent safety profile and was well tolerated by SC 
administration in rats, dogs, and monkeys. The primary target tissues for AKB-9778 were 
identified as injection sites and liver in rat, dog and monkey; skin/subcutis (vascular) in dog and 
monkey; and gastrointestinal (GI; vascular) in dog.  
In the 6-month rat study elevations in AST and ALT were correlated with microscopic 
observations of scattered, individual, minimally necrotic hepatocytes. Similar findings were 
observed in the shorter duration (28- and 91-day) rat studies. In dogs, adverse liver findings have 
only been observed in the 28-day toxicity study, at the high dose, and included one incidence of 
mild randomly distributed foci of mild necrosis, associated with centrilobular vacuolation; non-
adverse findings included hepatocellular degeneration also associated with centrilobular 
vacuolation, and one incidence of mild, randomly distributed microgranulomas in the liver. 
In the dog 9-month study, reversible, non-adverse and minimal panlobular hypertrophy of the 
liver was observed in all dose groups without any associated changes in liver transaminases. In 
the 28-day monkey study there was no test article-related mortality and no definitive test article-
related mortality in the 273-day monkey study. In the 273-day study, one of the 16 monkeys at 
22.5 mg/kg (33-fold the clinical exposure at 15 mg BID) was sacrificed on Day 109 with 
cholestatic liver injury and associated anemia which developed over a minimum of several 
weeks. The initial inciting event leading to early termination was not clear based on full 
evaluation of all available data and the relationship to test article is uncertain. The different 
characteristics of the liver responses in rat, dog, and monkey suggest different processes and/or 
pathogenesis for the liver effects in each species. For guidance on assessment and monitoring of 
potential liver findings refer to the Investigator’s Brochure.  
In rat, dog, and monkey, injection sites had findings related to the subcutaneous injection 
procedure (repeated injection of a limited number of injection sites on animals) with 
exacerbation by the presence of AKB-9778.  SC injections of AKB-9778 as a solution in these 
nonclinical studies were generally well tolerated by rats, dogs and monkeys with only sporadic 
or transient observation of injection site redness, thickening, or scabbing. These findings were 
correlated histopathologically with focal SC hemorrhage, inflammation, fibrosis, and necrosis 
that were observed to largely recover. In early clinical trials with the AKB-9778 HPβCD 


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formulation, few adverse effects at the injection site were reported for injection volumes of less 
than 1 mL and mild to moderate transient pain was reported for injection volumes of 1 mL or 
greater. 
In the 9-month dog toxicity study, broadly distributed dermal-localized nodules were observed 
on all dogs at 15 and 30 mg/kg/day and one nodule was observed on one male dog at 6 
mg/kg/day. The majority of nodules were identified microscopically as focal angiectasis, 
characterized as ectatic, blood-filled vessels with varying degrees of thrombosis that was 
occasionally associated with papillary endothelial hyperplasia; and one nodule in a high dose dog 
identified as benign hemangioma. The nodules ranged in size between 1 and 50 mm in diameter 
and appeared to slowly enlarge or remain static in size. The majority of nodules were persistent, 
but a few nodules were self-limiting while AKB-9778 dosing continued. The dermal nodules 
were observed to rapidly resolve upon drug withdrawal. In addition, largely GI tract-localized 
minimal to mild angiectasis was observed by microscopic examination at all dose levels in dog 
(at exposures 6- to 24-fold the human exposure at 15 mg BID) and not present in the vehicle 
control group. The vascular findings were not associated with any clinical observations, serum 
chemistry, or other microscopic changes. In the rat 6-month study, minimal focal angiectasis was 
observed by microscopic examination in the uterus with cervix of one high-dose rat (at higher 
AUC exposure than exposures assessed in dog) and was considered incidental.  There were no 
skin nodules or GI-related findings in rat. In the 9-month monkey study, a solitary dermal nodule 
on the tail of one high dose animal was characterized as angiectasis with resolving thrombosis, 
and associated with AUC exposure higher than exposures assessed in dog. There were no GI-
related findings in monkey. These observations suggest an increased sensitivity of the dog to 
vascular effects of AKB-9778. No unusual or unexpected dermal findings have been observed in 
clinical studies with AKB-9778. For guidance on assessment and monitoring of potential 
vascular effects refer to the Investigator’s Brochure. 
A consistent finding in both rat and dog was a non-adverse decrease in blood pressure. In 
normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), blood 
pressure was decreased (the decrease in systolic pressure was greater than the decrease in 
diastolic pressure [systolic > diastolic]) with a compensatory increase in heart rate. Similarly, in 
the dog cardiovascular (CV) study, blood pressure was decreased (systolic > diastolic) with a 
compensatory increase in heart rate. Changes in blood pressure in both species were transient (4-
6 hours), correlated with the drug plasma profile, and appeared to plateau with increasing dose, 
consistent with a pharmacological effect. As mentioned previously, activation of Tie2 results in 
endothelial nitric oxide synthase (eNOS) activation, which generates the potent vasodilator, 
nitric oxide (NO). AKB-9778 activates Tie2 and eNOS in cultured vascular endothelial cells, 
which supports a pharmacologic basis for vasodilation and decreased blood pressure.  
Another consistent finding in dog was a non-adverse increase in cholesterol and triglycerides 
without microscopic correlate. These changes resolved during the recovery period and were not 
associated with microscopic changes. In early clinical trials with AKB-9778, no clinically 
meaningful changes in clinical chemistry (including total cholesterol and triglycerides) have 
been observed.  


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4.3 Summary of AKB-9778 Clinical Experience 
Please see the AKB-9778 Investigator Brochure for additional discussion and information for 
the following section. 
To date, AKB-9778 has been evaluated in six completed early phase studies: a Phase 1a single 
ascending dose (SAD) study (AKB-9778-CI-2001) in healthy male volunteers, a Phase 1 
pharmacokinetic-pharmacodynamic crossover single dose study of an extended release 
suspension formulation (AKB-9778-CI-3001), a 1-month Phase 1b multiple ascending dose 
(MAD) study in subjects with DME (AKB-9778-CI-2002), a 3-month Phase 2a POC study in 
subjects with DME (AKB-9778-CI-2003), a Phase 1 pharmacokinetic-pharmacodynamic 
crossover single dose study evaluating extended release solution and suspension formulations 
(AKB-9778-CI-3002); and a Phase 1 repeat-dose, PK/tolerability study evaluating extended 
release solution formulations (AKB-9778-CI-3003). AKB-9778 is also being evaluated in two 
ongoing studies: a single-center, 3-month Phase 2a POC study in subjects with retinal vein 
occlusion (RVO) (AKB-9778-CI-4001) and a Phase 1 ADME study (AKB-9778-CI-3004).  
The initial Phase 1a study, (Study AKB-9778-CI-2001) was a double-masked, placebo 
controlled, SAD study conducted to assess the safety, tolerability, pharmacokinetics and 
pharmacodynamics of 6 single ascending subcutaneous doses of AKB-9778 including one 
administered as a divided dose in healthy male volunteers. Six cohorts of eight subjects each 
were randomized to receive either AKB-9778 or placebo (6:2). AKB-9778 doses evaluated over 
a single day of dosing were 5, 10.5, 20, 40, or 80 mg administered as a single dose, or 120 mg 
[(administered as 2 doses, 60 mg each, separated by 12 hours (i.e. 60 mg BID)]. Exposure 
following single ascending doses of AKB-9778 was dose proportional with no evidence of 
accumulation when administered as 2 doses separated by 12 hours (60 mg BID). Absorption and 
elimination were rapid (Tmax ~ 15-30 minutes and T1/2 ~ 1-2 hours). Single doses of AKB-9778 
through 40 mg were generally well tolerated. At doses of 60, 80, and 120 mg (60 mg BID), an 
increase in the type and frequency of systemic AEs consistent with the exaggerated vasodilatory 
pharmacology of AKB-9778 was observed. These events were transient and generally resolved 
within 2-8 hours post-dose. At doses ≥ 60 mg, orthostatic symptomology observed during a 
3-5 minute standing blood pressure (BP) assessment improved upon return of subjects to supine 
position, and resolved by 1-3 hours post-dose without treatment other than oral fluids. There 
were no severe or serious adverse events (SAEs) and no clinically significant changes or trends 
in safety laboratory tests, electrocardiogram (ECG) parameters, vital signs (except orthostatic 
BP), or physical exams in AKB-9778 or placebo treated subjects. 
Study AKB-9778-CI-2002, a Phase 1b, open-label, MAD cohort study, was conducted to assess 
the safety, tolerability, pilot efficacy, PK and pharmacodynamic (PD) effects of 28-day repeat 
subcutaneous doses of AKB-9778 in subjects with DME. Four dose cohorts were administered 5, 
15, 22.5 and 30 mg AKB-9778 BID, respectively. Twenty-six subjects in total were enrolled. 
Consistent with plasma exposure profiles in the healthy volunteer study, exposure in DME 
subjects increased with increasing dose levels of AKB-9778 with no evidence of significant 
accumulation. Absorption and elimination were rapid with an elimination half-life of 
approximately 1 hour. All AKB-9778 doses were generally well tolerated. There were no SAEs. 
Adverse events, consistent with the exaggerated vasodilatory pharmacology of AKB-9778, 
emerged at AKB-9778 doses of 22.5 and 30 mg BID and included dizziness, headache, and 
presyncope/syncope. These events were transient, usually occurred within the first hour after 


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dosing, and generally resolved within 5 minutes to one hour after onset. There were no clinically 
meaningful abnormalities or changes from baseline in safety laboratory tests (chemistry, 
hematology, and urinalysis), ECG parameters, vital signs or physical exams. In the 22.5 and 
30 mg BID dose groups, consistent modest decreases in resting systolic BP (with corresponding 
modest increases in heart rate (HR)) were observed following dosing (30 mg >22.5 mg). These 
effects were largely asymptomatic and transient, and the timing of the effects correlated with the 
rapid AKB-9778 absorption and elimination plasma concentration-time curve. Pilot efficacy 
evaluations, including assessments of retinal thickness and visual acuity, suggest that AKB-9778 
exhibited biologic activity. 
AKB-9778-CI-2003 was a Phase 2 proof of concept (POC) study which further explored the 
efficacy of AKB-9778 in DME when administered for 3 months. In this trial, AKB-9778 was 
evaluated as monotherapy (subcutaneous administration of 15 mg BID), and in combination with 
ranibizumab intravitreal (IVT) injection. A ranibizumab active control group was also evaluated. 
AKB-9778 was well tolerated in subjects when administered BID either as monotherapy or as 
combination therapy with monthly ranibizumab IVT injection. There were no meaningful 
imbalances among treatment groups in either ocular or non-ocular treatment emergent adverse 
events (TEAEs), and no deaths or treatment-related SAEs were reported. Transient effects on 
baseline BP and HR following Day 1 dosing were observed, but the effects were not of clinical 
concern, and after 3 months (end of treatment), there were no differences in BP and HR between 
treatment groups. Hematology and blood chemistry did not yield clinically meaningful results for 
any treatment group, and clinically significant changes in physical examination, slit-lamp 
biomicroscopy parameters, intraocular pressure evaluations, and indirect dilated ophthalmoscopy 
evaluations were few and distributed similarly among treatment groups. When used in 
combination with ranibizumab, AKB-9778 demonstrated a statistically significant improvement 
in the reduction of central subfield thickness (CST) that also was statistically significantly 
greater than the improvement seen in the use of ranibizumab alone. Analysis of diabetic 
retinopathy severity score (DRSS) showed evidence that AKB-9778 monotherapy increased the 
percent of eyes that gain 2 or more steps in DRSS compared to placebo and had an effect on 
DRSS similar to ranibizumab (Campochiaro et al., 2016). 
The previously described studies utilized an AKB-9778 formulation prepared using HPβCD as a 
solubilizing agent. A recently completed Phase 1 SAD study, AKB-9778-CI-3002, evaluated the 
safety, tolerability and bioavailability of an AKB-9778 solution formulation utilizing 1.5% 
benzyl alcohol (BA) as a solubilizing agent relative to AKB-9778 in 12.5% HPβCD.   
Study AKB-9778-CI-3002, conducted in healthy subjects, evaluated the single-dose PK, 
hemodynamic effects (BP and HR), and the safety and tolerability of two dose levels (15 and 30 
mg) of AKB-9778 containing 1.5% BA relative to 15 mg AKB-9778 containing 12.5% HPβCD. 
All formulations and doses evaluated in the study were safe and well tolerated. Similar to the 
results of the previous clinical studies, all formulations and doses of AKB-9778 demonstrated a 
small, transient reduction in BP and increase in HR within first hour after dosing.  
Study AKB-9778-CI-3003, conducted in healthy subjects, evaluated 7-day BID subcutaneous 
administration of three different formulations of AKB-9778. In this study a 1.5% BA 
formulation was used to test 15 mg and 30 mg doses of AKB-9778, a 3.0% BA formulation was 
used to test 30 mg, 45 mg, and 60 mg AB-9778 doses, and a 12.5% HPβCD formulation was 
used to test 15 mg AKB-9778. Placebo injections of 1.5% BA and 3.0% BA were also tested. All 


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doses were given subcutaneously BID for 7 days (volume 0.75 ml). The trial was randomized 
and double-masked.  The 15 mg AKB-9778 in 12.5% HPβCD formulation was well tolerated 
both systemically and locally.  The AKB-9778 in BA formulations, while being well tolerated 
systemically, demonstrated injection site reactions (mild to moderate in intensity) in at least 2 
subjects in each of the treatment arms.  Injection site reactions were also observed in the 3% BA 
vehicle arm.  Therefore, the current study will evaluate the AKB-9778 in an HPβCD 
formulation. 
The totality of the nonclinical and clinical data support continued clinical development of 
AKB-9778 as a treatment for DR.  The current clinical study, AKB-9778-CI-5001, is a Phase 2 
study which will explore the safety and efficacy of 15 mg AKB-9778 in the treatment of subjects 
with moderate to severe NPDR in the absence of center-involved DME when administered QD 
or BID for 12 months (48 weeks).      
4.4 Potential Benefits and Risks 
4.4.1  Potential Benefits and Risks of AKB-9778 
Please see the AKB-9778 Investigator Brochure for additional discussion and information for 
the following section. 
Collectively, the nonclinical pharmacology data in diverse models is consistent with the 
proposed mechanism whereby AKB-9778 inhibits VE-PTP resulting in Tie2 activation and 
improves endothelial function and vascular stabilization, supporting the potential efficacy of VE-
PTP inhibition with AKB-9778 in a broad range of retinal pathology. The completed clinical 
Phase 2a study in subjects with DME shows that Tie-2 activation via AKB-9778 enhances 
treatment of macular edema when combined with an anti-VEGF inhibitor and has evidence of 
efficacy as monotherapy in the treatment of NPDR.  
The safety of VE-PTP inhibition with AKB-9778 has been explored in nonclinical safety studies, 
in multiple nonclinical pharmacology studies and in seven clinical studies.   
Clinically, AKB-9778 has shown no evidence of significant safety issues to date. A transient, 
generally asymptomatic reduction in blood pressure is observed reflecting the vasodilatory 
pharmacodynamic effect of Tie-2 activation. At doses above the 15 mg dose used in the Phase 1b 
AKB-9778-CI-2002 study, vasovagal events (presyncope/syncope) have been observed 
following the first dose of AKB-9778. A vasovagal event was observed after the first dose in 
1/144 (0.7%) subjects in the Phase 2 AKB-9778-CI-2003 study. This subject did not experience 
any such events during the subsequent 3 months of dosing. No other vasovagal events were 
observed in this study. In both studies there was a significant correlation between baseline BP 
and change in BP. Specifically, subjects with higher BP had greater reductions in BP. 
Based on nonclinical studies and clinical studies conducted to date, identified risks include 
transient injection site reactions, hepatotoxicity, hemodynamic effects, hematologic and plasma 
lipid effects, and vascular effects.   
In the nonclinical rat studies, findings of reversible and acute, individual hepatocellular necrosis 
of minimal severity were observed that correlated with elevations in AST and ALT in some 
animals.  In dogs, adverse liver findings have only been observed in the 28-day toxicity study, at 
the high dose, and included one incidence of mild randomly distributed foci of mild necrosis, 


