Clinical trial NCT03466099
Conditions: Diabetic Macular Edema
Sponsor: KalVista Pharmaceuticals, Ltd.
Start date: 2018-02-16; Completion date: 2019-10-10
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a clinical study where patients with diabetes and a vision threatening eye condition called "Diabetic Macular Edema" receive four injections into the eye at monthly intervals. The patients will already have tried the standard of care without complete success. The patients will be randomized to receive either a high dose, a low dose or a sham control treatment. The study will evaluate whether the new treatment improves vision and whether it changes the underlying course of the disease in the eye.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: KVD001 Injection intervention 2: Sham Procedure
Intervention descriptions: intervention 1: Intravitreal KVD001 Injection intervention 2: Sham Procedure

Protocol documents:
Prot_000.pdf: 
 
 
 
 
PROTOCOL 
 
 
 
A randomized sham-controlled double-masked Phase 2a study of 
the efficacy, safety and tolerability of the intravitreal plasma 
kallikrein inhibitor, KVD001, in subjects with center-involving 
diabetic macular edema (ciDME) who have had prior anti-vascular 
endothelial growth factor (VEGF) treatment 
 
 
 
 
 
 
 
NCT03466099 
 
 
 
 
9 April 2018 


 
 
PROTOCOL TITLE 
A randomized sham-controlled double-masked Phase 2a study of the efficacy, safety 
and tolerability of the intravitreal plasma kallikrein inhibitor, KVD001, in subjects with 
center-involving diabetic macular edema (ciDME) who have had prior anti-vascular 
endothelial growth factor (VEGF) treatment 
 
 
Sponsor: 
KalVista Pharmaceuticals, Ltd. 
Tetricus Science Park 
Building 227 
Porton Down SP4 0JQ 
United Kingdom 
Clinical Research Organization: 
Ora, Inc. 
300 Brickstone Square 
Andover, MA 01810 
USA 
Sponsor Protocol No.: 
KVD001-201 
IND No.: 
 
Study Drug Name: 
KVD001 Injection 
Development Phase: 
2a 
Date of Protocol: 
09APR2018 
Date of Previous Protocol: 
31OCT2017  
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki and with other applicable 
regulatory requirements. 
This document contains confidential information of KalVista Pharmaceuticals, Ltd. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 


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SIGNATURE PAGE 
 
Title: A randomized sham-controlled double-masked Phase 2a study of the efficacy, 
safety and tolerability of the intravitreal plasma kallikrein inhibitor, KVD001, in subjects 
with center-involving diabetic macular edema (ciDME) who have had prior anti-vascular 
endothelial growth factor (VEGF) treatment 
 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki (1989), and the guidelines on Good Clinical 
Practice. 
_______ 
_____________________ 
 
Date 
 
 
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_____________________ 
Date 
 
 
____ 
_____________________ 
Date 
 
 
 
 
 
 
4/10/2018
4/10/2018
4/9/2018


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Declaration of the Investigator 
Title: A randomized sham-controlled double-masked Phase 2a study of the efficacy, 
safety and tolerability of the intravitreal plasma kallikrein inhibitor, KVD001, in subjects 
with center-involving diabetic macular edema (ciDME) who have had prior anti-vascular 
endothelial growth factor (VEGF) treatment. 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure (IB), electronic case report form (eCRF), and other 
scientific data. 
The study will not be commenced without the prior written approval of a properly 
constituted Institutional Review Board (IRB) and/or Independent Ethics Committee 
(IEC). No changes will be made to the study protocol without the prior written approval 
of the Sponsor and the IRB and/or IEC, except where necessary to eliminate an 
immediate hazard to the patients. 
I have read and understood and agree to abide by all the conditions and instructions 
contained in this protocol. 
 
I agree and understand that as the Principal Investigator, it is my responsibility to train 
my staff on all updates to the clinical protocol, and to ensure that such training is 
acknowledged in the appropriate study documentation. 
 
Responsible Investigator of the local study center 
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
_____________________________________ 
Name (block letters) 
 
_____________________________________ 
Title (block letters) 
 
_____________________________________ 
Institution (block letters) 
 
_____________________________________ 
Phone number 


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PROTOCOL SYNOPSIS 
Title 
A randomized sham-controlled double-masked Phase 2a study 
of the efficacy, safety and tolerability of the intravitreal plasma 
kallikrein inhibitor, KVD001, in subjects with center-involving 
diabetic macular edema (ciDME) who have had prior 
anti-vascular endothelial growth factor (VEGF) treatment 
Sponsor Study No. 
KVD001-201 
Phase 
2a 
Sponsor 
KalVista Pharmaceuticals, Ltd. 
Study Center(s) 
Ophthalmology clinics in the United States (US) with experience 
in the conduct of diabetic macular edema (DME) clinical studies 
Objective(s) 
Primary Objective:  
 
To evaluate the efficacy of monthly dosing of 
intravitreal (IVT) injection of KVD001 in subjects with 
ciDME who have had prior anti-VEGF treatment 
Secondary Objective: 
 
To evaluate the local and systemic safety and 
tolerability of monthly dosing of KVD001 Injection in 
subjects with ciDME who have had prior anti-VEGF 
treatment 
Design 
This is a phase 2a, randomized, double-masked,  
sham-controlled, 3-arm study to evaluate the efficacy, safety, and 
tolerability of KVD001 Injection as monotherapy in adult subjects 
with ciDME who have had prior anti-VEGF treatment. 
Approximately 123 eligible subjects will be randomized into the 
study.  
The maximum duration of the study for each randomized subject 
will be up to 28 weeks (including up to 4 weeks for screening, 
12 weeks treatment period, and 12 weeks follow-up). 
The study will be conducted on an out-patient basis. 
The study schedule of events will be as follows: 
Screening Phase: The screening period will be up to 4 weeks. 
All subjects will sign an Informed Consent Form (ICF) prior to any 
study related procedures being performed. Subjects will be 
18 years of age or older, at the time of screening, and will have a 
diagnosis of ciDME with prior anti-VEGF treatment. 
Treatment Phase: On the day of first study drug administration 
(Day 1), the subject’s eligibility will be reconfirmed and baseline 
assessments will be performed. Eligible subjects will be 
randomized 1:1:1 to receive KVD001 Injection (6 μg or 3 μg 
KVD001) or a sham procedure during a 12-week, double-masked 
treatment period (a total of 4 doses given at approximately 
monthly intervals).  
Subjects will visit the study clinic on Day 1 and Weeks 4, 8, and 
12 during the Treatment Phase for study drug administration or 
sham procedure, safety, and ophthalmic assessments (see 


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Table 2). The subject will remain in the clinic after study drug 
administration or sham procedure until all post-dose procedures 
and observations have been completed and the Investigator 
confirms that the subject may be discharged. Investigators 
should schedule visits at Week 4, 8, and 12 to provide 28 days 
between visits. The visit window for these visits is -3 days to +7 
days. 
Approximately twenty-four (24) hours after each study drug 
administration or sham procedure on Day 1 and Weeks 4, 8, and 
12, subjects will be contacted by telephone to evaluate any 
reported adverse events (AEs) and changes in concomitant 
medications. In the event of any reported ocular or systemic AEs 
that are considered by the Investigator to be a possible cause for 
concern, the subjects will return to the clinic for assessment as 
soon as possible. 
Follow up Phase: All subjects will visit the clinic at Weeks 16, 
20, and 24 after the last study drug administration or sham 
procedure for safety and ophthalmic assessments (see Table 2). 
The visit window for Weeks 16, 20, and 24 is ±7 days. 
Early Discontinuation: If any subject discontinues the trial early, 
every effort should be made to complete the Week 24/early 
discontinuation (ED) evaluations as soon as possible and, 
whenever possible, prior to starting any new medication or 
treatment. All attempts will be made to not discontinue the 
subject unless necessary. 
Rescue Treatment: Rescue intervention (e.g., anti-VEGF, 
focal/grid macular laser photocoagulation, (IVT) steroids ) may 
be administered due to worsening DME (i.e., attributable to 
worsening DME and not another cause;) if either of the following 
occurs and, where possible, after consultation with the Medical 
Monitor:  
 
During Treatment Phase 
o Best corrected visual acuity (BCVA) deteriorates 
3 lines (15 letters) or more from baseline 
o Central Subfield Thickness (CST) worsening of 
>100 µm from baseline 
 
During Follow up Phase (i.e., after week 16) 
o BCVA deteriorates 3 lines (15 letters) or more 
from highest BCVA during treatment phase or 
baseline 
o CST worsening of >100 µm from lowest CST 
during treatment phase or baseline. 
 
Subjects who receive a rescue intervention in the study eye will 
be discontinued from further study participation.  
Investigational 
Product 
KVD001 Injection consists of KVD001 (as hydrochloride [HCl] 
salt), trehalose dihydrate, histidine, and water for injection. 
KVD001.HCl will be supplied in 2 mL glass vials at the 


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concentration of 60 μg/mL and 30 μg/mL KVD001. 
KVD001 Injection is 6 μg or 3 μg KVD001 administered as a 100 
µL volume IVT injection. 
Number of 
Subjects 
Approximately 123 eligible subjects will be randomized into this 
study.  
Population 
The study population will include male and female subjects 
18 years of age or older with ciDME who have received prior 
anti-VEGF treatment. 
Except as otherwise defined, subjects must fulfill all of the 
following criteria both at Screening and on Day 1 to be eligible for 
inclusion in the study.  For applicable conditions, subjects who do 
not meet the inclusion criteria at Visit 1 or 2 may be rescreened 
with permission from the Sponsor or Ora. 
The study eye will be defined as the eye that meets all of the 
inclusion and none of the exclusion criteria. If both eyes qualify, 
the eye with the worse BCVA ETDRS at Day 1 will be used as 
the study eye. If both eyes have the same BCVA ETDRS at Day 
1, the eye with the highest CST on spectral-domain optical 
coherence tomography (SD-OCT) on Day 1, as assessed by the 
Investigator, will be used as the study eye. If both eyes qualify 
and neither is preferred based on the inclusion/exclusion criteria 
and have the same BCVA ETDRS and CST on Day 1, either eye 
may be chosen as the study eye. In this instance, the 
Investigator should select the eye that, in their opinion, is most 
likely to respond to treatment as the study eye. 
Inclusion Criteria: 
1. Male or female adult subjects 18 years of age and older. 
2. Confirmed diagnosis of Type I or Type II diabetes mellitus 
(DM). Any of the following are sufficient: 
o Current regular use of insulin for the treatment of diabetes 
o Current regular use of oral anti-hyperglycemia agents for 
the treatment of diabetes 
o Documented diabetes by American Diabetes Association 
and/or World Health Organization (WHO) criteria 
3. BCVA, using Standard Early Treatment Diabetic Retinopathy 
Study (ETDRS) chart, of ≥19 letters (~20/400) and 
≤73 letters (~20/40) in the study eye and ≥34 letters (~20/200 
or better) in the fellow eye at Screening and Day 1. 
4. Presence of ciDME in the study eye defined as Heidelberg 
Spectralis Optical Coherence Tomography (SD-OCT) CST 
≥305 μm in women and ≥320 μm in men in the study eye (as 
assessed at Screening by the Investigator and Central Image 
Reading Center (CIRC) and on Day 1 by the Investigator). 
5. Subjects’ first anti-VEGF injection in the study eye occurred 
≤36 months prior to Day 1. 
6. Subjects have received at least 3 anti-VEGF injections in the 
study eye within a 6-month period within the 36 months prior 


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to Day 1. 
7. The last anti-VEGF injection in the study eye is ≥ 8 weeks 
prior to Day 1. 
8. Subjects, who in the view of the Investigator, are able to 
defer treatment in the study eye for at least 6 months 
following Day 1. Note, rescue treatment is available (see 
Section 5.8). 
9. Values for blood and urine safety labs at the Screening visit 
showing no clinically significant deviation as determined by 
the Investigator. 
10. Women who are post menopausal for at least 1 year, 
surgically sterile for at least 3 months prior to Day 1, or who 
are agreeable to using highly effective contraception 
(adequate contraceptive measures include stable use of oral 
contraceptives or other prescription pharmaceutical 
contraceptives for two or more menstrual cycles prior to 
screening; intrauterine device (IUD); bilateral tubal ligation; 
vasectomy; condom plus contraceptive sponge, foam, or jelly 
or diaphragm plus contraceptive sponge, foam, or jelly), or 
abstinence.  
11. Sexually active men who are not vasectomized and have 
sexual partners of childbearing potential should be agreable 
to using highly effective contraception. 
12. Provide signed informed consent and are willing and capable 
of complying with clinic visits and study  procedures. 
 
Exclusion Criteria: 
1. Females who are pregnant or lactating, or expecting to 
become pregnant during the course of the study. 
2. Evidence of ocular pathology (e.g. visually significant 
cataract) that impacts subject’s vision in the study eye from 
any cause other than DME, in the opinion of the Investigator. 
3. Evidence/presence of amblyopia, vitreomacular traction, 
epiretinal membrane, foveal atrophy, or foveal ischemia, or 
any other condition in the macula that is thought to impair the 
subject’s vision (other than DME) in the opinion of 
Investigator. 
4. Prior treatment with panretinal photocoagulation or focal grid 
macular photocoagulation in the study eye within the 
previous 3 months prior to Day 1. 
5. Prior treatment with IVT steroid in the study eye (in the 
3 months prior to Day 1 for triamcinolone, 6 months prior to 
Day 1 for Ozurdex and at any time for Iluvien). 
6. Prior treatment with topical NSAIDs or topical  steroids in the 
study eye within 1 month prior to Day 1.  
7. Prior treatment with Jetrea® (ocriplasmin) injection in the 
study eye within the previous 3 months prior to Day 1. 
 