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associated with centrilobular vacuolation; non-adverse findings included hepatocellular 
degeneration also associated with centrilobular vacuolation, and one incidence of mild, randomly 
distributed microgranulomas in the liver. In the dog chronic 9-month study, reversible, non-
adverse and minimal panlobular hypertrophy of the liver was observed in all dose groups without 
any associated changes in liver transaminases. In the monkey chronic 9-month study, one of the 
16 monkeys at 22.5 mg/kg (33-fold the clinical exposure at 15 mg BID) was sacrificed on Day 
109 with cholestatic liver injury and associated anemia which developed over a minimum of 
several weeks. In prior AKB-9778 clinical trials, in subjects treated for 3 months with AKB-
9778 15mg BID, 0/113 had transaminase (ALT or AST) elevation >5X upper limit of normal 
(ULN) at any monthly assessment timepoint; 1/113 subjects (1/16 RVO patients; 0/97 DME 
patients) had a single occurrence of asymptomatic ALT elevation >3X but < 5X ULN at the end 
of treatment. This subject had an ALP slightly above ULN at pre-treatment and 2.05X ULN at 
the end of treatment, with all other labs (including AST, bilirubin and total protein) normal 
throughout the study. ALT and ALP levels were normal on repeat assessment 4 weeks later.  The 
rate of LFT findings observed to date in patients treated with AKB-9778 is in the range reported 
for placebo groups in clinical trials (Llanos et al, 2010), particularly given the absence of any 
cases associated with elevated bilirubin levels.   
In the subchronic (28-day) dog and monkey studies, decreases in hemoglobin and hematocrit 
were observed at the high doses with no microscopic correlate and were considered possibly 
associated with effects at the injection sites.  However, in the chronic rat, dog and monkey 
studies, except for the single monkey described above with cholestatic liver injury and associated 
anemia, decreases in hemoglobin or hematocrit were not observed. Non-adverse increases in 
cholesterol and triglycerides were observed in dogs in all pivotal studies with no associated 
microscopic changes. These changes resolved within the recovery periods.  No significant 
hematologic or plasma lipid abnormalities were observed in the 9-month monkey study. In all 
clinical trials with AKB-9778 to date, no clinically meaningful changes in hematological 
parameters (including hemoglobin and hematocrit) or plasma lipids (including total cholesterol 
and triglycerides) have been observed.  
Dermal nodules, characterized microscopically as angiectasis (dilated, blood filled vessels),  
have been observed in the chronic 9-month dog toxicity study and with a single incidence in one 
high-dose monkey in the chronic 9-month monkey study; however, no unusual dermal findings 
have been observed in human clinical studies of durations of up to 3 months. Whether ectasias 
will be seen when patients are dosed for longer periods is unknown. In the chronic dog study, 
angiectasis was also identified microscopically largely in the GI tract after the 9-month dosing 
period. These changes were asymptomatic (i.e. there was no bleeding, loss of appetite, or other 
observable clinical abnormalities of the GI tract) at exposures up to 24-fold above the human 
clinical exposure.  
The current clinical study employs robust safety monitoring to assess for potential adverse 
effects.  Safety assessments in the current study include body system assessments, vital sign 
monitoring, clinical laboratory assessments (including blood chemistry, hematology, fecal occult 
blood testing, and urinalysis), vision and ocular assessments.   
On an ongoing basis throughout the conduct of the study, a variety of planned safety monitoring 
reviews of available study data will be conducted (as detailed in Section 6.4 Oversight of Safety 
and in the AKB-9778 Safety Surveillance Plan).  These include weekly reviews conducted by the 


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Aerpio Medical Monitor, monthly masked reviews by the Aerpio Clinical Safety Review Team 
(CSRT), and quarterly masked reviews by the Safety Assessment Committee (SAC: composed 
of members independent of the clinical team including Aerpio physician/cardiologist, a non-
sponsor independent physician experienced in the assessment of clinical trial safety data, a non-
sponsor independent physician with expertise in gastrointestinal/hepatology safety assessment, 
and a non-sponsor independent physician/ophthalmologist with expertise in ophthalmology 
safety assessment).    
Given the safety history of AKB-9778 and the robust safety monitoring implemented in this 
study, there is anticipated to be minimal risk of drug-related severe adverse effects as a result of 
participation in this study.  
In nonclinical reproductive toxicology studies (rats and rabbits), AKB-9778 was not associated 
with embryo-fetal abnormalities.  Additionally, in the chronic repeated-dose rat (6-month) and 
dog (9-month) toxicity studies, there was no evidence of reproductive organ toxicity.  
Nonetheless, enrollment of women of child bearing potential and non-vasectomised male 
subjects will remain limited to subjects willing and able to use acceptable methods of 
contraception.  
5 STUDY OBJECTIVES AND ENDPOINTS 
5.1 Primary Objective 
1. To assess the effects of AKB-9778 15 mg once daily or 15 mg twice daily for 12 months 
on severity of diabetic retinopathy in subjects with moderate to severe NPDR  
5.2 Secondary Objective 
1. To assess the safety and tolerability of AKB-9778 15 mg once daily or 15 mg twice daily 
for 12 months in subjects with moderate to severe NPDR  
2. To determine the AKB-9778 systemic exposure based on sparse PK sampling in subjects 
with NPDR 
5.3 Exploratory Objectives 
1. To explore the potential benefit of AKB-9778 on renal function in subjects with NPDR 
2. To explore the relationship between AKB-9778 systemic exposure and efficacy and safety 
in subjects with NPDR 
5.4 Exploratory Efficacy Sub-Study Objectives (To be conducted at a subset of 
sites) 
1. To explore the effects of AKB-9778 on optical coherence tomography angiography (OCT-
A) in subjects with NPDR 
2. To explore the effects of AKB-9778 on retina function as measured by electroretinogram 
(ERG) assessment in subjects with NPDR 
3. To explore the effects of AKB-9778 on peripheral retinal abnormalities using ultra-wide 
field (UWF) fundus photography and UWF fluorescein angiography 


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5.5 Primary Efficacy Endpoints  
1. Percentage of subjects with an improvement in study eye severity of diabetic retinopathy 
(DR) (ETDRS DR Severity Score or DRSS) of ≥ 2 steps at Month 12   
5.6 Secondary Efficacy Endpoints  
1. Mean change from baseline in DRSS in the study eye at Month 12  
2. Patient level (binocular) change from baseline in DRSS (according to methods of Klein et 
al, 2001) at Month 12 
3. Proportion of subjects with a worsening in the study eye DRSS of ≥ 2 steps at Month 12  
4. Proportion of subjects with an improvement or worsening in the study eye DRSS of ≥ 3 
steps at Month 12  
5. Proportion of patients developing center-involved DME or PDR or PDR-related outcomes 
event during study  
6. Primary and secondary endpoints (1 through 4) assessed at Months 3, 6 and 9 
7. Primary and secondary assessments in all fellow eyes, fellow eyes that meet all eligibility 
criteria (qualified fellow eyes), and either eye (i.e. best response) 
5.6.1 Exploratory Efficacy Endpoints:  
1. Change from baseline in urine-albumin-to-creatinine ratio (UACR) and estimated 
glomerular (eGFR) at Month 12 
5.6.2 Exploratory Efficacy Sub-Study Endpoints  
1. Mean change from baseline in ERG parameters at Month 12 
2. Mean change from baseline in indices of macular perfusion, as measured by OCT-A, at 
Month 12 
3. Mean change from baseline in area of peripheral nonperfusion, peripheral leakage, and 
peripheral retinopathy using UWF imaging, at Month 12 
5.6.3 Safety Endpoints: 
1. Incidence and severity of systemic and ocular AEs 
2. Change from baseline in body system assessments 
3. Change from baseline in vital sign measurements 
4. Change from baseline in ECG parameters 
5. Change from baseline in clinical laboratory assay results (blood chemistry, hematology, 
fecal occult blood, and urinalysis) 
6. Change from baseline in intraocular pressure (IOP) 
7. Change from baseline in slit lamp examination parameters 
8. Change from baseline in dilated funduscopic examination parameters 


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9. Change from baseline in fluorescein angiogram (FA) parameters 
10. Mean change from baseline in ETDRS best corrected visual acuity (BCVA) letter score in 
the study eye at Month 12  
11. Proportion of subjects with a loss of ≥15 letters in BCVA at Month 12 (compared to 
baseline) 
6 STUDY DESIGN  
6.1 Study Design 
This is a Phase 2 randomized, double-masked, placebo controlled, multi-center study, to evaluate 
the safety and efficacy of 12 months (48 weeks) of subcutaneous AKB-9778 administered 15 mg 
QD or 15 mg BID in subjects with moderate to severe NPDR. Exploratory evaluations include 
pharmacokinetic assessments, as well as exploratory efficacy assessments (OCT-A, UWF 
imaging and non-invasive ERG) at a subset of sites. Blood samples will be retained for 
biomarker and genetic analysis.   
 
Subjects will participate in the study for approximately 56 weeks (Screening period up to 4 
weeks, Baseline and Treatment periods for 48 weeks, and Follow-up period for 4 weeks). 
The study will be conducted at approximately 50 investigative sites.   
Subjects will be randomized 1:1:1 to either AKB-9778 15mg QD, AKB-9778 15mg BID, or 
placebo treatment groups.  Fifty (50) subjects are planned per group.  The treatment groups are 
as follows:  
• Active Group: SC AKB-9778 15 mg (QD); To maintain masking, subjects will receive 
BID dosing with masked study medication administered as one dose of active and one 
dose of matching placebo 
• Active Group: SC AKB-9778 15 mg (BID)  
• Placebo Group: SC Phosphate-Buffered-Saline (PBS) (BID)  
Subjects will self-administer study medication as SC injections in the abdomen (preferably) 
around the same time every morning and evening, if possible (See Section 8.3.5). The 
Investigator, all study-site personnel, Central Image Reading Center personnel, and subjects will 
be masked to treatment assignment during the entirety of the study.  
For safety monitoring throughout the conduct of the study, ocular image data (fundus 
photographs, including red free images, fluorescein angiography, and OCT) for both the study 
and fellow eye will be read locally by the Investigator.   
All ocular image data will be transmitted to a Central Image Reading Center.  Modified 7-Field 
or 4-Wide Field color fundus photos will be graded for ETDRS DRSS by the Central Image 
Reading center.  The Central Image Reading center will confirm study eye eligibility based on 
ocular imaging criteria.  The Central Image Reading Center will provide the Screening DRSS 
value to investigative sites which will be used for randomization stratification based on 
Screening photos (See Section 8.3.2).  Ocular images analyzed at the Central Image Reading 


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Center will be used for final statistical analyses.  Reading center personnel will be masked to 
subject treatment and the reading and grading will be done in a masked fashion. 
Randomization will be stratified by study eye screening ETDRS DRSS (levels 43, 47 and 53 
equally distributed between the treatment groups). The number of study eyes with moderate 
severity of DR (level 43) will be limited to 50.   
Spot UACR and eGFR will be assessed as exploratory assessments to evaluate for any potential 
effects on renal function. UACR will be evaluated at Baseline, Month 6, Month 9, and Month 12 
(EOT). eGFR will be evaluated at Screening, Baseline, Month 6, Month 9, and Month 12 (EOT). 
Plasma samples will be collected at specified times on Day 1 and Month 6 visit for PK 
assessments.  These samples will be analyzed for AKB-9778 using validated bioanalytical 
methods. 
A blood sample will be retained for exploratory genetic analysis that may provide insight into the 
role of the VE-PTP/Tie2 pathway in diabetic retinopathy and an individual subject's response to 
AKB-9778 treatment. Similarly, blood samples collected at baseline and Month 12 End of 
Treatment (EOT) will be retained for exploratory analysis of biomarkers in plasma associated 
with VE-PTP inhibition and Tie2 activation.  Once results of the study are known, the Sponsor 
will determine the value of conducting the genetic and biomarker assessments.  
Subjects will be seen at the investigative site every 4 weeks while participating in the study.  At 
each monthly visit, subjects will undergo blood pressure and heart rate monitoring and visual 
acuity assessments. Subjects will also be questioned about any symptoms since their prior visit, 
and any adverse events and changes or additions to concomitant medications will be 
documented. Subjects will undergo blood sampling for clinical laboratory assessments (monthly 
for chemistry and every other month for hematology assessments). Fecal occult blood will be 
evaluated at Screening, Month 6, Month 9, and Month 12 (EOT). Subjects will collect their stool 
specimens at home and ship directly to the central clinical laboratory for testing; Investigative 
sites will distribute instructions and supplies for specimen collection and shipping. Every three 
months, subjects will also undergo a battery of comprehensive ocular assessments at the 
investigative site including slit lamp biomicroscopy, IOP, dilated indirect ophthalmoscopy, SD-
OCT, fundus photography and fluorescein angiography (at Months 6 and 12 only). Exploratory 
efficacy assessments (OCT-A, UWF imaging and non-invasive ERG) will also be included at a 
subset of sites.    
In addition to the assessments at the study site visits, at Screening and every three months during 
the treatment period, subjects will be visited at their homes by a home healthcare nurse, who will 
conduct body system assessments and review status of specimen collection for fecal occult blood 
testing (on relevant visits). The home health care nurse will also conduct the 1 month Follow-Up 
visit.  At this visit, the nurse will collect medical history and conduct a body system assessment.  
If the home healthcare nurse identifies any potential AEs during the home visit, the nurse will 
communicate directly to the study site and the Investigator will be responsible for determination 
of AEs and any necessary follow-up with the subject. The home healthcare nurse visits are 
anticipated to provide an additional measure of safety oversight. 
The safety and tolerability of AKB-9778 will be determined by incidence and severity of 
treatment emergent AEs and changes from baseline in ECG, vital sign measurements, clinical 


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laboratory assay results (blood chemistry, hematology, fecal occult blood, and urinalysis), 
BCVA, IOP, slit lamp examinations, funduscopic examinations and fluorescein angiograms 
(FA). 
6.2 Rationale for Study Design  
This Phase 2 study is being conducted to assess the safety and efficacy of AKB-9778 15 mg QD 
and AKB-9778 15 mg BID when administered daily for 12 months (48 weeks) in subjects with 
moderate to severe NPDR and no center-involved DME.     
6.3 AKB-9778 Dose Justification 
In two previous studies of AKB-9778 in subjects with DME, a 15 mg BID dose regimen using 
the HPβCD formulation has been well tolerated for up to 1 month and 3 months of treatment, 
respectively. The AKB-9778 dose regimen selected for this study is anticipated to be well 
tolerated based on nonclinical toxicology studies and clinical evaluation in humans and should 
allow for evaluation of efficacy without undue safety risk for participating subjects. Additionally, 
this dose regimen was associated with an increased percent of DME subjects achieving at least a 
2-step improvement in DRSS compared to placebo. To evaluate if less frequent administration 
may also achieve efficacy, an AKB-9778 15 mg QD dose regimen arm is also included in this 
study. 
6.4 Oversight of Safety 
On an ongoing basis throughout the conduct of the study a variety of planned safety monitoring 
reviews of available study data will be conducted.  These include weekly reviews conducted by 
the Aerpio Medical Monitor, monthly masked reviews by the Aerpio Clinical Safety Review 
Team (CSRT), and quarterly masked reviews by the Safety Assessment Committee (SAC: 
composed of members independent of the clinical team including Aerpio physician/cardiologist, 
a non-sponsor independent physician experienced in the assessment of clinical trial safety data, a 
non-sponsor independent physician with expertise in gastrointestinal/hepatology safety 
assessment, and a non-sponsor independent physician/ophthalmologist with expertise in 
ophthalmology safety assessment).  Ad hoc review by any review committee will be conducted 
anytime an important safety signal is identified. If unmasked reviews are needed to understand a 
potential safety signal, these will be conducted by the SAC.  These reviews are detailed further in 
the AKB-9778 Safety Surveillance Plan.   
7 SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 General Criteria 
Subjects will be recruited for screening by investigative Sites.   
To be eligible for this study, a subject must provide valid informed consent and must meet all of 
the following criteria.  No study procedures (including screening tests) may be performed until 
after the informed consent process has been conducted and the subject has legally signed. 


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A subject number will be allocated to each subject at the Screening visit.  If during the course of 
the Screening tests and procedures, a subject does not meet the eligibility criteria or does not 
continue in the study, the subject will be considered a Screening failure (not a withdrawal). 
7.2 Subject Eligibility Criteria 
7.2.1 Subject-Level Inclusion Criteria 
1. Males and non-pregnant females between 18 to 80 years of age, inclusive. 
2. Body mass index (BMI) between 18 to 40 kg/m2, inclusive.  
3. Diagnosis of diabetes mellitus (type 1 or type 2).  Any one of the following will be 
considered to be sufficient evidence that diabetes is present:  
a. Current regular use of insulin for the treatment of diabetes for at least the 3 
months prior to screening. 
b. Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes 
for at least the 3 months prior to screening. 
c. Documented diabetes (type 1 or type 2) as classified by the American Diabetes 
Association (ADA) and/or World Health Organization (WHO) criteria. 
4. At least one eye meets the study eye criteria listed below. 
5. Ability, in the opinion of the Investigator, and willingness to return for all scheduled visits 
and assessments. 
6. Ability to compliantly self-administer subcutaneous study medication twice daily for 12 
consecutive months.  
7. Understands the procedures and requirements of the study and provides written informed 
consent and authorization for protected health information disclosure. 
7.2.2 Subject-Level Exclusion Criteria:  
1. For females of child-bearing potential: pregnant or breast-feeding or intending to become 
pregnant within the next 12 months. 
2. Females of child-bearing potential who are unable or unwilling to use an acceptable method 
of contraception (Refer to Section 9.1.3, Contraception and Pregnancy Avoidance Measures). 
3. Non-vasectomized male subjects who are unable or unwilling to use an acceptable method of 
contraception (Refer to Section 9.1.3, Contraception and Pregnancy Avoidance Measures). 
4. Hemoglobin A1C (HbA1C) ≥ 12.0% at Screening. 
5. Uncontrolled hypertension defined as resting (sitting) systolic BP of ≥180 mmHg or a 
diastolic BP of ≥100 mmHg at Screening.  Must be on a stable (≥ 6 weeks) antihypertensive 
regimen. 
6. Resting (sitting) systolic BP of <100 mmHg at Screening. 
7. A history of symptomatic orthostatic hypotension, vasovagal syndrome, syncope, or 
presyncope within one year prior to Screening.  


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8. Initiation of nitrate medications or history of nitrate-associated orthostatic symptoms within 
one month prior to Screening. 
9. History of stroke, transient ischemic attack, congestive heart failure > NYHA Class 2, 
angina, or acute coronary syndrome within 3 months prior to Screening or any acute 
cardiology medical issues within 30 days prior to screening.  
10. Coronary-artery bypass graft, percutaneous intervention (e.g., cardiac, cerebrovascular, 
aortic), or major cardiac surgery within 3 months prior to Screening or anticipated need 
during study participation.   
11. If atrial fibrillation is present, then it must have been continuously present for >2 months 
with adequate rate control (ventricular response <95 BPM) with no plans to return the subject 
to sinus rhythm during the study confirmed by either their primary care physician or 
cardiologist.  
12. QTcF > 470 ms.   
13. Major surgery within 28 days prior to Screening or major surgery planned during the study. 
Major surgery is defined as a surgical procedure that is more extensive than fine needle 
biopsy/aspiration, placement of a central venous access device, removal/biopsy of a skin 
lesion, or placement of a peripheral venous catheter. 
14. Serum transaminase ([AST] and [ALT]) levels > 2X the upper limit of normal (ULN). (May 
be repeated once). 
15. History of clinically significant chronic liver disease (defined as any complication of liver 
disease, ascites, varices, hepatic encephalopathy, hepatocellular cancer). 
16. History of chronic renal failure (stage 4 or 5).  
17. History of gastrointestinal bleeding within the last year, or any history of bleeding due to 
arteriovenous malformation. 
18. Ferritin < 30 ng/ml in combination with a transferrin saturation (TSAT) < 20%. 
19. Fecal occult blood > 4.0 mg total hemoglobin/g feces as determined by the central laboratory. 
20. Presence of New York Heart Classification congestive heart failure class III or IV. 
21. Severe aortic stenosis. 
22. Chronic anticoagulation with warfarin, a direct acting anticoagulant, or antiplatelet agent 
(other than low dose aspirin).  
23. History of any solid organ transplant or bone marrow transplant, requiring 
immunosuppressive medications. 
24. Any history of alcohol or drug abuse within the previous year prior to Screening. 
25. Previous treatment with AKB-9778. 
26. Use of an investigational medication or device or participation in an investigational study 
within 30 days or 5 half-lives of the investigational medication, whichever is longer, 
preceding Screening, or ongoing or scheduled participation in another investigational study 
during the current study.  


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27. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or study drug administration or may 
interfere with the interpretation of study results and, in the Investigator’s judgment, would 
make the subject inappropriate for study entry. 
28. Current treatment for serious systemic infection. 
29. History of allergy to fluorescein. 
30. Subject is expecting to move out of the area of the clinical site to an area not covered by 
another clinical site during the conduct of the study.  
7.3 Ocular Eligibility Criteria 
For a subject to be included in the study, at least one eye must meet all ocular inclusion and 
exclusion criteria. If both eyes meet all ocular eligibility criteria, then the eye with the worse 
ETDRS DRSS should be designated the study eye, and the other eye designated as a qualified 
fellow eye; in this case, the Central Image Reading Center will confirm selection of the study 
eye. 
7.3.1 Study Eye / Qualified Fellow Eye Inclusion Criteria: 
1. Moderate to severe NPDR (ETDRS Level 43 – 53 inclusive) as confirmed by the Central 
Image Reading Center 
2. No evidence of center involved DME on SD-OCT as confirmed by the Central Image 
Reading Center  
3. No history of treatment for DME or DR within 12 months prior to Day 1 and no history of 
treatment with Iluvien® within 36 months prior to Day 1 
4. ETDRS BCVA letter score ≥ 70 (Snellen 20/40 or better) 
7.3.2 Study Eye /Qualified Fellow Eye Exclusion Criteria  
1. A decrease in visual acuity due to causes other than DR (e.g., foveal atrophy, pigment 
abnormalities, dense subfoveal hard exudates, previous vitreoretinal surgery, non-retinal 
condition, substantial cataract). 
2. Any other ocular disease that may cause substantial reduction in visual acuity, including iris 
neovascularization, retinal detachment, visually significant epiretinal membrane, 
vitreomacular traction, vitreous hemorrhage or fibrosis, ocular inflammation (uveitis), other 
retinal inflammatory or infectious diseases.  
3. Evidence of active ocular infection (e.g., blepharitis, keratitis, scleritis, or conjunctivitis). 
4. History of non-infectious uveitis. 
5. High myopia (-8 diopter or more correction). 
6. History of prior pars plana vitrectomy. 
7. History of prior PRP 


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8. Evidence of neovascularization on clinical examination, including active neovascularization 
of the iris or angle neovascularization 
9. Evidence of neovascularization on FA within the area of the Modified 7-Field fundus 
photographs as confirmed by the Central Image Reading Center. 
10. History of any ocular surgery within 3 months prior to Day 1. 
11. Uncontrolled glaucoma defined as IOP ≥ 30 mmHg on maximum IOP reduction therapy. 
12. Media opacity, pupillary constriction (i.e. senile miosis), or poor subject cooperation that, in 
the opinion of the investigator, would interfere with any study procedures, evaluations or 
interpretation of data. 
13. Any ocular condition that, in the opinion of the investigator, may require intervention, 
interfere with the study procedures, or interfere with evaluations of efficacy or safety or 
interpretation of data collected in the study. 
7.4 Waivers 
No waivers will be granted in the study. 
7.5 Replacement of Subjects  
Subjects withdrawn for reasons other than lack of efficacy (treatment for PDR or DME) may be 
replaced. 
7.6 Discontinuation of Study Medication/Withdrawal of Subjects  
Subjects will discontinue study medication for any of the following conditions: 
• In the opinion of the Investigator, it is medically necessary 
• The subject withdraws consent 
• Major toxicity considered to be related to study medication 
• The investigator obtains the treatment code for the subject  
• Administrative reasons, such as, subject non-compliance or a major protocol violation 
• Upon request of the Subject, Sponsor, Institutional Review Board (IRB) or regulatory 
agency 
• Study termination 
 
In addition to the above reasons for study medication discontinuation, if the subject meets 
criteria for treatment of PDR or DME (e.g. Anti-VEGF, steroids, laser, vitrectomy) in the study 
eye or qualified fellow eye, study medication may be discontinued at the discretion of the 
principal investigator and the subject. 
o Criteria for treatment of PDR or DME in the study eye or qualified fellow eye are 
given in Appendix B. Non-qualified fellow eyes may be treated at the discretion of 
the Investigator.  
o Refer to Section 8.4.3 for additional details regarding assessments to be conducted 
prior to treatment of PDR or DME.  
 


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Once it is identified that a subject will discontinue study medication, the subject should undergo 
all EOT (Month 12/Early Withdrawal) assessments (See Section 9.3.2.16) as soon as possible 
after study medication is stopped. The subject will then enter the 1-month Follow-up period 
provided that the subject has not withdrawn consent. 
If a subject does not return for a scheduled site visit or complete a homecare nurse visit, every 
effort should be made to contact the subject.  In any circumstance, every effort should be made 
to document subject outcome by completing the End of Treatment (Month 12/ Early 
Withdrawal) assessments. 
The Investigator must document the primary reason for discontinuation of study medication on 
the appropriate case report form (CRF).  If the reason for discontinuation of study medication is 
a clinical AE, monitoring will continue until the AE resolves or the Investigator assesses the AE 
as chronic or stabilized. 
8 STUDY PRODUCT AND TREATMENT OF SUBJECTS   
8.1  Study Medication, Supplies and Storage 
AKB-9778 and matching placebo will be provided as sterile pre-filled syringes.  The pre-filled 
syringes will be packaged in kits containing a one-week supply of study medication (seven 
“AM” doses and seven “PM” doses).  Kits will be shipped by the Sponsor or its designated 
supplier/distributor to the investigative site.  Study medication will be provided as masked 
supplies.  Syringes containing doses to be administered in the morning will be labelled “AM” 
and syringes containing doses to be administered in the evening will be labelled “PM”.   
The Investigator or designated study personnel will be responsible for study medication supply 
accountability (Section 8.5) and dispensing study medication and supplies to subjects.  
AKB 9778 
AKB-9778 is supplied as a sterile solution for subcutaneous administration packaged in a clear 
glass pre-filled syringe sealed with a Flurotec-coated stopper.  Each syringe is filled to a volume 
of 0.75 mL which delivers a dose of 15 mg AKB-9778. 
The drug product formulation contains 20 mg/mL AKB-9778, 100 mg/mL HPβCD (United 
States Pharmacopeia [USP]) and 25 mg/mL dextrose, USP.  The formulation is controlled to pH 
5.0 - 8.5 with an osmolality of between 250 and 350 mOsm/kg. 
Placebo 
The matching placebo formulation is supplied as a sterile solution for subcutaneous 
administration packaged in a clear glass pre-filled syringe sealed with a Flurotec-coated stopper.  
Each syringe is filled to a volume of 0.75 mL.  
The placebo formulation (PBS) contains 8 mg/mL sodium chloride, USP, 1.5 mg/mL sodium 
phosphate dibasic, USP, and 0.6 mg/mL sodium phosphate monobasic, USP.  The formulation is 
controlled to pH 5.0 - 8.5 with an osmolality of between 250 and 350 mOsm/kg. 


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8.1.1 Storage and Handling of Study Medication 
At the investigational site, study medication will be locked under controlled access and 
maintained at USP/National Formulary (NF) Controlled Room Temperature 15ºC - 30ºC (59ºF - 
86ºF) inclusive, with excursions permitted of up to and including 40ºC (104ºF) for no more than 
24 hours.    
The subject will be directed to store study medication in a secure location away from children at 
ambient temperature. 
8.2 Dispensing Procedures 
Assignment of masked study medication for dispensing will be made using an interactive web 
response system (IWRS). 
The Investigator will maintain a Drug Accountability Form itemizing all masked medication 
dispensed to and returned from each subject during the study.   
At Day 1 and visits on Months 1 through 11, subjects will be provided with sufficient supply for 
1 month (4 weeks) of dosing plus overage to allow for some flexibility in study visit scheduling.  
At the Day 1 visit, the subject will also be provided with a tote bag which contains ancillary 
supplies for dosing (e.g., sterile wipes, band aids, sharps container). 
Subjects should be instructed to bring all unused study medication to each monthly study visit 
for product accountability.  Full sharps containers should be returned and replaced as necessary.  
Subject dosing diaries should be returned at each monthly visit and subjects will be questioned 
regarding dosing compliance and whether they have questions or have experienced any problems 
related to the dosing of study medication.   
All unused and returned study medication should be retained at the investigative site and must be 
returned to the Sponsor or its designee for destruction.  If authorized by the Sponsor, 
investigative sites that have SOPs for destruction of study medication on site may destroy study 
medication once accountability procedures have been completed.  
8.3 Treatment of Subjects 
The Treatment period will last 12 months (48 weeks).     
8.3.1 Treatment Group Assignments 
Subjects meeting all eligibility criteria will be randomized 1:1;1 to either AKB-9778 15 mg QD, 
AKB-9778 15 mg BID, or Placebo treatment groups.  Fifty (50) subjects are planned per group.  
The treatment groups are as follows:  
• Active Group: SC AKB-9778 15 mg (BID)  
• Active Group: SC AKB-9778 15 mg (QD) 
• Placebo Group: SC PBS (BID)  
8.3.2 Randomization and Allocation to Treatment Group 
Approximately 150 subjects will be treated in the study.  