 


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8. Prior treatment with systemic corticosteroids or systemic 
anti-VEGF therapy within 3 months prior to Day 1. 
9. Prior vitrectomy in the study eye. 
10. Prior intraocular surgery in the study eye except for cataract 
surgery. Cataract surgery within the previous 6 months of 
Day 1 in the study eye is excluded. 
11. Intraocular pressure (IOP) at Screening or Day 1 of   
>22 mmHg in the study eye or use of >2 antiglaucoma 
agents (combination agents count as 2 agents) in the study 
eye. 
12. Evidence of infectious dacrocystitis, significant blepharitis, 
active conjunctivitis, infectious keratitis, or scleritis in either 
eye, or any other condition that might affect the safety of the 
IVT injection in the opinion of Investigator. 
13. Evidence of active intraocular inflammation in the study eye. 
14. Current active proliferative diabetic retinopathy (PDR), active 
anterior segment neovascularization (ASNV), active retinal 
neovascularization, or the presence of vitreous hemorrhage 
in the study eye. (Note, quiescent PDR is not exclusionary). 
15. Any concurrent ocular condition in the study eye which, in 
the opinion of the Investigator, could interfere with the 
evaluation of efficacy or safety. 
16. Poorly controlled DM defined as glycosylated hemoglobin 
[HgA1c] ≥12.0% or having initiated intensive insulin 
treatment (a pump or multiple daily injections) within prior 4 
months or planning to do so in the next 2 months, or two (2) 
or more episodes of diabetic ketoacidosis requiring 
hospitalization within the preceding 6 months. 
17. Uncontrolled hypertension at Screening or Day 1 defined as 
systolic ≥180 mmHg or diastolic ≥110 mmHg.  
18. Significant co-existing disease such as marked hepatic 
impairment, end stage renal disease (defined as a current or 
imminent requirement for dialysis), symptomatic cardiac 
failure, or significant pulmonary dysfunction that may place 
the subject at higher risk for treatment complications, failure 
of follow-up, and/or may impact the outcome of the data 
interpretation of the study, in the opinion of the Investigator. 
19. History of other disease (e.g., unstable psychiatric illness), 
metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a 
disease or condition that contraindicates the use of an 
investigational product, might affect interpretation of the 
results of the study, or renders the subject at high risk for 
treatment complications or lack of follow-up, in the opinion of 
Investigator. 
20. History of alcohol and/or drug abuse in the last 2 years. 
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within 3 months or within 5 half-lives of the last dosing of 
investigational drug (whichever is longer) prior to Screening.  
22. Inadequate media clarity or pupillary dilation that does not 
allow acquisition of an adequate quality OCT and/or fundus 
image.  
Criteria for 
Evaluation of 
Efficacy 
Primary Efficacy Endpoints: 
 
Change from baseline in BCVA letter count as 
measured by ETDRS at Week 16 
Secondary Efficacy Endpoints 
 
Change from baseline in CST as measured by 
Spectral Domain OCT (SD-OCT) 
 
Proportion of eyes with a ≥2 step improvement from 
baseline in Diabetic Retinopathy Severity Scale 
(DRSS) score  
 
Change from baseline in BCVA letter count as 
measured by ETDRS at Weeks 4, 8, 12, 20 and 24 
 
Proportion of study eyes with ≥5, ≥10, and ≥15 BCVA 
letter change from baseline (gain and loss)  
Efficacy Variables 
 
BCVA in letters as measured by ETDRS 
 
CST in µm as measured by Spectral Domain 
(SD)-OCT 
 
Retinopathy severity as measured by the DRSS and 
graded from fundus photography 
Safety Variables 
 
AEs 
 
Ophthalmic and physical exam findings 
 
Laboratory test results (clinical chemistry, 
hematology, and urinalysis) 
 
Vital signs (systolic blood pressure [SBP], diastolic 
blood pressure [DBP], pulse rate (PR), and respiratory 
rate) 
General Statistical 
Methods and 
Types of Analyses 
Analysis Populations: 
 
Full Analysis Set (FAS) – All randomized subjects 
following the principle of intention-to-treat (ITT). 
Subjects will be included in the analysis according to 
the treatment to which they were randomized. 
 
Per Protocol Set (PPS) – All randomized subjects who 
are compliant with the study protocol, i.e., who do not 
experience any major protocol deviations.  Subjects 
will be included in the analysis according to the 
treatment received. 
 
Safety Set (SAF) – All randomized subjects who 
receive at least one dose of study treatment. Subjects 
will be included in the analysis according to the 
treatment received.  
Sample Size: 
The proposed sample size (41 per treatment group) will provide 


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approximately 80% power to detect a difference in change from 
baseline of 5 letters between either of the KVD001 treatment 
groups and sham based on a two-sided, two-sample t-test with 
significance level 0.05 and assuming a pooled standard deviation 
(SD) of 7.5 letters.  
Multiplicity Considerations: 
No multiplicity adjustments are planned in this exploratory Phase 
2a study. 
Primary Efficacy Analyses: 
The primary efficacy endpoint is the change from baseline in 
BCVA letter count in the study eye at Week 16. Change from 
baseline in BCVA letter count will be calculated as Week 16 
BCVA letter count minus Day 1 BCVA letter count such that a 
negative difference indicates a worsening in vision. In addition, 
treatment comparisons between each dose of the KVD001 
Injection and the sham procedure will be calculated as KVD001 
Injection minus sham, such that a positive result indicates more 
letters gained in the KVD001 Injection treatment group. 
The study eye ETDRS letter scores including changes from 
baseline will be summarized using continuous descriptive 
statistics. An analysis of covariance (ANCOVA) model will be 
used to compare the change from Day 1 in BCVA letter count at 
Week 16 between each dose of the KVD001 Injection and the 
sham. The ANCOVA model will include treatment as a main 
effect and baseline BCVA letter count as a covariate. Least-
squares means (LSMeans) for each treatment group, the 
LSMeans difference between each dose of the KVD001 Injection 
group and the sham procedure group, the corresponding 
confidence intervals (CIs) and the p-values will be presented. 
The primary analysis 
 
in the FAS population at the Week 16 visit, as described in 
Section 8.2. 
As a sensitivity analysis, treatment group differences for changes 
from baseline in BCVA letter count will be evaluated using a 
mixed model repeated measures (MMRM) ANCOVA fitted with 
treatment group, visit and the treatment by visit interaction as 
categorical variable terms with baseline BCVA letter score and 
baseline CST as covariates with contrasts included for each visit. 
LSMeans and 95% confidence intervals for each treatment 
group, the LSMeans difference between each dose of the 
KVD001 Injection and the sham, the corresponding confidence 
intervals, and the p-values will be presented for each visit. 
Secondary Efficacy Analyses: 
Change from baseline in BCVA letter count in the study eye at 
Week 24 and change from baseline in CST in the study eye as 
measured by SD-OCT at Week 16 and Week 24 will be 
analyzed, separately, using the same method described for the 
primary efficacy analysis. 


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The proportion of study eyes with improvement of 2 or more 
steps from baseline on the ETDRS DRSS score between the 
sham procedure group and each of the KVD001 Injection groups 
will be summarized by visit using discrete summary statistics, 
including 95% asymptotic normal CIs for each treatment group. 
The difference in proportions between each of the KVD001 
Injection groups and the sham procedure group will be analyzed 
at Week 16 and Week 24 using a Pearson’s chi-squared test. 
The 95% asymptotic normal CIs for the differences in proportions 
will also be calculated. Fisher’s exact tests and exact CIs will be 
employed in cases of expected counts <5. 
The proportion of study eyes with ≥5, ≥10 and ≥15 BCVA letter 
change from baseline (gain and loss) at Weeks 16 and 24 will be 
analyzed using the same method described for the proportion of 
study eyes with improvement of 2 or more steps from baseline on 
the ETDRS DRSS score. 
Safety Variables: 
AEs will be coded using the MedDRA dictionary. Frequencies 
and percentages of subjects with treatment-emergent adverse 
events (TEAEs), serious TEAEs and TEAEs causing premature 
discontinuation will be provided by treatment group. An AE is 
treatment emergent if it occurs or worsens after the first dose of 
randomized study treatment. Furthermore, frequencies will be 
given of subjects with TEAEs by system organ class (SOC) and 
preferred term (PT); by SOC, PT and maximal severity; by SOC, 
PT and strongest relationship; by SOC and PT for SAEs; and by 
SOC, PT and day of onset. Separate analyses will be performed 
for ocular specific and all AEs (including systemic). 
Other safety endpoints including manifest refraction/BCVA, slit 
lamp biomicroscopy, dilated ophthalmoscopy, IOP, SD-OCT, 
ETDRS DRSS, physical exam findings, laboratory test results, 
and vital signs will be summarized by treatment group and visit 
using descriptive statistics. Changes or shifts from baseline will 
also be summarized where appropriate. For assessments 
performed by eye, study eye and fellow eye will be summarized 
separately. 