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Using a central IWRS randomization system, eligible subjects will be assigned in a double-
masked fashion 1:1:1 to one of the 3 treatment groups.  To maintain balance between treatment 
groups with respect to DR severity, randomization will be stratified by Screening ETDRS DRSS 
(levels 43, 47 and 53).  The number of study eyes randomized with Screening ETDRS DRSS 
level 43 will be capped at 50.  
8.3.3 Masking in the Study 
This study will be conducted in a double-masked manner.   
Treatment group assignment will be done through a central randomization system and completed 
using an IWRS.   
Study medication will be shipped as masked supplies.   
All investigative site staff will be masked to study treatment assignment 
Subjects will be masked to treatment assignment during the entirety of the study.  
Central Image Reading Center personnel will be masked to treatment assignment for the entirety 
of the study and the reading and grading will be done in a masked fashion. 
Blood specimens will be obtained from subjects for PK analysis in a manner that maintains 
treatment masking. Select personnel at the bioanalytical contract laboratory will be unmasked to 
subject treatment in order to permit analyses of samples from active treatment subjects only.  
8.3.4 Unmasking 
Unmasking of the Investigator is restricted to emergency situations and should only be used 
under circumstances where knowledge of the treatment is necessary for the proper management 
of the subject.  When possible, the Investigator should first discuss the unmasking request with 
the Sponsor and or Medical Monitor prior to unmasking.  If treatment is unmasked, the subjects 
should be discontinued from the study.  
8.3.5 Study Drug Administration 
Subjects will be responsible for self-administering study medication and will receive training 
during the Day 1 visit.   
On Day 1, Within 30 minutes to 1 hour prior to dosing, the subject should eat a meal or snack 
and drink 1-2 glasses of fluids preferably juice or electrolyte-containing as per the subject's usual 
diet management.  
Following the first dose of study medication on Day 1, subjects should remain seated for the first 
30 minutes, when not conducting study assessments.  
On Day 1, subjects will be dosed with the AM dose at the site, regardless of the time of day.  
Subjects will only self-administer the AM dose of study medication on Day 1. The subject will 
self-inject BID on a morning and evening schedule as detailed below.  Subjects will dose BID 
except for Day 1 when the subject will administer the first dose of study medication at the site 
using the AM dose (regardless of the time of day) and will begin the BID dosing schedule on 
Day 2; the PM dose will not be administered on Day 1. Subjects will only use AM syringes for 
dose administration in the morning and PM syringes for dose administration in the evening. 


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Subjects should administer their daily doses around the same time every morning and evening, if 
possible. If a dose is missed, this dose should be skipped and the subject should maintain the 
morning and evening dosing schedule.  Subjects will maintain a study medication diary noting 
time and location of injection. Subjects should be encouraged to follow their normal diet and 
maintain fluid intake (per their diabetes management). 
Study medication will be administered subcutaneously in the abdomen (preferably) following 
standard subcutaneous administration practices.  A distance of at least 3 cm between injection 
site and the midline, and between injection site and any scar should be maintained.  The subject 
should avoid tender, bruised, red or indurated areas and should maintain a distance of at least 
3 cm between consecutive injections.  If possible, subjects should not dose in the same quadrant 
of the abdomen between consecutive injections.  If the subject does not prefer to inject in the 
abdomen, the subject is allowed to dose in other standard regions for subcutaneous 
administration (e.g., upper arm or thigh); the location of the injection site will be identified in the 
subject medication diary. 
For subjects on injectable hypoglycemic drugs (e.g., insulin or GLP-1 analogues), it is preferable 
that a separate anatomical region be used for study drug administration.  For example, if the 
subject usually injects insulin or GLP-1 analogue in the upper arm, then study drug would 
preferably be injected in the abdomen. 
Before injection, the skin at the injection site should be cleaned and prepared with a skin 
disinfectant.  Care must be taken to ensure the study medication is not injected into a blood 
vessel.   
The subject must be able to compliantly self-administer study medication.  If the subject lives 
with a caretaker, the caretaker is allowed to assist the subject with dosing. 
8.4 Prior and Concomitant Therapy 
8.4.1 General 
All medications taken within 30 days prior to the start of study medication through the Month 12 
EOT visit should be recorded on the appropriate CRF.   
Diabetes management is left to the subject’s medical care provider.   
Subjects will take allowed non-study medication including insulin or oral-hyperglycemia agents 
per their normal routine. (For additional details see Section 9.1.4).  
Procedural ophthalmic medications are not required to be recorded (e.g., fluorescein dye, dilating 
drops, etc.). 
8.4.2 Investigational Medications 
Study subjects should not have received any investigational medication or participated in an 
investigational study within 30 days or 5 half-lives of the investigational medication, whichever 
is longer, preceding Day 1. 
Additionally, ongoing or scheduled participation in another investigational study during the 
current study through the Month 12 visit is not allowed. 


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8.4.3 Treatment of PDR or DME  
Criteria for treatment of PDR or DME in the study eye or qualified fellow eye during the study 
are summarized in Appendix B. Treatment of PDR of DME in a non-qualified fellow eyes is at 
the discretion of the Investigator. Treatment will be recorded on the appropriate CRFs. 
Subjects who receive treatment for PDR or DME in a study eye or qualified fellow eye may 
discontinue study medication at the discretion of the Investigator and subject. Subjects who 
remain in the trial will continue study medication.  
The following scenarios apply depending on eye being treated for PDR or DME. 
• For a study eye or qualified fellow eye requiring treatment, the Sponsor Medical Monitor 
should be informed prior to initiation of treatment. Additionally,  
o If the subject will discontinue study medication, the subject should undergo all 
EOT (Month 12/Early Withdrawal assessments (See Section 9.3.2.16) as soon as 
possible after study medication is stopped. EOT procedures should be conducted 
prior to treatment for PDR or DME in the study eye or qualified fellow eye. 
Treatment for PDR or DME will be in accordance with criteria in Appendix B; 
following treatment, the subject will enter the 1-month Follow-up period.  
o If the subject will continue study medication, consult the Sponsor Medical 
Monitor to determine appropriate ocular assessments to be conducted prior to 
treatment for PDR or DME. Treatment for PDR or DME will be in accordance 
with criteria in Appendix B.  
• For a non-qualified fellow eye requiring treatment: 
o The subject will remain in the study and study assessments will be conducted per 
protocol prior to any treatment for PDR or DME. Treatment for PDR or DME in a 
non-qualified fellow eye is at the discretion of the Investigator.   
8.5 Product Accountability and Destruction  
Product accountability should be an ongoing process throughout the study.  All study medication 
must be accounted for and any discrepancies explained.   
Proper drug accountability includes, but is not limited to: 
• 
Continuously monitoring expiration dates if expiry date or retest date is provided to the 
Investigator. 
• 
Frequently verifying that actual inventory matches documented inventory. 
• 
Verifying that the master drug log is completed for all subcutaneous study medication 
received at the site and that all required fields are complete, accurate, and legible. 
• 
Review of temperature log, and that the study medication is stored in locked access 
controlled conditions. 
• 
Verifying the subject individual drug accountability log is completed for each subject and 
that all required fields (units dispensed, returned, used, compliance) etc., are complete 
accurate and legible. 


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If any dispensing errors or discrepancies are discovered, the Sponsor must be notified 
immediately. 
Prior to site close-out, a representative from the Sponsor will perform clinical study material 
accountability and reconciliation. 
At the end of the study, the Investigator will retain all the original documentation regarding 
clinical study material accountability, return, and/or destruction, and copies will be sent to the 
Sponsor. 
The Investigator or designated study personnel is responsible for keeping accurate records of the 
study medication received from the Sponsor or its designee, all supplies retained in inventory at 
the site, and study medication dispensed to and returned from each subject.  This record will be 
maintained on a Drug Accountability Log that accurately reflects the accountability of the study 
medication at all times. 
During the study, the Investigator will be notified of any expiry dates or retest date extensions of 
study medication.  If an expiry date notification is received during the study, the site must 
complete all instructions outlined in the notification, including segregation of expired study 
material for return to the Sponsor or its designee for destruction. 
At the end of the study, any unused study medication must be returned to the Sponsor or its 
designee for destruction.  If an investigative site has SOPs for destruction of study medication on 
site, the Sponsor may authorize destruction of at the investigative site following completion of 
accountability procedures.  
9 STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES  
Please see Appendix A for a detailed table of the Schedule of Activities. 
A one-month duration in this study is defined as 4 weeks/28 days. The 12-month Treatment 
period is 48-weeks/336 days. 
This study includes the following periods and visits: 
• 
Screening visit (up to 28 days prior to Baseline) 
• 
Baseline visit (pre-dosing period on Day 1) 
• 
Treatment Period (Days 1 through Month 12 (Week 48)); including: 
o Investigative site visits on Day 1, Day 7 (phone-call), and monthly (i.e., every 4 
weeks) thereafter until the Month 12 (Week 48) EOT visit  
o Homecare nurse visits on Screening and Months 3, 6, 9, 12 (EOT)  
• 
Follow-Up Period 1 Month (4 weeks) Post-Treatment 
The following sections describe the procedures to be completed during the study.  Subjects are to 
be assessed by the same Investigator or site personnel whenever possible.    


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9.1 Administrative Procedures 
9.1.1 Informed Consent Procedure 
Informed consent must be obtained prior to the subject entering into screening for the study and 
before any protocol-specific procedures are performed (see Section 15.3).  
9.1.2 Documentation of Screen Failures 
Investigators will maintain a log of pre-screened subjects and indicate who was brought in for 
informed consent and Screening or who was not.  For subjects not brought in for informed 
consent and Screening, the reason(s) for not passing the pre-screen will be documented by the 
Investigator. 
Investigators must account for all subjects who sign informed consent and will maintain a log of 
subjects screened and indicate who was randomized or screen-failed.  If the subject is found not 
to be eligible prior to randomization, the reason(s) for ineligibility/screen fail must be 
documented by the Investigator. 
Subject numbers assigned to subjects who fail screening will not be re-used. 
9.1.3 Contraception and Pregnancy Avoidance Measures 
 Summary of AKB-9778 Reproductive Toxicology Studies 
In nonclinical animal embryo-fetal development studies, there was no evidence of external fetal 
teratogenic effects, or of skeletal or visceral malformations, at dose levels up to the highest doses 
tested; 180 mg/kg/day in rats and 140 mg/kg/day in rabbits. In rats and rabbits, decreased 
maternal body weight and food consumption were observed at these high doses.   
Fertility and peri-postnatal development studies have not yet been conducted with AKB-9778, 
and there are no data on the transmission of AKB-9778 in breast milk or the effect of AKB-9778 
on infants. 
 Guidance for Study AKB-9778-CI-5001 
Due to the unknown effects of AKB-9778 on sperm and the developing fetus, all subjects must 
agree to use adequate contraception throughout the study and for 30 days after administration of 
last dose of any study medication.  
Adequate contraception is defined as follows: 
Female subjects must be surgically sterile, postmenopausal (for at least one year), or have 
negative pregnancy test results at Screening (serum) and at Baseline (urine). 
Female subjects not surgically sterile or postmenopausal (for at least one year), and non-
vasectomized male subjects must practice at least one of the following methods of birth control: 
• 
total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to 
Screening visit, throughout the study, and for 30 days after the last dose of study 
medication) 
• 
a vasectomized partner or partner of non-child bearing potential 


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• 
hormonal contraceptives (oral, parenteral, Nexplanon, or transdermal) for at least three 
months prior to study drug administration 
• 
double-method of birth control and must include condoms in addition to one other 
method: spermicide, IUD, diaphragm with spermicide, hormonal contraceptive, bilateral 
tubal ligation, Essure procedure. 
 
Female subjects may not donate eggs (ova, oocytes) during this study and for 30 days after the 
last dose of study medication. 
Male subjects must not donate sperm during the study and for at least 60 days after the last dose 
of any study drug. 
9.1.4 Diet, Fluid and Activity Control  
Subjects should be encouraged to follow their normal diet and maintain fluid intake (per their 
diabetes management). 
Subjects will take allowed non-study medication including insulin or oral-hyperglycemia agents 
per their normal routine.  Subjects will monitor blood sugar as per their normal routine.  Diabetes 
management is left to the subject’s medical care provider. 
Subjects are to refrain from physical activity greater than their normal level of activity for the 
duration of the study.  
Subjects will be advised that it is important to refrain from excessive alcohol intake for the 
duration of the study.   
Subjects taking medication for erectile dysfunction (e.g., Viagra®, Cialis®, Levitra®), should 
not take this medication within 2 hours before or after study medication.  
For three days prior to and during the days of stool sample collection for fecal occult blood testing, 
subjects are to refrain from eating any red meat (beef, pork or lamb). Also, for three days before 
and during the days of stool sample collection, subjects will avoid taking aspirin.  However, 
subjects taking daily low dose aspirin are allowed to continue their aspirin but must not change 
their dose.  
On Day 1 and on Month 6, within 30 minutes to 1 hour prior to dosing at the site, the subject 
should eat a meal or snack and drink 1-2 glasses of fluids preferably juice or electrolyte 
containing as per the subject's usual diet management.  Following dosing on the Day 1 and 
Month 6 visits, subjects should remain seated for the first 30 minutes, when not conducting study 
assessments.   
9.1.5 Laboratory Accreditation and Reference Ranges 
The Investigator and the Sponsor will maintain a copy of the laboratory accreditation and the 
reference ranges for the central laboratory used for clinical laboratory evaluations.   
9.2 Study Procedures and Evaluations  
Please see the Schedule of Activities presented in Appendix A for designated time points for 
assessments. 