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LIST OF STUDY PERSONNEL 
Sponsor 
KalVista Pharmaceuticals, Ltd. 
Tetricus Science Park 
Building 227 
Porton Down SP4 0JQ 
United Kingdom 
 
 
 
 
 
 
 
 
 
Contract Research 
Organization 
 
Ora, Inc. 
300 Brickstone Square 
Andover, MA 01810 
USA  
 
 
 
 
 
Adverse Event Reporting 
 
 
 
 
 
 
 
 
Central Laboratory 
  
  
  
 
 
 
 
 
 
Reading Center 
 
 
 
 
 


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Biomarker Lab 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ...................................................................................... 4 
LIST OF STUDY PERSONNEL ......................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................... 17 
1 
INTRODUCTION AND BACKGROUND ................................................. 19 
 
Rationale for the Study ............................................................................... 20 
 
Benefit Risk Assessment ............................................................................ 20 
2 
STUDY OBJECTIVES ............................................................................. 21 
 
Primary Objective ........................................................................................ 21 
 
Secondary Objective(s) ............................................................................... 21 
3 
OVERALL DESIGN AND PLAN OF THE STUDY .................................. 22 
 
Overview ...................................................................................................... 22 
 
Criteria for Evaluation of the Study ............................................................ 24 
3.2.1 
Efficacy Endpoints ............................................................................ 24 
3.2.1.1 
Primary Efficacy Endpoints ......................................................... 24 
3.2.1.2 
Secondary Efficacy Endpoints .................................................... 24 
3.2.2 
Safety endpoints ............................................................................... 24 
 
Justification of the Study Design ............................................................... 24 
4 
STUDY POPULATION ............................................................................ 25 
 
Inclusion Criteria ......................................................................................... 25 
 
Exclusion Criteria ........................................................................................ 26 
 
Subject Withdrawal ..................................................................................... 27 
4.3.1 
Withdrawal from Participation ........................................................... 28 
4.3.2 
Lost to Follow–up ............................................................................. 28 
 
Planned Sample Size ................................................................................... 28 
 
Subject Identification and Randomization ................................................. 28 
4.5.1 
Subject Identification......................................................................... 28 
4.5.2 
Randomization Scheme .................................................................... 28 
4.5.3 
Allocation/Randomization of Subjects to Treatment .......................... 28 
5 
STUDY DRUG ......................................................................................... 30 
 
Identity ......................................................................................................... 30 
 
Administration ............................................................................................. 30 
 
Packaging, Labelling and Storage ............................................................. 30 
 
Masking and Breaking the Masking ........................................................... 31 
 
Drug Accountability .................................................................................... 31 
 
Compliance .................................................................................................. 31 
 
Concomitant Medications/Therapy ............................................................ 32 
 
Rescue Treatment ....................................................................................... 32 
6 
VARIABLES AND METHODS OF ASSESSMENT ................................. 33 
 
Efficacy Variables ........................................................................................ 33 
 
Safety Variables ........................................................................................... 33 
6.2.1 
Adverse Events ................................................................................ 33 
6.2.1.1 
Severity ....................................................................................... 33 


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6.2.1.2 
Relationship to Investigational Product ....................................... 34 
6.2.1.3 
Expectedness ............................................................................. 34 
6.2.1.4 
Serious Adverse Events .............................................................. 34 
6.2.1.5 
Procedures for Reporting Adverse Events .................................. 35 
6.2.1.6 
Reporting a Suspected Unexpected Adverse Reaction ............... 35 
6.2.1.7 
Reporting a Serious Adverse Event ............................................ 36 
6.2.1.8 
Type and Duration of the Follow-up of Subjects after Adverse 
Events......................................................................................... 36 
6.2.1.9 
Pregnancy .................................................................................. 36 
6.2.2 
Laboratory Variables......................................................................... 37 
 
Methods of Assessment ............................................................................. 38 
6.3.1 
Subject Demography ........................................................................ 38 
6.3.2 
Medical and Ocular History ............................................................... 38 
6.3.2.1 
DME Disease History .................................................................. 38 
6.3.3 
Previous and Concomitant Medications ............................................ 39 
6.3.4 
Vital Signs ........................................................................................ 39 
6.3.5 
Physical Examinations ...................................................................... 39 
6.3.6 
Safety Laboratory Assessments ....................................................... 39 
6.3.7 
Ophthalmic Assessments ................................................................. 39 
6.3.8 
Biomarker Evaluation ........................................................................ 40 
7 
STUDY CONDUCT .................................................................................. 41 
 
Schedule of Procedures ............................................................................. 41 
 
Procedures by Visit ..................................................................................... 44 
7.2.1 
Screening Phase (Weeks -4 to Day -1 [Visit 1]) ................................ 44 
7.2.2 
Treatment Phase .............................................................................. 45 
7.2.2.1 
Day 1 and Weeks 4, 8, and 12 (Visits 2, 3, 4, and 5)................... 45 
7.2.2.2 
Post–treatment Follow–up Call ................................................... 45 
7.2.3 
Follow–up Phase .............................................................................. 46 
7.2.3.1 
Weeks 16, 20, and 24 (Visits 6, 7, and 8) .................................... 46 
7.2.4 
Early Discontinuation Visit ................................................................ 46 
8 
STATISTICAL METHODS ....................................................................... 47 
 
Study Subjects ............................................................................................ 47 
8.1.1 
Disposition of Subjects ..................................................................... 47 
8.1.2 
Protocol Deviations ........................................................................... 47 
8.1.3 
Analysis Sets .................................................................................... 47 
 
General Considerations .............................................................................. 48 
 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications ........................................................................... 49 
 
Treatment Compliance ................................................................................ 49 
 
Efficacy Analyses ........................................................................................ 49 
8.5.1 
Primary Efficacy Analysis ................................................................. 49 
8.5.1.1 
Hypothesis to be Tested ............................................................. 49 
8.5.1.2 
Statistical Methods ...................................................................... 49 
8.5.2 
Secondary Efficacy Analyses ............................................................ 50 
 
Safety Analyses ........................................................................................... 50 
8.6.1 
Adverse Events ................................................................................ 50 
8.6.2 
Laboratory Assessments .................................................................. 51 
8.6.3 
Vital Signs ........................................................................................ 51 
8.6.4 
Physical Examination ........................................................................ 51 


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8.6.5 
Slit Lamp Biomicroscopy .................................................................. 52 
8.6.6 
Indirect Dilated Ophthalmoscopy ...................................................... 52 
8.6.7 
Intraocular Pressure ......................................................................... 52 
8.6.8 
Best Corrected Visual Acuity and Manifest Refraction ...................... 52 
8.6.9 
SD-OCT ............................................................................................ 52 
8.6.10 
ETDRS DRSS .................................................................................. 53 
 
Interim Analyses .......................................................................................... 53 
 
Determination of Sample Size .................................................................... 53 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ........................ 54 
 
Data Quality Assurance .............................................................................. 54 
9.1.1 
Database Management and Quality Control ..................................... 54 
 
Case Report Forms and Source Documentation ...................................... 54 
9.2.1 
Data Collection ................................................................................. 54 
 
Access to Source Data ................................................................................ 55 
 
Data Processing .......................................................................................... 55 
 
Archiving Study Records ............................................................................ 56 
 
Good Clinical Practice ................................................................................ 56 
 
Informed Consent ........................................................................................ 56 
 
Protocol Approval and Amendment ........................................................... 56 
 
Duration of the Study .................................................................................. 57 
 
Premature Termination of the Study .......................................................... 57 
 
Confidentiality ............................................................................................. 57 
 
Other Ethical and Regulatory Issues (optional) ........................................ 57 
 
Publication Policy ....................................................................................... 57 
10 
SUMMARY OF CHANGES ..................................................................... 58 
11 
REFERENCE LIST .................................................................................. 65 
 
Tables in Text 
Table 1: Laboratory Assessments ............................................................................... 37 
Table 2: Schedule of Procedures ................................................................................ 42 
 
Figures in Text 
Figure 1: Study Flow Chart ........................................................................................... 23 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ASNV 
anterior segment neovascularization 
ATC 
anatomical therapeutic chemical 
BCVA 
best corrected visual acuity 
BMI 
body mass index 
BP 
blood pressure 
C1-INH 
C1-esterase Inhibitor 
ciDME 
center-involving diabetic macular edema 
CIRC 
Central Image Reading Center 
CST 
central subfield thickness 
DBP 
diastolic blood pressure 
DRSS 
Diabetic Retinopathy Severity Scale 
DM 
diabetes mellitus 
DME 
diabetic macular edema 
DRL 
Drug Reference List 
eCRF 
electronic case report form 
ED 
early discontinuation 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
full analysis set 
FE 
fellow eye 
GCP 
Good Clinical Practice 
HgA1c 
glycosylated hemoglobin 
HMWK 
high-molecular-weight kininogen 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IOP 
intraocular pressure 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intention-to-treat 
IVT 
intravitreal 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed adverse effect level 
NSAID 
nonsteroidal anti-inflammatory drug 
OCT 
optical coherence tomography 
PDR 
proliferative diabetic retinopathy 
PKal 
plasma kallikrein 
PPS 
per protocol set 
PR 
pulse rate 
RVP 
retinal vascular permeability 
SAE 
serious adverse event 
SAF 
safety set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD-OCT 
spectral-domain optical coherence tomography 


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SD 
standard deviation 
SE 
study eye 
SUSAR 
serious unexpected suspected adverse reaction 
TEAE 
treatment-emergent adverse event 
US 
United States 
VA 
visual acuity 
VEGF 
vascular endothelial growth factor 
WHO 
World Health Organization 
 
 
 


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1 
INTRODUCTION AND BACKGROUND 
Diabetic macular edema (DME) is a common complication of diabetes mellitus (GS, N et 
al. 2017). It leads to vision loss, if untreated, and becomes increasingly prevalent with 
progressing diabetes. In 2015, over 30 million Americans were estimated to be affected 
by diabetes and almost 10 million by diabetic retinopathy; 1.5M were estimated to have 
vision-threatening diabetic retinopathy and 908,000 of these would have DME (Lee, 
Wong et al. 2015). DME is the leading cause of moderate vision loss among working 
age adults in most developed countries (Diabetes, Complications Trial/Epidemiology of 
Diabetes et al. 2009).  
The clinical signs of diabetic retinopathy begin with retinal hemorrhages and 
micro-aneurysms, usually associated with areas of retinal pericyte loss and loss of the 
endothelial cell barrier function (GS, N et al. 2017). The resulting leakage can lead to 
macular edema, consisting of an accumulation of fluid and lipoproteins in the retina. 
Visual acuity declines dramatically when the central macula is affected.  
Therapies directed against the vascular endothelial growth factor (anti-VEGF therapies) 
have made a significant difference in the treatment of DME (Campochiaro, Aiello et al. 
2016). The treatments currently in use, aflibercept, bevacizumab and ranibizumab, were 
shown in clinical trials to be more effective than laser therapy after one year. While laser 
therapy is expected to improve vision by 3 or more lines in one in 10 people with DME, 
about three in 10 people are expected to gain vision with anti-VEGF treatment: risk ratio 
(RR) versus laser 3.66 (95% CI: 2.79 to 4.79) for aflibercept; 2.47 (95% CI 1.81 to 3.37) 
for bevacizumab; 2.76 (95% CI 2.12 to 3.59) for ranibizumab (Virgili, Parravano et al. 
2017). However, a significant proportion (up to 50%) of patients with DME does not 
achieve vision gain under anti-VEGF therapy (Nguyen, Brown et al. 2012).  
Researchers associated with Kalvista have shown that retinal vascular permeability can 
also be induced by contact system activation, which would be a complementary 
pathobiologic explanation for the macular edema observed in patients with DME (Gao, 
Clermont et al. 2007). Observations on human vitreous samples confirmed activation of 
carbonic anhydrase I, possibly through hemolysis, to be a physiologic trigger of the 
plasma kallikrein (PKal) – kinin system cascade. Release of the vasoactive peptide 
bradykinin upon cleavage of high molecular weight kininogen by plasma kallikrein would 
be the final mediator of vascular permeability and edema generation. Animal 
experiments confirmed that it is possible to abrogate the vascular permeability induced 
by bradykinin (Gao, Clermont et al. 2007).  
Further experiments in diabetic rats confirmed the presence of bradykinin mediated 
edema in the eye subsequent to induced diabetes (Clermont, Chilcote et al. 2011). 
Inhibition of plasma kallikrein activation either via a small-molecule plasma kallikrein 
inhibitor or physiologic C1-esterase inhibitor significantly reduced edema generation and 
confirmed PKal inhibition as a potential treatment target for DME.  
Plasma kallikrein and its cleavage products were also highly elevated in samples of 
vitreous from human subjects with diabetes (Kita, Clermont et al. 2015). Moreover, 
many human samples with clear signs of PKal activation were low in VEGF stimulation, 
and vice versa, confirming PKal inhibition as a therapeutically independent target in 
patients with DME. 
 
 
 
 


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The proposed study is a phase 2a, randomized, double-masked, sham-controlled, 3-arm 
study to evaluate the efficacy, safety, and tolerability of KVD001 Injection as 
monotherapy in adult subjects with center-involving DME (ciDME) who have had prior 
anti-VEGF treatment. 
 
Rationale for the Study 
Strong pathobiologic data support activation of the PKal – kinin cascade as a VEGF-
independent explanation for DME. This mechanism is amenable to intervention with 
PKal, both intravitreally and systemically in animal models, and intravitreally in humans. 
Relevant investigations were performed with KVD001.HCl in animals and humans to 
justify proceeding with a phase 2a dose-finding study. The aim of this study is to confirm 
the therapeutic rationale through multiple injections and over a longer time horizon. 
 