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9.2.1 Clinical Evaluations  
The following clinical evaluations will be conducted during the course of the study.   
• Medical/ophthalmic history and demographics:  Relevant medical history (with particular 
emphasis on previous medical conditions that may lead to exclusion) and significant 
ongoing medical conditions or diseases should be documented. Ophthalmic history 
should include treatment history for DR/DME. 
• Body System Assessments:  Body systems to be evaluated include general appearance, 
HEENT (head, ears, eyes, nose and throat), cardiovascular, respiratory, 
abdomen/gastrointestinal (including query of any changes in bowel habit frequency, 
consistency, or color), musculoskeletal, and skin (including query of any skin 
abnormalities noted as well as direct observation of skin of head, neck, chest, abdomen, 
back and extremities). Subjects will be instructed that if they note any abnormalities 
between visits they should contact their study doctor so that any such findings can be 
assessed.  
• Height (at Screening only), weight, and temperature 
• 12-Lead ECG:  A standard 12-lead ECG will be obtained after the subject has been 
resting comfortably in a supine position for approximately 5 minutes and prior to vital 
sign assessments and blood draws when possible.  With the subject in a supine position, 
obtain the 12-lead tracing.  Each 12-lead ECG must be recorded with a paper speed of 
25 mm/sec and printed as a paper copy.  The Investigator (or a qualified observer) will 
interpret the ECG and record the results including the following parameters: heart rate, 
PR interval, QT interval, QRS interval, and QTcF (corrected). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in 
the same positions each time in order to achieve precise ECG recordings.  If a machine-
read QTcF value is prolonged, repeat measurements may not be necessary if a qualified 
physician’s interpretation determines that the QTcF values are in the acceptable range. 
All abnormal rhythms will be reviewed by the study physician for the presence of 
rhythms of potential clinical concern.  The Investigator should utilize medical judgment 
in the reporting of AEs and SAEs as well as determination of additional cardiac work-up.  
A printed record of the tracing(s) of the clinically significant rhythm(s) will be made and 
retained with other source documents. An ECG will be performed at the Screening, 
Month 6, and Month 12 (EOT) visits. 
• Vital Signs: Vital signs include blood pressure and heart rate.  Vital sign assessments 
should be taken prior to blood draws when possible. The subject should be seated, with 
legs uncrossed and feet resting comfortably on the floor, for at least 5 minutes prior to 
measuring blood pressure and heart rate. 
• ETDRS Best Corrected Visual Acuity (BCVA):  Visual acuity of both eyes will be 
assessed using the ETDRS protocol at 4 meters.   
• Slit Lamp Biomicroscopy: Slit-lamp biomicroscopy will include examination of the 
cornea, conjunctiva, anterior chamber, iris/pupil, lens, and eyelid of both eyes.  Findings 


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will be graded as normal, abnormal not clinically significant, or abnormal clinically 
significant.    
• Intraocular Pressure (IOP): IOP will be assessed with either applanation tonometry or 
tonopen; the method should be consistent throughout the study. 
• Dilated Indirect Ophthalmoscopy: Dilated indirect ophthalmoscopy will be performed to 
assess the vitreous, macula, optic nerve, and peripheral retina of both eyes.  Findings will 
be graded as normal, abnormal not clinically significant, or abnormal clinically 
significant.    
• SD OCT: Spectral domain optical coherence tomography (SD OCT) will be utilized to 
assess retinal characteristics of both eyes. The OCT instrument type used throughout the 
study must be consistent for an individual subject. OCT imaging data will be transmitted 
to a central reading center for independent analysis. Detailed instructions for imaging and 
data transfers will be provided in the study-specific imaging manual. 
• Fundus Photography: Modified 7-Field or 4-Wide Field color fundus photographs 
(including red free images) of both eyes will be taken to evaluate retinal anatomy.  
Photographs will be transferred to a central reading center.  Detailed instructions for 
imaging and data transfers will be provided in the study-specific imaging manual.  
o For sites participating in the UWF imaging sub-study, in addition to Modified 7-
Field or 4-Wide Field color fundus photographs, UWF color fundus photographs 
should be taken using the Optos P200Tx or Optos California system. Parameters 
obtained are detailed further in this section under “UWF imaging”.  
• Fluorescein Angiography (FA): Retinal vasculature of both eyes will be evaluated by 
fluorescein angiography (FA).  FA images will be transferred to a central reading center.  
Detailed instructions for imaging and data transfers will be provided in the study-specific 
imaging manual. 
o For sites participating in the UWF imaging sub-study, in lieu of standard FA, 
UWF FA images should be taken using the Optos P200Tx or Optos California 
system. Parameters obtained are detailed further in this section under “UWF 
Imaging”. 
• Adverse Event Assessments:  Beginning with informed consent and through final 
protocol required visit, the Investigator and study personnel will review each subject’s 
laboratory and clinical evaluation findings and query the subject directly regarding AEs 
(see Section 10).  If a home healthcare nurse identifies any potential AEs during a home 
visit, the nurse will communicate directly to the study site and the Investigator will be 
responsible for determination of AEs and any necessary follow-up with the subject. 
Subjects must be followed for AEs until the final required protocol visit or until all drug-
related toxicities and serious adverse events have resolved (or are considered 
chronic/stable), whichever is later.   
• Concomitant Medication Recording:  All medications, both prescription and non-
prescription, and including vitamins, herbals, topicals, inhaled, and intranasal, taken 
within 30 days prior to the start of study medication and through the Month 12 EOT visit 


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should be recorded on the appropriate CRF.  At each study visit, subjects will be asked 
whether they have started or discontinued any medication since their previous study visit.  
This includes single use or PRN (as needed) medication use.  All medications and 
treatments, including vitamin supplements, over-the-counter medications, and oral herbal 
preparations must be recorded in the CRFs.   
• Exploratory Efficacy Sub-Study Evaluations (to be conducted at a subset of sites): 
o OCT-A – OCT-angiography should be obtained from both eyes using a SD OCT 
machine according to instructions provided by the manufacturer  
o ERG – Flicker ERGs will be obtained from both eyes using the RETeval system 
(LKC Technologies, Gaithersburg MD). Responses will be obtained from 
electrodes placed on the skin under light-adapted conditions. Parameters obtained 
will include flicker ERG amplitude, ERG peak latency, and pupillary response to 
each of 3 different flicker intensities. RETeval score will also be derived from 
these data (Maa et al, 2015).  
o UWF imaging – UWF FA and UWF color fundus photographs will be obtained 
using the Optos P200Tx or Optos California instrument following procedures 
specified in the study specific imaging manual.  As described previously, UWF 
FA will be performed in lieu of standard FA, but UWF photographs will be 
obtained in addition to standard Modified 7-Field or 4-Wide Field color fundus 
photographs. UWF fundus photographs are only obtained on visits when UWF 
FA is performed (e.g. Screening, Month 6, and Month 12 (EOT). Parameters 
obtained from UWF FA include area of peripheral non-perfusion, area of 
peripheral leakage. Parameters measured in UWF color fundus photographs 
include peripheral microaneurysms, vitreous hemorrhage, venous beading, intra-
retinal microvascular abnormalities (IRMA) and neovascularization elsewhere 
(NVE).  
9.2.2 Laboratory Evaluations:  
All samples collected (with the exception of urine pregnancy tests) will be sent to a central 
clinical laboratory.   
If to be conducted at the same time points, blood sampling should occur after vital sign 
assessments and ECGs have been conducted.  
Samples for clinical laboratory evaluations (hematology, chemistry, fecal occult blood testing, 
and urinalysis assays) and Screening serum pregnancy tests will be analyzed at the central 
laboratory.  The Investigator is responsible for reviewing laboratory results for clinical 
significance. 
The central laboratory is also responsible for distribution of PK samples to the respective PK 
laboratory for analysis.  Once the results of the study are known, the Sponsor will determine if 
biomarker and genetic analyses will be conducted and will direct the central clinical laboratory 
on distribution of samples for biomarker and genetic analyses to the appropriate laboratories.    
The following clinical laboratory evaluations will be conducted during the course of the study: 


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• Pregnancy test:  A serum pregnancy test will be performed at Screening for females of 
childbearing potential.  The investigative site will perform a urine pregnancy test at the 
Baseline, Month 6 and Month 12 EOT visits.  The Screening and Baseline results must be 
available and must be negative before the subject takes the first dose of any study 
medication on Day 1.  At each monthly visit, the site will query subjects of childbearing 
potential regarding the potential for pregnancy.  
• Hematology:  The complete blood count (CBC) will include: hemoglobin (Hgb), 
hematocrit, red blood cell (RBC) count, mean corpuscular (cell) volume (MCV), mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), 
red cell distribution width (RDW), mean platelet volume (MPV), white blood cell (WBC) 
count with differential (neutrophils, immature granulocytes, lymphocytes, monocytes, 
eosinophils, basophils), platelet count, reticulocyte count and HbA1C. Hematology will 
be assessed every other month except for HbA1C which will be assessed at Screening, 
Baseline, Month 6, and Month 12 (EOT) visits.    
Chemistry:  The serum chemistry will include the following assays: sodium, potassium, 
bicarbonate, chloride, calcium, phosphorus, glucose, creatinine, blood urea nitrogen 
(BUN), creatinine phosphokinase (CPK), uric acid, albumin, total protein, total bilirubin, 
alkaline phosphatase, alanine transaminase ((ALT (SGPT)), aspartate transaminase (AST 
(SGOT)), lactate dehydrogenase (LDH), total cholesterol, triglycerides, ferritin, serum 
iron, total iron binding capacity (TIBC) and transferrin saturation (TSAT). Chemistries 
will be assessed monthly. eGFR will be determined on serum chemistry samples 
collected at the Screening, Baseline, Month 6, Month 9, and Month 12 (EOT) visits.  
• Fecal occult blood testing: A small amount of stool will be collected on 3 separate days 
as per standard procedure to measure fecal blood levels using the HemoQuant test 
(Rockey et al, 1999; Barber et al, 2002; Harewood et al, 2002).  At the Screening, Month 
6, Month 9, and Month 12 (EOT) site visits, Investigative sites will distribute instructions 
and supplies for home specimen collection to the subject. For 3 days prior to and during 
the days of stool sample collection, subjects will refrain from eating red meat and taking 
high dose aspirin as detailed in Section 9.1.4. Subjects will collect their specimens and 
are responsible for shipping to the central laboratory for testing; specimen collection and 
shipping should be conducted within one week following the site visit.  
• Urinalysis: Urinalysis will include bilirubin, blood, glucose, ketones, pH, protein, specific 
gravity and microscopic examination (only if urinalysis is positive for blood or protein).   
• Urine-albumin-to-creatinine ratio (UACR): UACR will be determined on urine samples 
collected at the Baseline, Month 6, Month 9, and Month 12 (EOT) visits; subjects should 
refrain from heavy exercise 24 hours before these visits. 
• Pharmacokinetic analysis:  Analysis of plasma samples for AKB-9778 concentration 
determinations will be performed by a central PK laboratory using a validated Liquid 
Chromatography-Mass Spectrometry and Liquid Chromatography-Tandem Mass 
Spectrometry (LC-MS/MS) method.  Detailed instructions for processing and shipment 
of samples will be provided by the Sponsor or Central laboratory   


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• Biomarker analysis in Plasma:  Biomarkers will be assessed in plasma samples.  Detailed 
instructions for processing and shipment of samples for biomarker analyses will be 
provided by the Sponsor or Central laboratory. 
• Genetic analysis:  Detailed instructions for processing and shipment of samples for 
biomarker analyses will be provided by the Sponsor or Central laboratory. 
9.3 Schedule of Activities  
The Schedule of Activities is presented in Appendix A and shows the timing of planned study 
procedures to be conducted at the study site and at the home care nursing visits.  Every effort 
should be made to adhere to the procedure schedule and all assessments should be completed at 
each study visit. 
The Screening, Baseline, Treatment, and Follow-up Periods will require subject participation for 
approximately 56 weeks. 
Study procedures, clinical assessments (including laboratory assays), and PK, biomarker and 
genetic sampling will be performed as indicated in the Schedule of Activities.   
Subjects will be responsible for self-administration of study medication which is provided in 
prefilled sterile syringes.  The subject will self-inject BID on a morning and evening schedule as 
detailed in Section 8.3.5.  Subjects will dose BID with the exception of Day 1 when the subject 
will dose the first (AM) dose at the clinic and will begin the BID dosing schedule on Day 2. No 
PM dose will be taken on Day 1.  
At the visit on Day 1, the site will train the subject on SC study medication administration and 
dosing diary completion.  After the pre-dose activities have been completed, the subject will self-
administer the AM dose of study medication.  
After the subject has completed the EOT visit, no further subcutaneous dosing will occur. 
Study visits on Day 1, Month 6 and Month 12 EOT should be scheduled for the morning.  The 
remainder of the site visits should also be scheduled for the morning when possible. Subjects will 
maintain a daily study medication diary and will record timing and location of dose. 
At the site visits on Day 1 and Months 1 through 11, subjects will be dispensed subcutaneous 
study medication and dosing supplies. 
Subjects discontinuing study medication sooner than the planned 12-month dosing period or 
withdrawing from the study should complete the Month 12 EOT assessments including the EOT 
assessments at the EOT site visit (See Section 9.3.2.16) and the EOT homecare nurse visit (See 
Section 9.3.3.5).  
Detailed descriptions of procedures and activities to be followed during each site and homecare 
nurse visit are presented in the following sections.  For specific time points please refer to the 
Schedule of Activities in Appendix A.  Procedures and activities to be conducted at the 
investigative site are presented in Section 9.3.2 followed by procedures to be conducted at the 
homecare nurse visits presented in Section 9.3.3.   


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9.3.1 Visit Windows 
Plasma PK samples collected at 30 and 90 minutes after dosing of study medication on Day 1 
and Month 6 should be collected within ±10 minutes of the target time.  If for any reason, the 
sampling time point for a given sample falls outside of the visit window, the sample must still be 
collected.  For all samples; the exact time of sample collection will be recorded.  
Blood pressure and heart rate evaluations performed must be conducted within ±20 minutes of 
the designated time.   
Subjects will only use AM syringes for dose administration in the morning and PM syringes for 
dose administration in the evening. Subjects should administer their daily doses around the same 
time every morning and evening, if possible. If a dose is missed, this dose should be skipped and 
the subject should maintain the morning and evening dosing schedule. 
The Day 7 phone call must be conducted within ±3 days. 
Site visits scheduled for Months 1 through 12 should be conducted within 28 days times the 
study month number ±3 days relative to the baseline visit (e.g. Month 1 visit window is 28 ±3 
days from Day 1, Month 2 visit window is 56 ±3 days from Day 1, etc.).   
Homecare nurse visits scheduled for Screening, Months 3, 6, 9 and 12 should be conducted 
within 1 week after the corresponding site visit. The Follow-up homecare visit occurs 4 weeks 
±3 days after the EOT visit at the site.   
The fecal occult blood specimen collection and shipping to the Central Laboratory should be 
conducted by the subject within the week following the corresponding site visit.  
9.3.2 Activities to be conducted at the Study Site 
 Screening Visit  
The Screening visit must be performed within 28 days prior to dosing.  The Investigator will 
maintain a log of subjects screened and indicate who was enrolled or excluded and the reason for 
exclusion (Section 9.1.2). 
After obtaining informed consent and receiving a unique subject number, subjects will undergo a 
number of screening activities.   
If possible, all screening activities should be conducted on the same day.  At the Screening visit, 
the following activities/procedures will be performed: 
• Informed consent obtained 
• Assignment of subject number 
• Review of eligibility criteria 
• Demographics 
• Medical/ophthalmic history including treatment history for DR/DME  
• Temperature, height and weight 
• 12 Lead ECG (prior to vital signs and blood draws) 
• Vital signs: 
o sitting blood pressure and heart rate measurements 
• Eye and Vision Exams: 


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o ETDRS BCVA 
o slit-lamp biomicroscopy 
o IOP 
o dilated indirect ophthalmoscopy 
o SD OCT 
o fundus photography (and UWF fundus photography at select sub-study sites)  
o fluorescein angiography (or UWF fluorescein angiography at select sub-study 
sites) 
• Laboratory Procedures 
o serum pregnancy test for women of childbearing potential 
o hematology 
o clinical chemistry 
• Concomitant Medication recording 
• AE monitoring 
• Dispense instructions and kit for subject to perform home fecal occult blood specimen 
collection   
 Baseline Period (Pre-Treatment, Day 1)  
Eligible randomized subjects will be dosed at the Site on Day 1.  At Baseline on Day 1, the 
following activities/procedures will be performed prior to any dosing of study medication: 
• Interim medical/ophthalmic history 
• Vital signs (to be performed within 2 hours prior to dosing and prior to blood draws): 
o sitting blood pressure and heart rate measurements 
• Eye and Vision Exams: 
o ETDRS BCVA 
o slit-lamp biomicroscopy 
o IOP 
o dilated indirect ophthalmoscopy 
o ERG (at select sub-study sites) 
o OCT-A (at select sub-study sites) 
• Laboratory Procedures  
o urine pregnancy test for women of childbearing potential (results must be known 
prior to dosing) 
o hematology 
o clinical chemistry 
o urinalysis 
o biomarker blood sampling 
o blood sampling for genetic analysis 
• Concomitant Medication recording as needed 
• AE monitoring 
 Treatment Period – Day 1 
Following Baseline on Day 1, the following activities/procedures will be performed at the site 


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• Train subject on self-administration of study medication and diary completion.  Distribute 
diaries. 
• Subjects should eat a snack or meal and drink 1-2 glasses of fluid (See Section 9.1.4) 
within 1 hour to 30 minutes prior to dosing.  
• Dose administration:  
o Subjects will self-dose the AM dose in the seated position and remain seated for 30 
minutes following dosing.  
• Sitting blood pressure and heart rate measurements will be conducted at 30 and 90 
minutes after dosing.  These assessments are to be conducted prior to any blood draws. 
o If a subject develops symptoms of lightheadedness, presyncope, or of possible 
hypotension, consistent with medical practice it is recommended that the blood 
pressure and heart rate be re-measured and the subject placed in the supine 
position until symptoms resolve. The Investigator should also contact the study 
medical monitor.  
• PK blood sampling at 30 and 90 minutes after dosing.  Sampling is to be conducted after 
blood pressure and heart rate measurements are completed.  
• AE monitoring 
• Concomitant Medication recording as needed 
• Dispense 1 month supply of study medication kits and study medication diary. 
 Treatment Period – Day 7 (Week 1 Phone call) 
• AE monitoring and AE recording since last visit  
• Question subject regarding dosing compliance and whether they have questions or have 
experienced any problems related to the dosing of study medication 
 Treatment Period – Month 1 Visit (Week 4) 
• Vital signs: 
o sitting blood pressure and heart rate measurements 
• Eye and Vision Exams: 
o ETDRS BCVA 
• Laboratory Procedures  
o clinical chemistry 
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  
• Dispense 1 month supply of study medication kits  
 Treatment Period – Month 2 Visit (Week 8) 
• Vital signs: 
o sitting blood pressure and heart rate measurements 
• Eye and Vision Exams: 
o ETDRS BCVA 
• Laboratory Procedures  
o hematology 


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o clinical chemistry 
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  
• Dispense 1 month supply of study medication. 
 Treatment Period – Month 3 Visit (Week 12) 
• Vital signs  
o sitting blood pressure and heart rate measurements 
• Eye and Vision Exams: 
o ETDRS BCVA 
o slit-lamp biomicroscopy 
o IOP 
o dilated indirect ophthalmoscopy 
o SD OCT 
o fundus photography 
o ERG (at select sub-study sites) 
o OCT-A (at select sub-study sites) 
• Laboratory Procedures  
o clinical chemistry 
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  
• Dispense 1 month supply of study medication kits 
 Treatment Period – Month 4 Visit (Week 16) 
• Vital signs  
o sitting blood pressure and heart rate measurements 
• Eye and Vision Exams: 
o ETDRS BCVA 
• Laboratory Procedures  
o hematology 
o clinical chemistry 
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  
• Dispense 1 month supply of study medication kits  
 Treatment Period – Month 5 Visit (Week 20) 
• Vital signs  
o sitting blood pressure and heart rate measurements 
• Eye and Vision Exams: 
o ETDRS BCVA 
• Laboratory Procedures  


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o clinical chemistry 
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  
• Dispense 1 month supply of study medication kits  
 Treatment Period – Month 6 Visit (Week 24) 
Given that post-dose PK sample collection is included in this visit, subjects will be 
instructed to not administer their AM dose prior to their visit and to bring their AM dose 
along with other study medication in kits, as the AM dose will be administered in the 
clinic.  
 
• Weight and Temperature 
• 12 Lead ECG (prior to vital signs and blood draws) 
• Vital signs  
o sitting blood pressure and heart rate measurements 
• Eye and Vision Exams: 
o ETDRS BCVA 
o slit-lamp biomicroscopy 
o intraocular pressure 
o dilated indirect ophthalmoscopy 
o SD OCT 
o fundus photography (and UWF fundus photography at select sub-study sites) 
o fluorescein angiography (or UWF fluorescein angiography at select sub-study 
sites) 
o ERG (at select sub-study sites) 
o OCT-A (at select sub-study sites) 
• Laboratory Procedures  
o urine pregnancy test for women of childbearing potential  
o hematology 
o clinical chemistry 
o urinalysis 
• Subjects should eat a snack or meal and drink 1-2 glasses of fluid (See Section 9.1.4) 
within 1 hour to 30 minutes prior to dosing.  
• Dose administration:  
o Subjects will self-dose AM dose in the seated position and remain seated for 30 
minutes following dosing.  
• Sitting blood pressure and heart rate measurements will be conducted at 30 and 90 
minutes after dosing.  These assessments are to be conducted prior to any blood draws. 
• PK blood sampling at 30 and 90 minutes after dosing.  Sampling is to be conducted after 
blood pressure and heart rate measurements are completed.  
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  


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• Dispense 1-month supply of study medication kits 
• Dispense instructions and kit for subject to perform home fecal occult blood specimen 
collection    
 Treatment Period – Month 7 Visit (Week 28) 
• Vital signs  
o sitting blood pressure and heart rate  
• Eye and Vision Exams: 
o ETDRS BCVA 
• Laboratory Procedures  
o clinical chemistry 
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  
• Dispense 1 month supply of study medication kits 
 Treatment Period – Month 8 Visit (Week 32) 
• Vital signs  
o sitting blood pressure and heart rate  
• Eye and Vision Exams: 
o ETDRS BCVA 
• Laboratory Procedures  
o hematology 
o clinical chemistry 
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  
• Dispense 1 month supply of study medication kits 
 Treatment Period – Month 9 Visit (Week 36) 
• Vital signs  
o sitting blood pressure and heart rate measurements 
• Eye and Vision Exams: 
o ETDRS BCVA 
o slit-lamp biomicroscopy 
o intraocular pressure 
o dilated indirect ophthalmoscopy 
o SD OCT 
o fundus photography 
o ERG (at select sub-study sites) 
o OCT-A (at select sub-study sites) 
• Laboratory Procedures  
o clinical chemistry 
o urinalysis 


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• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  
• Dispense 1 month supply of study medication kits 
• Dispense instructions and kit for subject to perform home fecal occult blood specimen 
collection   
 Treatment Period – Month 10 Visit (Week 40) 
• Vital signs  
o sitting blood pressure and heart rate  
• Eye and Vision Exams: 
o ETDRS BCVA 
• Laboratory Procedures  
o hematology 
o clinical chemistry 
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  
• Dispense 1-month supply of study medication kits 
 Treatment Period – Month 11 Visit (Week 44) 
• Vital signs  
o sitting blood pressure and heart rate 
• Eye and Vision Exams: 
o ETDRS BCVA 
• Laboratory Procedures  
o clinical chemistry 
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit  
• Dispense 1-month supply of study medication kits  
 Treatment Period – Month 12 End of Treatment Visit (Week 48) 
• 12 Lead ECG (prior to vital signs and blood draws) 
• Weight and temperature 
• Vital signs  
o sitting blood pressure and heart rate measurements 
• Eye and Vision Exams: 
o ETDRS BCVA 
o slit-lamp biomicroscopy 
o intraocular pressure 
o dilated indirect ophthalmoscopy 
o SD OCT 
o fundus photography (and UWF fundus photography at select sub-study sites)  


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o fluorescein angiography (or UWF fluorescein angiography at select sub-study 
sites) 
o ERG (at select sub-study sites) 
o OCT-A (at select sub-study sites) 
• Laboratory Procedures  
o urine pregnancy test  
o hematology 
o clinical chemistry 
o urinalysis 
o biomarker blood sampling 
• AE monitoring and AE recording since last visit  
• Concomitant Medication recording as needed since last visit 
• Collect returned used supplies and review medication use since last visit 
• Dispense instructions and kit for subject to perform home fecal occult blood specimen 
collection   
9.3.3 Activities to be conducted at the Homecare nurse visit 
Homecare nurse visits scheduled for Screening, Months 3, 6, 9 and 12 should be conducted 
within 1 week after the corresponding site visit. The Follow-up homecare visit occurs 4 weeks 
±3 days after the EOT visit at the site. Nurse visits will likely occur at subject’s home; however 
alternate locations acceptable to the subject are allowed (e.g. investigative site).  
Investigative sites will distribute instructions and kits for the subject to perform home fecal 
occult blood specimen collection and shipping to the Central Laboratory; nurses will review 
status of specimen collection and shipping with subjects on corresponding homecare visits.     
During homecare nurse visits, if any change in status, the nurse will contact the Investigator, so 
that the Investigator can assess for any new adverse event or change in status of existing adverse 
event, and document and report accordingly.  
 Screening Visit 
• Body systems assessment 
• Review Status of fecal occult blood testing 
 Treatment Period – Month 3 Visit (Week 12) 
• Body systems assessment 
 Treatment Period – Month 6 Visit (Week 24) 
• Body systems assessment 
• Review status of fecal occult blood testing 
 Treatment Period – Month 9 Visit (Week 36) 
• Body systems assessment  
• Review status of fecal occult blood testing 


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 Treatment Period – Month 12 Visit (Week 48) 
• Body systems assessment 
• Review status of fecal occult blood testing  
 Follow-up Period -1 Month (4 weeks) Post-Treatment Visit (Week 52) 
• Medical history since last visit 
• Body systems assessment 
 
10 ADVERSE EVENTS  
10.1 Definitions 
10.1.1 Adverse Events (AEs) 
An adverse event (AE) is any untoward medical occurrence in a patient or trial subject 
administered a drug or biologic (medicinal product) or using a medical device; the event does not 
necessarily have a causal relationship with that treatment or usage. 
AEs include the following: 
• All suspected adverse medication reactions. 
• All reactions from medication overdose, abuse, withdrawal, sensitivity, or toxicity.  
• Apparently unrelated illnesses, including the worsening of a preexisting illness (see 
paragraph below on Preexisting Conditions). 
• Injury or accidents.  Note that if a medical condition is known to have caused the injury 
or accident (e.g., a fall secondary to dizziness), the medical condition (dizziness), the 
accident (e.g., fall secondary to dizziness), and any adverse outcome (e.g., hip fracture 
secondary to the fall) should be reported as three separate adverse events.   
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
• Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already 
reported clinical event.  Laboratory abnormalities associated with a clinical event (e.g., 
elevated liver enzymes in a subject with jaundice) should be described under Comments 
on the report of the clinical event (e.g., jaundice) rather than listed as a separate adverse 
event. 
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as adverse events.  However, the medical condition for which the 
procedure was performed should be reported if it meets the definition of an AE.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as the 
adverse event and the resulting appendectomy noted under Comments. 


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Preexisting Conditions – In this trial, a preexisting condition (i.e., a disorder present before the 
adverse event reporting period) should not be reported as an AE unless the condition worsens or 
episodes increase in frequency during the AE reporting period.  
Abnormal Test Findings – All laboratory test results will be reviewed by the Investigator.  The 
Investigator will utilize his/her judgment in determining if out of range laboratory values are 
clinically significant and should denote this using the abbreviation “CS” on the laboratory report 
for source documentation.  Laboratory tests that are labeled as clinically significant should be 
reported as AEs, either separately or as part of a description of a symptomatic AE.  If there are 
significant changes in a laboratory report from a previous visit that are determined to be 
clinically significant, these should also be reported as AEs.  Any abnormal laboratory value 
which requires treatment or further diagnostic testing and/or results in discontinuation from study 
should be reported as AEs. 
10.1.2 Serious Adverse Events (SAEs) 
Each adverse event is to be classified by the Investigator as SERIOUS or NONSERIOUS.  An 
adverse event that meets one or more of the following criteria/outcomes is classified as serious: 
• Results in death 
• Is life -threatening (see paragraph below on Life-threatening) 
• Requires in -patient hospitalization or prolongation of existing hospitalization (see 
paragraph below on Hospitalization) 
• Results in persistent or significant disability/incapacity (see paragraph below on 
Disability)  
• Is a congenital anomaly/birth defect 
Important adverse events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject or may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
The term serious also includes any other event that the Investigator or Sponsor judges to be 
serious or which is defined as serious by the regulatory agency in the country in which the event 
occurred.  If there is any doubt whether the information constitutes an AE or SAE, the 
information is to be treated as an SAE. 
Life-threatening – Any AE that places the subject at immediate risk of death from the event as 
it occurred.  A life-threatening event does not include an event that might have caused death had 
it occurred in a more severe form but that did not create an immediate risk of death as it actually 
occurred.  For example, drug-induced hepatitis that resolved without evidence of hepatic failure 
would not be considered life threatening, even though drug-induced hepatitis of a more severe 
nature can be fatal. 
Hospitalization – Hospitalization is defined as an overnight admission with observation of a 
minimum of 24 hours.  A hospitalization planned before the start of the study for a preexisting 
condition that has not worsened does not constitute an SAE (e.g., elective hospitalization for a 


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total knee replacement due to a preexisting condition of osteoarthritis of the knee that has not 
worsened during the course of the study). 
Disability – Defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
10.1.3 Severity 
The Investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum intensity of the adverse event.  For purposes of consistency, these intensity grades are 
defined as follows: 
MILD: 
Does not interfere with subject's usual function 
MODERATE: 
Interferes to some extent with subject's usual function 
SEVERE:  
Interferes significantly with subject's usual function 
Note the distinction between the gravity and the intensity of an adverse event.  Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction.  For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events listed above. 
10.2 Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject.  In addition, each study subject will be questioned about AEs at each site visit 
following the initiation of treatment. 
10.3 Reporting 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS.  This 
classification of the gravity of the event determines the reporting procedures to be followed.  If 
an SAE occurs, expedited reporting will follow local and international regulations, as 
appropriate. 
All AEs that occur in study subjects during the adverse event reporting period specified in the 
protocol must be reported, WHETHER OR NOT THE EVENT IS CONSIDERED 
MEDICATION RELATED. 
10.3.1 Reporting Period 
The AE reporting period for this study begins from the time of informed consent and ends at the 
final protocol required visit. 
IN ADDITION, any known untoward event that occurs subsequent to the AE reporting period 
that the Investigator assesses as possibly or probably related to the study medication should also 
be reported as an AE. 
10.3.2 Reporting AEs 
NONSERIOUS AEs are to be reported on the adverse event case report forms. 