Benefit Risk Assessment 
Patients with DME who have been treated with anti-VEGF therapy and continue to 
experience impaired vision can potentially benefit from a therapy that targets a different 
pathobiologic mechanism. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   


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2 
STUDY OBJECTIVES 
 
Primary Objective 
To evaluate the efficacy of monthly dosing of IVT injection of KVD001 in subjects with 
ciDME who have had prior anti–VEGF treatment. 
 
Secondary Objective(s) 
To evaluate the local and systemic safety and tolerability of monthly dosing of KVD001 
Injection in subjects with ciDME who have had prior anti–VEGF treatment. 


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
 
Overview 
This is a phase 2a, randomized, double-masked, sham-controlled, 3-arm study to 
evaluate the efficacy, safety, and tolerability of KVD001 Injection as monotherapy in 
adult subjects with ciDME who have had prior anti-VEGF treatment. Approximately 123 
eligible subjects will be randomized into the study.  
The maximum duration of the study for each randomized subject will be up to 28 weeks 
(including up to 4 weeks for screening, 12 weeks treatment period, and 12 weeks  
follow-up). 
The study will be conducted on an out-patient basis. 
The study schedule of events will be as follows: 
Screening Phase: The screening period will be up to 4 weeks prior to study Day 1. All 
subjects will sign an Informed Consent Form (ICF) prior to any study related procedures 
being performed. Subjects will be 18 years of age or older, at the time of screening, and 
will have a diagnosis of ciDME with prior anti-VEGF treatment. 
Treatment Phase: On the day of first study drug administration (Day 1), the subject’s 
eligibility will be reconfirmed and baseline assessments will be performed. Eligible 
subjects will be randomized 1:1:1 to receive KVD001 Injection (6 μg or 3 μg KVD001) or 
a sham procedure during a 12-week, double-masked treatment period (a total of 
4 doses given at approximately monthly intervals).  
Subjects will visit the study clinic on Day 1 and Weeks 4, 8, and 12 during the Treatment 
Phase for study drug administration or sham procedure, safety, and ophthalmic 
assessments (see Table 2). The subject will remain in the clinic after study drug 
administration or sham procedure until all post-dose procedures and observations have 
been completed and the Investigator confirms that the subject may be discharged. 
Investigators should schedule visits at Week 4, 8, and 12 to provide 28 days between 
visits. The visit window for these visits is -3 days to +7 days. 
Approximately twenty-four (24) hours after each study drug administration or sham 
procedure on Day 1 and Weeks 4, 8, and 12, subjects will be contacted by telephone to 
evaluate any reported AEs and changes in concomitant medications. In the event of any 
reported ocular or systemic AEs that are considered by the Investigator to be a possible 
cause for concern, the subjects will return to the clinic for assessment as soon as 
possible. 
Follow up Phase: All subjects will visit the clinic at Weeks 16, 20, and 24 after the last 
study drug administration or sham procedure for safety and ophthalmic assessments 
(see Table 2). The visit window for Weeks 16, 20, and 24 is ±7 days. 
Early Discontinuation: If any subject discontinues the trial early, every effort should be 
made to complete the Week 24/early discontinuation (ED) evaluations as soon as 
possible and, whenever possible, prior to starting any new medication or treatment. All 
attempts will be made to not discontinue the subject unless necessary. 
Rescue Treatment: Rescue intervention (e.g., anti-VEGF, focal/grid macular laser 
photocoagulation, IVT steroids) may be administered due to worsening DME (i.e., 
attributable to worsening DME and not another cause) if either of the following occurs 
and, where possible, after consultation with the Medical Monitor:  
 
During Treatment Phase 


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o Best corrected visual acuity (BCVA) deteriorates 3 lines (15 letters) or 
more from baseline 
o Central Subfield Thickness (CST) worsening of >100 µm from baseline 
 
During Follow up Phase (i.e., after week 16) 
o BCVA deteriorates 3 lines (15 letters) or more from highest BCVA during 
treatment phase or baseline 
o CST worsening of >100 µm from lowest CST during treatment phase or 
baseline. 
 
If a study subject meets the criteria for rescue intervention and receives a rescue 
treatment in the study eye, the study subject will be discontinued from further 
participation in the study.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Study Flow Chart 
Screening (28 days) 
Eligible subjects with ciDME 
N = 123 
1:1:1 Randomization 
Arm 1 
N = 41 
KVD001 Injection (3 µg) 
Monthly x 4 
Day 1 and Weeks 4, 8, 
and 12  
Arm 2 
N = 41 
KVD001 Injection (6 µg) 
Monthly x 4 
Day 1 and Weeks 4, 8, 
and 12  
12 weeks Follow-up after last study 
drug administration or sham procedure 
Arm 3 
N = 41 
Sham Procedure  
Monthly x 4 
Day 1 and Weeks 4, 8, 
and 12  


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Criteria for Evaluation of the Study 
3.2.1 Efficacy Endpoints 
3.2.1.1 
Primary Efficacy Endpoints 
 
Change from baseline in BCVA letter count as measured by ETDRS at 
Week 16. 
3.2.1.2 
Secondary Efficacy Endpoints 
 
Change from baseline in CST as measured by Spectral Domain OCT (SD-
OCT) 
 
Proportion of eyes with a ≥2 step improvement from baseline in Diabetic 
Retinopathy Severity Scale (DRSS) score  
 
Change from baseline in BCVA letter count as measured by ETDRS at 
Weeks 4, 8, 12, 20 and 24 
 
Proportion of study eyes with ≥5, ≥10, and ≥15 BCVA letter change from 
baseline (gain and loss). 
3.2.2 Safety endpoints 
 
AEs; 
 
Ophthalmic and physical exam findings; 
 
Laboratory test results (clinical chemistry, hematology, and urinalysis); 
 
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], 
pulse rate (PR), and respiratory rate). 
 
Justification of the Study Design 
This phase 2a study is the first clinical investigation of the potential efficacy of KVD001 
Injection in the treatment of DME. The randomized, double-masked design has been 
chosen to allow an unbiased and controlled assessment of the safety and efficacy of the 
drug. The control group will receive a sham injection procedure rather than placebo to 
avoid unnecessary breaching of the integrity of the eye and risk of endophthalmitis, 
retinal detachment, cataract, etc. 
The study population is representative of the likely target population for the product. The 
sample size of 123 subjects is appropriate for this stage of development. 
The dosing schedule for KVD001 Injection (4 doses at approximately monthly intervals 
intervals) is supported by animal toxicology data and is within the range shown in the 
first-in-man study to be well tolerated and to result in potentially beneficial 
pharmacodynamics effects. 
The endpoints are commonly-measured in DME and are clinically relevant. 


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4 
STUDY POPULATION 
The study population will include male and female subjects 18 years of age or older with 
ciDME who have received prior anti-VEGF treatment. 
Except as otherwise defined, subjects must fulfill all of the following criteria both at 
Screening and on Day 1 to be eligible for inclusion in the study.  For applicable 
conditions, subjects who do not meet the inclusion criteria at Visit 1 or 2 may be 
rescreened with permission from the Sponsor or Ora. 
The study eye will be defined as the eye that meets all of the inclusion and none of the 
exclusion criteria. If both eyes qualify, the eye with the worse BCVA ETDRS at Day 1 
will be used as the study eye. If both eyes have the same BCVA ETDRS at Day 1, the 
eye with the highest CST on spectral-domain optical coherence tomography (SD-OCT) 
on Day 1, as assessed by the Investigator, will be used as the study eye. If both eyes 
qualify and neither is preferred based on the inclusion/exclusion criteria and have the 
same BCVA ETDRS and CST on Day 1, either eye may be chosen as the study eye. In 
this instance, the Investigator should select the eye that, in their opinion, is most likely to 
respond to treatment as the study eye. 
 