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10.3.3 Reporting SAEs 
Serious adverse events should be reported on both the clinical trial adverse event CRF and 
the Serious Adverse Event Report Form. 
Note:  Where the same data are collected, the forms must be completed in a consistent manner.  
For example, the same AE term should be used on both forms. 
Any SAE, regardless of causal relationship, must be reported to the Sponsor within 24 hours 
after the Investigator becomes aware of the SAE by completing and sending an SAE report form.  
Compliance with this time requirement is essential so that the Sponsor may comply with its 
regulatory obligations. 
The initial SAE report should be completed as fully as possible but should contain, at a minimum: 
• A description of the event and the reason why the event is categorized as serious 
• Subject identification number 
• Investigator’s name and site identification number 
• Name of the suspected medicinal product (not applicable for double-masked studies) 
• Causality assessment 
Follow-Up information relating to an SAE must be reported to the clinical safety contact at the 
Sponsor within 24 hours of receipt by the Investigator by sending a completed SAE report form 
with new information.  The subject should be observed and monitored carefully until the 
condition resolves or stabilizes. 
All deaths are to be thoroughly investigated and reported.  Autopsy reports are to be obtained, if 
possible. 
The Sponsor and/or its designee are responsible for reporting SAEs to all applicable regulatory 
agencies and the central ethics committees within the required timeline. 
The Investigator is responsible for submitting required safety information to their local IRB. This 
information includes but is not limited to any safety alert letter received from the Sponsor and 
any SAEs occurring at their site. 
10.3.4 Relationship to Study Medication 
The causal relationship of the AE to study drug will be assessed by both the Investigator and the 
Sponsor.  The following definitions will be used in assessment. 
Probably Related:  The AE follows a reasonable temporal sequence from the time of drug 
administration.  It follows a known response pattern to the study drug.  The AE cannot be 
reasonably explained by other factors such as the subject’s clinical state, therapeutic 
interventions, or concomitant drugs. 
Possibly Related:  The AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the subject’s clinical state, 
other therapeutic interventions, or concomitant drugs. 


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Unrelated:  The AE does not follow a reasonable temporal sequence from administration of the 
product or the AE is clearly related to other factors such as the subject’s clinical state, other 
therapeutic interventions, or concomitant drugs administered to the subject. 
10.3.5 Follow-Up of Unresolved Events 
All AEs should be followed until they are resolved or the Investigator assesses them as chronic 
or stable or the subject’s participation in the trial ends (i.e., until a final report is completed for 
that subject). 
In addition, all serious adverse events and those nonserious events assessed by the Investigator as 
possibly or probably related to the study medication should continue to be followed even after 
the subject's participation in the trial is over.  Such events should be followed until they resolve 
or until the Investigator assesses them as “chronic” or “stable.”   
10.4  Exposure In Utero  
If any study subject becomes or is found to be pregnant while receiving study medication during 
the treatment period or within 30 days of discontinuing the study medication, the Investigator is 
to submit this information on a Pregnancy Notification Cover Sheet along with a completed 
Serious Adverse Event Form.  This must be done irrespective of whether an AE has occurred.  
Pregnancy during this time frame of the female partner of a male subject should also be reported.  
To ensure subject safety, each pregnancy must be reported to the Sponsor’s Medical Monitor or 
CRO designee within 24 hours of awareness of the pregnancy.  
If the pregnancy of a female study participant is discovered during the study, study medication 
should be discontinued. 
The Investigator will follow the subject (or female partner of a male subject) until completion of 
the pregnancy and will follow the neonate up to 1 month of birth. 
Within 24 hours of awareness, Investigator sites will notify the Sponsor’s Medical Monitor or 
CRO designee of abnormal pregnancy outcomes.  Normal outcomes may be reported within 5 
days of awareness.  Reporting of outcome will be provided on the Pregnancy Reporting Form. 
In addition to reporting the outcome on the Pregnancy Reporting Form, if the outcome of the 
pregnancy meets the criteria for immediate classification as a SAE (i.e., spontaneous abortion, 
stillbirth, neonatal death within one month of birth, or congenital anomaly [including that in an 
aborted fetus]), the Investigator should also follow the procedures for reporting a SAE within 24 
hours of awareness. 
Additional information about pregnancy outcomes follows: 
• Note that “spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within one month of birth should be reported, without 
regard to causality, as SAEs.  In addition, any infant death after one month that the 
Investigator assesses as possibly or probably related to the in utero exposure to the study 
medication should also be reported. 
• In the case of a live birth, the “normality” of the newborn can be assessed at time of birth. 


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• The “normality” of an aborted fetus can be assessed by gross visual inspection unless 
there are pre-abortion laboratory findings suggestive of a congenital anomaly. 
11 DATA ANALYSIS 
11.1 Sample Size Determination 
Estimates for sample size calculations are derived from published data from the analysis of the 
effect of ranibizumab (Lucentis) and aflibercept (Eylea) intravitreal administration regimens on 
DR severity score in the RISE/ RIDE studies and VIVID/VISTA studies, respectively, in which 
at least 28-46% of subjects improved by ≥ 2 steps after 12 months of treatment. 
With 45 evaluable subjects per treatment group, the study has >85% power (based on Fisher’s 
Exact Test and a 2-sided alpha =0.05) to demonstrate a statistically significant improvement in 
percent of subjects improving by ≥ 2 steps on the ETDRS severity scale, assuming underlying 
rates for active and placebo of 30% and 5%, respectively.  Assuming 10% drop-out/non-
evaluable rate, a sample size of 50 subjects per treatment arm (approximately 150 total) has been 
selected. 
11.2 Study Populations 
11.2.1 Safety Populations 
The safety population will include all enrolled subjects who receive at least one (1) dose of study 
medication.  All safety analyses will be conducted using the safety population. 
11.2.2 Efficacy Populations 
 Modified Intent-to-Treat Population 
The modified intent-to-treat (MITT) population will include all enrolled subjects who receive at 
least one dose of study medication. The primary efficacy analysis will be conducted using the 
MITT population. 
 Per Protocol Population 
The per protocol (PP) population will consist of all subjects in the MITT population who do not 
have major protocol deviations considered to affect the primary efficacy variable DRSS, have 
completed a minimum of 12 months of treatment and have been at least 70% compliant.  
Sensitivity analyses of the primary efficacy variables will be conducted using the PP population. 
11.3 Analysis of Demographics and Baseline Variables 
Descriptive statistics (e.g., number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum) will be generated for selected continuous variables (age, selected 
laboratory assays, vital signs, etc.) for each treatment group and for all subjects.  The number and 
percentage of subjects in each class of categorical demographic and baseline variables (e.g., 
ethnicity, and race) will be tabulated for each treatment group and for all subjects.  Individual 
subject demographic and baseline characteristic data will be listed. 


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11.4 Disposition of Subjects 
The number and percentage of subjects who are enrolled, complete the study, discontinue study 
medication, or withdraw from the study including reasons for study medication discontinuation 
or study withdrawal will be summarized along with the number and percentage of subjects in 
each of the analysis populations (safety, MITT, and PP) in tabular format by treatment group and 
for all subjects.  Individual subject disposition data will be listed.  
11.5 Study Days and Assessment Windows  
Study days will be numbered relative to the first day of dosing.  The start of study (Day 1) will 
be defined as the date on which a subject takes the first dose of any study medication, as 
recorded on the CRF.  Relative to study start, days will be numbered …-2, -1, 1, 2, ... with Day -
1 being the day prior to the start of study medication (Pre-Dose).   
Recorded data will be assigned to evaluation/assessment windows.  If more than one clinical 
evaluation is made within a window for a particular visit, the record with the worst assessment 
will be used for the assessment in that window. 
11.6 Safety Analysis 
All subjects who receive at least one dose of any study medication will be included in the safety 
analysis.  All safety endpoints are listed in Section 5.6.3. 
All AEs reported during the study period will be recorded and coded using MedDRA 
terminology.  An AE will be considered as treatment-emergent if it has an onset during the 
treatment period or is pre-existing and worsens after the first dose of study medication is 
administered.  The incidence of all reported treatment-emergent adverse events (TEAEs) will be 
summarized using system organ class and preferred term by treatment group and overall, using 
counts and percentages.  Separate analyses will be performed for ocular and non-ocular TEAEs.  
These summaries will also be provided for treatment related TEAEs and TEAEs by severity.  For 
ocular TEAEs, the subject will be considered to have had the TEAE if at least one eye had the 
TEAE. 
Continuous safety endpoints collected at each visit will be summarized with number of subjects, 
mean, standard deviation (SD), median, minimum, and maximum for each treatment group and 
for all subjects.  Qualitative variables collected at each visit will be summarized using counts and 
percentages for each treatment group and for all subjects.  Summaries will also include change 
from baseline and shift tables, where appropriate.  Individual subject safety data will be listed. 
11.7 Efficacy Analyses 
All efficacy endpoints are listed in Sections 5.5 and 5.6. All efficacy data will be summarized by 
treatment group and time point using appropriate descriptive statistics. Summaries will be 
presented for both the MITT and PP populations. Due to the small number of subjects that are 
expected to be enrolled at each center, all summaries and analyses will be performed using data 
pooled across centers.  
The primary hypotheses to be tested is that AKB-9778 15mg twice daily and AKB-9778 15mg 
once daily will be superior to placebo in the improvement of DR as measured by the ETDRS 
severity scale change from baseline at 12 months. Specifically, the primary endpoint is the 


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percentage of subjects with an improvement in study eye severity of DR (ETDRS DR Severity 
Score or DRSS) of ≥ 2 steps at Month 12 without need for treatment of PDR or DME (by IVT, 
laser, or vitrectomy) in the study eye.  The primary hypotheses will be tested in the MITT 
population using a Fisher’s Exact Test with a 2-sided 5% significance level.  To adjust for 
multiplicity, a pre-specified testing order will be used.  AKB-9778 15mg twice daily will be 
tested first, and AKB-9778 15mg once daily will be tested second.  Details of how missing data 
will be handled for the primary endpoint, along with sensitivity analyses to assess the impact of 
missing data will be outlined in the statistical analysis plan (SAP). 
Secondary and exploratory endpoints will be analyzed without adjustment for multiplicity, and 
all inferential analyses will use a 2-sided 5% significance level.  Continuous variables will be 
analyzed using ANCOVA models and/or repeated measures mixed effect models and 
dichotomous variables will be analyzed using the same approach as outlined for the primary 
endpoint.  Details of how missing data will be handled for secondary and exploratory endpoints 
will be provided in the SAP.   
Exploratory analyses will be conducted to understand the relationship between exposure and 
response and details of these analyses will be outlined in the SAP. 
11.8 Pharmacokinetic Analyses   
AKB-9778 plasma concentrations will be summarized by treatment group and nominal sampling 
time using descriptive statistics.  Individual subject pharmacokinetic data will be listed. 
Additional analyses including the potential relationship of plasma concentration and selected 
safety and efficacy parameters and/or subject demographic variables will be performed. 
11.9 Pharmacodynamic Analyses   
Blood samples collected at baseline and Month 12 End of Treatment (EOT) will be retained for 
exploratory analysis of biomarkers in plasma.  Once results of the study are known, the Sponsor 
will determine the value of conducting these analyses. 
11.10  Exploratory Genetic Analyses   
For subjects who have provided consent for genetic sampling, a blood sample will be retained for 
exploratory genetic analysis that may provide insight into the role of Tie2 in diabetic retinopathy 
and an individual subject's response to AKB-9778 treatment.  Once results of the study are 
known, the Sponsor will determine the value of conducting these analyses. 
12 DATA HANDLING AND RECORD KEEPING 
12.1 Case Report Forms (CRFs) 
Case Report Forms (CRFs) are required and should be completed for each included subject.  The 
completed original CRFs are the sole property of the Sponsor and should not be made available 
in any form to third parties, except for authorized representatives of the Sponsor or appropriate 
regulatory authorities, without written permission from the Sponsor.  CRFs for this study will be 
electronic (eCRFs). 


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The Investigator has ultimate responsibility for the accuracy, authenticity, and timely collection 
and reporting of all clinical, safety, and laboratory data entered on the CRFs and any other data 
collection forms.  The CRFs must be signed by the Investigator (for electronic CRFs, they can be 
signed electronically) to attest that the data contained on the CRFs is true.  Any corrections to 
entries made in the CRFs and source documents must be dated, initialed and explained (if 
necessary) and should not obscure the original entry.  
In most cases, the source documents are contained in the subject’s chart at the hospital or the 
physician's office.  In these cases, data collected on the CRFs must match the data in those 
charts.  
12.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, e.g., CRFs and hospital records), all original signed Informed Consent Forms, 
copies of all CRFs, SAE forms, source documents, detailed records of drug disposition, and 
adequate documentation of relevant correspondence (e.g., letters, meeting minutes, telephone 
calls reports).  The records should be retained by the Investigator according to the International 
Conference on Harmonisation (ICH), local regulations, or as specified in the Clinical Study 
Agreement, whichever time period is longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), the Sponsor should be prospectively notified.  The 
study records must be transferred to a designee acceptable to the Sponsor, such as another 
Investigator, another institution, or to the Sponsor.  The Investigator must obtain Sponsor’s 
written permission before disposing of any records, even if retention requirements have been 
met. 
13 QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) 
13.1 Study Site Monitoring Visits 
During study conduct, the Sponsor or its agent will conduct periodic monitoring visits to ensure 
that the protocol, Good Clinical Practice (GCP), and applicable local regulations are being 
followed.  The monitors will review source documents to confirm that the data recorded on CRFs 
is accurate.  The Investigator/institution will allow Sponsor monitors or designees and 
appropriate regulatory authorities direct access to source documents to perform this verification. 
The study site may also be subject to QA audits and Regulatory Inspections performed by the 
Sponsor or companies working with or on behalf of the Sponsor, and/or review by the IRB, 
and/or to inspection by appropriate regulatory authorities 
It is important that the Investigator and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 


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13.2 Protocol Deviations 
The Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects.  Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the Investigator should consult with the 
Sponsor or designee (and IRB, as required) to determine the appropriate course of action. 
The site should document all protocol deviations in the subject’s source documents.  In the event 
of a significant deviation, the site should notify the Sponsor or its designee (and IRB, as 
required) immediately.  Significant deviations include, but are not limited to, those that involve 
fraud or misconduct, increase the health risk to the subject, or confound interpretation of primary 
study assessments. 
14 TRIAL DISCONTINUATION/INVESTIGATIVE SITE TERMINATION 
The Sponsor reserves the right to discontinue the study prior to inclusion of the intended number 
of subjects, but intends only to exercise this right for valid scientific or administrative reasons.  
After such a decision, the Investigator must contact all participating subjects within a time period 
specified by the Sponsor to inform them of the decision to discontinue the trial.   
The study may also be put on hold or discontinued by IRB or Regulatory Authority. 
14.1 Criteria for Premature Termination or Suspension of the Study 
The following criteria may result in either temporary suspension or early termination of the 
study: 
• New information regarding the safety or efficacy of the study medication that indicates a 
change in the known risk/benefit profile for the compound, such that the risk/benefit is no 
longer acceptable for subjects participating in the study. 
• Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety. 
The Sponsor reserves the right to discontinue the trial for other valid administrative reasons. 
14.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the Investigator) 
is found to be in significant violation of GCP, protocol, contractual agreement, or is unable to 
ensure adequate performance of the study or guarantee safety of participating subjects. 
14.3 Procedures for Premature Termination or Suspension of the Study or 
Investigational Site(s) 
In the event that the Sponsor elects to terminate or suspend the study or the participation of an 
Investigational site, a study-specific procedure for early termination or suspension will be 
provided by the Sponsor; the procedure will be followed by applicable Investigational sites 
during the course of termination or study suspension. 