Inclusion Criteria 
Subject must fulfill all of the following criteria at Screening and on Day 1 to be eligible for 
inclusion in the study: 
Inclusion Criteria: 
1. Male or female adult subjects 18 years of age and older. 
2. Confirmed diagnosis of Type I or Type II diabetes mellitus (DM). Any of the following 
are sufficient: 
 
Current regular use of insulin for the treatment of diabetes 
 
Current regular use of oral anti-hyperglycemia agents for the treatment of 
diabetes 
 
Documented diabetes by American Diabetes Association and/or World Health 
Organization (WHO) criteria 
3. BCVA, using Standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart, 
of ≥19 letters (~20/400) and ≤73 letters (~20/40) in the study eye and ≥34 letters 
(~20/200 or better) in the fellow eye at Screening and Day 1. 
4. Presence of ciDME in the study eye defined as Heidelberg Spectralis Optical 
Coherence Tomography (SD-OCT) CST ≥305 μm in women and ≥320 μm in men in 
the study eye (as assessed at Screening by the Investigator and Central Image 
Reading Center (CIRC) and on Day 1 by the Investigator). 
5. Subjects’ first anti-VEGF injection in the study eye occurred ≤ 36 months prior to 
Day 1. 
6. Subjects have received at least 3 anti-VEGF injections in the study eye within a 6-
month period within the 36 months prior to Day 1. 
7. The last anti-VEGF injection in the study eye is ≥ 8 weeks prior to Day 1. 
8. Subjects, who in the view of the Investigator, are able to defer treatment in the study 
eye for at least 6 months following Day 1. Note, rescue treatment is available (see 
Section 5.8). 
9. Values for blood and urine safety labs at the Screening visit showing no clinically 
significant deviation as determined by the Investigator. 


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10. Women who are post menopausal for at least 1 year, surgically sterile for at least 
3 months prior to Day 1, or who are agreeable to using highly effective contraception 
(adequate contraceptive measures include stable use of oral contraceptives or other 
prescription pharmaceutical contraceptives for two or more menstrual cycles prior to 
screening; IUD; bilateral tubal ligation; vasectomy; condom plus contraceptive 
sponge, foam, or jelly or diaphragm plus contraceptive sponge, foam, or jelly), or 
abstinence.  
11. Sexually active men who are not vasectomized and have sexual partners of 
childbearing potential should be agreable to using highly effective contraception. 
12. Provide signed informed consent and are willing and capable of complying with clinic 
visits and study  procedures. 
 
Exclusion Criteria 
Subjects will be excluded from the study if one or more of the following statements are 
applicable at Screening and on Day 1: 
1. Females who are pregnant or lactating, or expecting to become pregnant during the 
course of the study. 
2. Evidence of ocular pathology (e.g. visually significant cataract) that impacts subject’s 
vision in the study eye from any cause other than DME, in the opinion of the 
Investigator. 
3. Evidence/presence of amblyopia, vitreomacular traction, epiretinal membrane, foveal 
atrophy, or foveal ischemia, or any other condition in the macula that is thought to 
impair the subject’s vision (other than DME) in the opinion of Investigator. 
4. Prior treatment with panretinal photocoagulation or focal grid macular 
photocoagulation in the study eye within the previous 3 months prior to Day 1. 
5. Prior treatment with IVT steroid in the study eye (in the 3 months prior to Day 1 for 
triamcinolone, 6 months prior to Day 1 for Ozurdex and at any time for Iluvien). 
6. Prior treatment with topical NSAIDs or topical  steroids in the study eye within 1 
month prior to Day 1. 
7. Prior treatment with Jetrea® (ocriplasmin) injection in the study eye within the 
previous 3 months prior to Day 1. 
8. Prior treatment with systemic corticosteroids or systemic anti-VEGF therapy within 
3 months prior to Day 1. 
9. Prior vitrectomy in the study eye. 
10. Prior intraocular surgery in the study eye except for cataract surgery. Cataract 
surgery within the previous 6 months of Day 1 in the study eye is excluded. 
11. Intraocular pressure (IOP) at Screening or Day 1 of >22 mmHg in the study eye or 
use of >2 antiglaucoma agents (combination agents count as 2 agents) in the study 
eye. 
12. Evidence of infectious dacrocystitis, significant blepharitis, active conjunctivitis, 
infectious keratitis, or scleritis in either eye, or any other condition that might affect 
the safety of the IVT injection in the opinion of Investigator. 
13. Evidence of active intraocular inflammation in the study eye. 
14. Current active proliferative diabetic retinopathy (PDR), active anterior segment 
neovascularization (ASNV), active retinal neovascularization, or the presence of 
vitreous hemorrhage in the study eye. (Note, quiescent PDR is not exclusionary). 


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15. Any concurrent ocular condition in the study eye which, in the opinion of the 
Investigator, could interfere with the evaluation of efficacy or safety. 
16. Poorly controlled DM defined as glycosylated hemoglobin [HgA1c] ≥12.0% or having 
initiated intensive insulin treatment (a pump or multiple daily injections) within prior 4 
months or planning to do so in the next 2 months, or two (2) or more episodes of 
diabetic ketoacidosis requiring hospitalization within the preceding 6 months. 
17. Uncontrolled hypertension at Screening or Day 1 defined as systolic ≥180 mmHg or 
diastolic ≥ 110 mmHg.  
18. Significant co-existing disease such as marked hepatic impairment, end stage renal 
disease (defined as a current or imminent requirement for dialysis), symptomatic 
cardiac failure, or significant pulmonary dysfunction that may place the subject at 
higher risk for treatment complications, failure of follow-up, and/or may impact the 
outcome of the data interpretation of the study, in the opinion of the Investigator. 
19. History of other disease (e.g., unstable psychiatric illness), metabolic dysfunction, 
physical examination finding, or clinical laboratory finding giving reasonable 
suspicion of a disease or condition that contraindicates the use of an investigational 
product, might affect interpretation of the results of the study, or renders the subject 
at high risk for treatment complications or lack of follow-up, in the opinion of 
Investigator. 
20. History of alcohol and/or drug abuse in the last 2 years. 
21. Participation in an interventional investigational clinical study within 3 months or 
within 5 half-lives of the last dosing of investigational drug (whichever is longer) prior 
to Screening.  
22. Inadequate media clarity or pupillary dilation that does not allow acquisition of an 
adequate quality OCT and/or fundus image.  
 
Subject Withdrawal 
Subjects are free to withdraw from participation in the study at any time, for any reason 
(or without providing reasons) and without prejudice to further treatment or they may be 
discontinued by the investigator, if deemed in their best medical interests. 
The Investigator may also discontinue a subject from further study drug dosing or 
withdraw a subject from the study at any time for the following reasons: 
 
Positive pregnancy test; 
 
AEs, serious adverse events (SAEs),  
 
Use of prohibited medication (see section 5.7) or rescue medication (see 
section 5.8); 
 
Administrative reasons (e.g., lack of subject compliance to study visits / 
procedures, lost to follow-up). 