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15 ETHICS 
15.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (1996). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 
15.2 Institutional Review Board (IRB)  
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, (e.g., recruitment 
advertisements, if applicable) from the IRB prior to implementation.  All correspondence with 
the IRB should be retained in the Investigator File.  Copies of IRB approvals should be 
forwarded to the Sponsor. 
The only circumstance in which an amendment may be initiated prior to IRB approval is where 
the change is necessary to eliminate apparent immediate hazards to the subjects.  In that event, 
the Investigator must notify the IRB and the Sponsor in writing immediately after the 
implementation. 
15.3 Subject Information and Consent 
It is the responsibility of the Investigator, or a person designated by the Investigator, to give each 
subject (or the subject’s acceptable representative), prior to inclusion in the study, potential 
benefits of participation, and the possible risks involved.  The Investigator should ensure all 
questions the subject may have regarding participation are answered.  The process must be 
conducted in a language understood by the subject.  The subject must be informed about their 
right to withdraw from the trial at any time without consequence.   
Furthermore, it is the responsibility of the Investigator, or a person designated by the 
Investigator, to obtain a freely signed informed consent from each subject or the subject’s legally 
acceptable representative prior to inclusion in the trial.  The Investigator will retain the original 
of each subject's signed consent form.  The subject (or the subject’s acceptable representative) 
must be provided a copy of the signed form. 
The informed consent form must be in compliance with ICH GCP, local regulatory requirements, 
and legal requirements.  The informed consent form used in this study, and any changes made 
during the course of the study, must be prospectively approved by both the IRB and the Sponsor 
before use. The Investigator must re consent subjects on updated material as required by the IRB 
and local regulatory, and legal requirements. 
15.4 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority, or if the Investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the Sponsor 
should be informed immediately.  


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In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that comes to the attention of the Investigator. 
15.5 Subject Confidentiality 
All parties will ensure protection of subject personal data and will not include subject names on 
any Sponsor forms, reports, publications, or in any other disclosures, except where required by 
laws.  In case of data transfer, the Sponsor will maintain high standards of confidentiality and 
protection of subject personal data. 
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number.  As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the Investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA), the Sponsor’s designated auditors, and the appropriate 
IRB to review the subject’s original medical records (source data or documents), including, but 
not limited to, laboratory test result reports, ECG reports, admission and discharge summaries for 
hospital admissions occurring during a subject’s study participation, and autopsy reports.  Access 
to a subject’s original medical records requires the specific authorization of the subject as part of 
the informed consent process. 
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s CRF). 
16 PUBLICATION OF STUDY RESULTS 
No publication or disclosure of study results will be permitted, except under the terms and 
conditions of a separate, written agreement between Sponsor and the Investigator and/or the 
Investigator’s institution.  The Sponsor must have the opportunity to review and approve all 
proposed abstracts, manuscripts, or presentations regarding this study prior to submission for 
publication/presentation.  Any information identified by the Sponsor as confidential must be 
deleted prior to submission. 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including:  Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
 
 
 


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Brindle NP, Saharinen P, Alitalo K. Signaling and functions of angiopoietin-1 in vascular 
protection. Circ Res. 2006 April 28; 98(8): 1014–1023. 
Campochiaro PA, Khanani A, Singer M, et al; Enhanced benefit in diabetic macular edema from 
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Ophthalmology. 2016 Aug;123(8):1722-30 
Campochiaro PA, Sophie R, Tolentino M, et al. Treatment of diabetic macular edema with an 
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Davis JS, Yeo TW, Piera KA, Woodberry T, Celermajer DS, Stephens DP, et al. Angiopoietin-2 
is increased in sepsis and inversely associated with nitric oxide-dependent microvascular 
reactivity. Crit Care. 2010;14(3):R89. Epub 2010 May 18. 
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#18. Invest Ophthalmol Vis Sci. 1998 Feb;39(2):233-52. 
Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends 
Immunol. 2006 Dec;27(12):552-8. Epub 2006 Oct 12.  
Fong DS, Aiello LP, Ferris FL 3rd, Klein R. Diabetic retinopathy. Diabetes Care. 2004;27:2540-
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Fong DS, Aiello L, Gardner TW, et al; American Diabetes Association. Retinopathy in diabetes. 
Diabetes Care. 2004;27 Suppl 1:S84-7. 
Guariguata L, Whiting DR, Hambleton I,  Beagley J, Linnenkamp U, Shaw JE. IDF Diabetes 
Atlas: Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes 
Research and Clinical Practice. 2014.  
Harewood GC, McConnell JP, Harrington JJ, et al. Detection of occult upper gastrointestinal 
tract bleeding: performance differences in fecal occult blood tests. Mayo Clin Proc. 2002 
Jan;77(1):23-8. 
Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term effects of ranibizumab on 
diabetic retinopathy severity and progression. Arch Ophthalmol. 2012 Sep;130(9):1145-52. 
Klein R, Klein BE, Moss SE. How many steps of progression of diabetic retinopathy are 
meaningful? The Wisconsin epidemiologic study of diabetic retinopathy. Arch 
Ophthalmol. 2001 Apr;119:547-53. 


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Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic Study of 
Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons 
with type 1 diabetes. Ophthalmology, 2008. 115(11): p. 1859-68. 
Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic Study of 
Diabetic Retinopathy XXIII: the twenty-five-year incidence of macular edema in persons 
with type 1 diabetes. Ophthalmology, 2009. 116(3): p. 497-503. 
Korobelnik JF, Do DV, Schmidt-Erfurth U, Boyer DS, et al. Intravitreal aflibercept for diabetic 
macular edema. Ophthalmology. 2014 Nov;121:2247-54. 
Llanos L, Moreu R, Ortin T, Peiro A, Pascual S, et al. Existence of a relationship between 
increased serum alanine aminotransferase levels (ALT) detected in premarketing clinical 
trials and postmarketing published hepatotoxicity case-reports. Alimentary Pharmacology 
and Therapeutics, Wiley, 2010, 31 (12), pp.1337. 
Maa AY, Feuer WJ, Davis CQ, Pillow EK, et al. A novel device for accurate and efficient testing 
for vision-threatening diabetic retinopathy. J Diabetes Complications. 2016;30(3):524-32. 
Milner CS, Hansen TM, Singh H, Brindle NP. Roles of the receptor tyrosine kinases Tie1 and 
Tie2 in mediating the effects of angiopoietin-1 on endothelial permeability and apoptosis. 
Microvasc Res. 2009 Mar;77(2):187-91. Epub 2008 Sep 20. 
Peters KG, Kontos CD, Lin PC, Wong AL, Rao P, Huang L, et al. Functional significance of 
Tie2 signaling in the adult vasculature. Recent Prog Horm Res. 2004;59:51-71. 
Rockey DC, Auslander A, Geenberg PD. Detection of upper gastrointestinal blood with fecal 
occult blood tests.  Am J Gastroenterology. 1999. Vol. 94(2): 344-350.  
Shen J, Frye M, Lee BL, et al. Targeting VE-PTP activates TIE2 and stabilizes the ocular 
vasculature. J Clin Invest 2014; 124:4564-76. 
Yau JW, Rogers SL, Kawasaki R, et al. Meta-Analysis for Eye Disease (META-EYE) Study 
Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 
2012;35:556-64. 
 
 


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18 APPENDICES   
18.1 Appendix A: Schedule of Activities  
   
 
 


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Schedule of Activities [A]  
Protocol Activities 
Screening 
Baseline  
Treatment Period [B] 
F/U 
Day 
Month 
 
Day - 28 to  
Day - 1 
Day 1 
Pre-Dose 
Day 1  
Day 7 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
(EOT) 
EOT + 
1M 
 
Informed Consent 
X 
 
Eligibility Criteria 
X 
 
Demographics 
X 
 
Medical/Ophthalmic History 
X 
X 
X 
Height Weight and Temperature [C] 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Body System Assessments [D]  
X 
X 
X 
X 
X 
X 
ECG [E]  
X 
X 
X 
 
  
 
Vitals [F] 
 
  Sitting BP and HR 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
 
Eye and Vision Exams  
 
   ETDRS BCVA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
   Slit Lamp Biomicroscopy  
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
   Intraocular Pressure   
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
   Dilated Indirect Ophthalmoscopy 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
   SD OCT  
X 
X 
X 
X 
X 
 
   Fundus Photography[G] 
X 
X 
X 
X 
X 
 
   Fluorescein Angiography [H] 
X 
X 
X 
 
   OCT Angiography Sub Study [I]   
X 
X 
X 
X 
X 
 
   ERG Sub Study [I] 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Laboratory Procedures 
 
   Serum/Urine Pregnancy [J] 
X 
X 
X 
X 
 
   Hematology[K] 
X  
X 
X 
X 
X 
X 
 
X 
X 
 
   Chemistry [L] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
   Urinalysis [M] 
X 
X 
X 
X 
 
   Fecal Occult Blood Test [N] 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
   Biomarker Blood Sampling  
X 
X 
 
   Blood sampling for Genetic Analyses 
X 
 
   PK Blood Sampling [O] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Dosing [P]  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
   Study medication dispensing & return, 
diary review [Q] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
  
  
 
AE collection [R] [S] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication Review [T] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
[A] Assessments are conducted at the study site unless otherwise noted.   


Protocol No. AKB-9778-CI5001 
 
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[B] Site visits scheduled for Months 1 through 12 should be conducted within 28 days times the study month number ±3 days relative to the baseline visit. Homecare nurse visits scheduled 
for Screening, Months 3, 6, 9 and 12 should be conducted within 1 week after the corresponding site visit.  The Follow-up homecare nurse visit is to be conducted 4 weeks (± 3 days) after 
the EOT visit at the investigative site. 
[C] Height is collected at screening only. 
[D] Body system assessments are conducted at the home care nursing visit. 
[E] ECGs will be performed after the subject rests in a supine position for approximately 5 minutes.  ECGs should be taken prior to any vital sign assessments or blood draws.  
[F] Assessments are conducted prior to any blood draws when possible. On Day 1, sitting BP and HR assessments will be conducted at Baseline (pre-dose) and at 30 and 90 minutes post-
dose.  On the Month 6 visit, sitting BP and HR assessments will be conducted prior to administration of the AM dose at the site and at 30 and 90 minutes after the AM dose.  
[G] For sites participating in the UWF imaging sub study, at the Screening, Month 6 and Month 12 (EOT) vists, UWF fundus photographs will be obtained in addition to standard fundus 
photographs.  
[H] For sites participating in the UWF imaging sub-study, UWF FA will be performed in lieu of FA. 
[I] Performed only at sites with required equipment available. 
[J] In women of child bearing potential, a serum pregnancy test will be conducted at the Screening visit. Prior to dosing on Day 1, a urine pregnancy test will be conducted on Day 1. At the 
Month 6 and Month 12 site visits, a urine pregnancy test will be conducted.  
[K] HbA1C is conducted at Screening, Baseline, Month 6, and Month 12. 
[L] eGFR will be determined on serum chemistry samples collected at the Screening, Baseline, Month 6, Month 9, and Month 12 (EOT) visits. 
[M] UACR is measured at Baseline, Month 6, Month 9, and Month 12 (EOT) visits; subjects should refrain from heavy exercise 24 hours before these visits. 
[N] Sites will distribute instructions and materials to subjects for home specimen collection and shipping to the central laboratory. Subjects will collect their specimens and are responsible for 
shipping to the clinical laboratory for testing; specimen collection and shipping should be conducted within one week following the site visit. Homecare nurses will review status of specimen 
collection and shipping with subjects. 
[O] Subjects are to be instructed prior to the Month 6 visit to NOT take the AM dose prior to their visit and to bring their AM dose to the visit along with other study medication in kits, as the 
AM dose will be administered in the clinic on this visit. The post-dose PK sample collection on Day 1 and Month 6 is relative to time of dose administration. PK blood sampling is conducted 
at 30 and 90 minutes after dosing ± 10 minutes. PK blood samples are to be collected after vital signs are conducted.  
[P] On Day 1 and Month 6, subjects will administer their AM dose at the site.  Prior to dosing on these visits, subjects should eat a snack or meal and drink 1-2 glasses of fluid.  Subjects will 
self-dose in the seated position and remain seated for 30 mins. Subjects will dose BID with the exception of Day 1 when the subject will dose the AM dose at the site and will begin the BID 
dosing schedule on Day 2.   
[Q] At Baseline, subjects will be trained on administration of study medication. Subjects will be provided with a dosing diary and dosing supplies at Day 1, and monthly during the treatment 
period. 
[R] All adverse events (serious and non-serious, and related and non-related) will be documented and recorded through the last protocol specified visit.   
[S] If the home healthcare nurse identifies any potential AEs during the home visit, the nurse will communicate directly to the study site and the Investigator will be responsible for 
determination of AEs and any necessary follow-up with the subject 
[T] All concomitant medications received up to and including 28 days prior to the start of study medication through the Month 12 visit will be recorded.  
 


Protocol No. AKB-9778-CI5001 
 
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18.2  Appendix B: Criteria for Treatment of PDR or DME in the Study Eye or 
Qualified Fellow Eye During the Study 
Standardizing the criteria to treat PDR or DME during this study will allow for enhanced 
evaluation of the effect of AKB-9778 monotherapy on diabetic retinopathy. These criteria have 
been adapted from the DRCR.net Protocol W (http://drcrnet.jaeb.org/Studies.aspx?RecID=340).  
If a study eye or qualified fellow eye treated for PDR or DME, study medication may be 
discontinued at the discretion of the Investigator and subject. If a non-qualified fellow eye 
requires treatment for PDR or DME, the subject will remain in the study.  
o Criteria for treatment of PDR or DME in the study eye or qualified fellow eye and 
allowed treatments are presented below. Non-qualified fellow eyes may be treated 
at the discretion of the Investigator.  
o Refer to Section 8.4.3 for additional details regarding assessments to be conducted 
prior to treatment of PDR or DME.  
 
Treatment for PDR in the study eye or qualified fellow eye should not be given unless at least 
one of the following is present: 
1. Neovascularization of the angle or neovascular glaucoma 
2. Neovascularization of the disc (NVD) greater than standard photograph 10A (1/4 to 1/3 
disc area)  
3. Any NVD with pre-retinal or vitreous hemorrhage  
4. Neovascularization elsewhere (NVE) greater than ½ disc area with pre-retinal or vitreous 
hemorrhage 
5. Vitreous hemorrhage (VH) requiring treatment that is presumed to be from PDR  
6. If none of the above is met, Reading Center confirmation of neovascularization within the 
7-field fundus photo area should be obtained prior to initiating treatment whenever 
possible 
Treatment of neovascularization outside of the 7-field fundus photo area without 
the presence of pre-retinal or vitreous hemorrhage is discouraged (If the 
Investigator believes treatment for peripheral neovascularization is necessary, the 
sponsor should be informed prior to initiation). 
Treatment for PDR can include: 
1. Anti-VEGF IVT  
2. PRP / sector Laser photocoagulation 
3. Vitrectomy 
 
Treatment for DME in the study eye or qualified fellow eye should not be given unless there is 
center-involved DME on clinical exam with ≥ 10% increase in CST from baseline and: 
1. ≥ 10 letter loss of BCVA at a single visit or 
2. 5 to 9 letter loss of BCVA at 2 consecutive visits 


Protocol No. AKB-9778-CI5001 
 
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Treatment for DME can include: 
1. Anti-VEGF or steroid IVT  
2. Grid / focal Laser photocoagulation