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4.3.1 Withdrawal from Participation 
Subjects who withdraw or are withdrawn from the study will complete the ED visit as 
soon as possible. The reason for discontinuation / withdrawal will be documented in the 
electronic case report form (eCRF) and the Medical Monitor must be informed 
immediately. If the reason for withdrawal is the occurrence of an AE, the subject will be 
followed up until the AE has resolved or is considered chronic and stable or the AE has 
been clearly shown to be unrelated to the investigational product. 
Subjects will also be withdrawn if the entire study is terminated prematurely as 
described in Section 9.10. 
Subjects who are randomized and subsequently withdraw from study participation will 
not be replaced.  
4.3.2 Lost to Follow–up 
If a subject does not return for a scheduled visit, every effort should be made at least 
once every month to contact the subject to reschedule the visit, including mandatory 
telephone contact and written letter. All efforts should be documented in the subject’s 
medical source record.  A subject is considered lost to follow–up if subject cannot be 
reached after 3 months from the scheduled visit. However, if the subject re–initiates 
contact beyond 3 months, the available data may still be collected on the eCRF, 
provided that subject consent has not been withdrawn. 
If a subject discontinues study medication or is withdrawn from the study for any reason, 
the study site must immediately notify the medical monitor. 
The Sponsor has the right to terminate the study at any time and for any reason. In the 
event, the Investigators will be informed of the reason for study termination by written 
notification. 
 
Planned Sample Size 
Ophthalmology clinics in the United States (US) will randomize approximately 123 
eligible subjects into the study. Only study sites with experience in the conduct of DME 
clinical studies will be selected. See Section 8.8 for a discussion of sample size. 
 
Subject Identification and Randomization 
4.5.1 Subject Identification 
Each subject will receive a unique screening ID number. Subjects who are screen 
failures and are not randomized will retain their screening ID number.  
4.5.2 Randomization Scheme 
Subjects will be randomized on a 1:1:1 basis to KVD001 Injection 60 µg/mL or 30 µg/mL 
(6 μg/eye or 3 μg/eye in a 100 μL dose volume) or a sham procedure. Randomization 
will be centralized with stratification by visual acuity and CST at Day 1. 
4.5.3 Allocation/Randomization of Subjects to Treatment 
Subjects must not be randomized unless all eligibility criteria have been met. 
Subjects who satisfy all the entry criteria will be centrally assigned to study medication 
by the Interactive Response Technology (IRT), according to the randomization scheme 
generated by Ora. Each randomized subject will receive a unique randomization 


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number. Subjects will be randomized in a 1:1 ratio to 60 µg/mL or 30 µg/mL KVD001 
Injection or sham procedure.  
The actual treatment given to subjects will be determined by the randomization scheme 
in IRT. The randomization scheme will be produced by a computer software program 
that incorporates a standard procedure for generating randomization numbers. One 
randomization list will be produced containing sufficient random numbers for both 
randomization strata. 
The dose and regimen of randomized therapy to be administered is as follows: 
 
KVD001 6 μg by IVT injection; 
 
KVD001 3 μg by IVT injection; 
 
Sham procedure. 
Subjects will be identified using subject initials, randomization number, and date of birth. 
Subjects will be randomized sequentially within their stratification category, as subjects 
are eligible for randomization. The IRT will inform the Investigator of the kit identification 
(ID) number to be allocated to the subject at each dispensing visit. 
First dose of study drug administration or sham procedure will be administered on 
Day 1, after completion of all pre–dose assessments.  
Randomized subjects who are discontinued from further study drug administration or are 
terminated from the study for any reason, regardless of whether study drug was taken or 
not, will not have their screening/randomization code be reused. 
 


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5 
STUDY DRUG 
 
Identity 
For clinical trial use, KVD001.HCl has been formulated as KVD001 Injection. 
 
 
 
 
 
Further information about KVD001 Injection can be found in the current IB (Gardner and 
Antonetti 2007). 
 
Administration 
KVD001 Injection or sham procedure will be administered to the study eye on Day 1 and 
Weeks 4, 8, and 12 during the Treatment Phase. At each scheduled visit, the date and 
time of study medication administration will be recorded in the eCRF. 
The injecting physician cannot be the Investigator as they should remain masked 
throughout the study. In order to avoid breaking the mask, real and sham injections will 
be performed by study personnel who are not masked and not otherwise involved in the 
study (note that post-injection IOP evaluations must be performed by study personnel 
who are unmasked). For sham injections, the subjects will be prepared exactly as for a 
real injection (i.e., including but not limited to: insertion of lid speculum, application of 
povidone-iodine and subconjunctival injection of an anesthetic) following which an empty 
syringe with no needle will be pressed against the eye to mimic the pressure of an 
injection. 
Please refer to the Pharmacy Manual for detailed instructions on administration. 
 
Packaging, Labelling and Storage 
The study packaging and labelling of drug product will be performed by Ora. The 
storage and distribution supply of drug product will be performed by Ora. All packaging 
and labelling operations will be performed according to Good Manufacturing Practice for 
Medicinal Products and the relevant regulatory requirements. 
 
 
 
 
 All boxes will remain closed 
except while being accessed by the nominated unmasked personnel administering the 
real and sham injections. 
The Investigator will ensure that the drug product is stored in appropriate conditions 
 
 
 
 Upon completion of dosing, the used drug product may be 
destroyed with routine medical waste at the clinical site. The Investigator (or designee) 
will dispense the drug product only to the identified subjects of this study following the 
procedures described in this study protocol and documented in the subject dispensing 
log. 
Drug Product inventory/dispensing will be documented in the source documentation and 
the eCRF for each subject. The Investigator is responsible for all drug products. Written 


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documentation is mandatory. After completion of the study, all unused drug product will 
be returned to the location designated by Ora for accountability and destruction. 
 
Masking and Breaking the Masking 
The study will be performed in a double–masked manner. The study is masked by sham 
procedure and sham packaging. The sham procedure will be identical to injecting study 
drug, except as described previously, thereby enabling double-masked conditions. 
The study mask should not be broken except in a medical emergency (where knowledge 
of the study drug received would affect the treatment of the emergency) or regulatory 
requirement (e.g., for SAEs or death). The subject’s safety takes priority over any other 
considerations in determining if a treatment assignment should be unmasked. 
Before breaking the mask of an individual subject’s treatment, the Investigator should 
determine that the unmasked information is necessary, i.e., that it will alter the subject’s 
immediate management. In many cases, particularly when the emergency is clearly not 
related to the study drug, the problem may be properly managed by assuming that the 
subject is receiving active product. The decision to unmask treatment assignment 
should be discussed with the Sponsor and Medical Monitor. The Investigator should only 
call in for emergency unmasking AFTER the decision to discontinue the subject has 
been made. 
If the mask is broken, the date, time, and reason must be recorded in the subject’s 
eCRF system and any associated AE report.  
Once approval for unmasking is obtained, the Investigator can unmask study drug 
assigned to a subject through the IRT system.  
If an Investigator, site personnel performing assessments, or subject is unmasked, the 
subject must be listed as major protocol deviation. 
Serious unexpected suspected adverse reactions (SUSARs), which are subject to 
expedited reporting, should be unmasked before submission to the Regulatory 
Authorities. 
The overall randomization code will be broken only for reporting purposes. This will 
occur once all final clinical data have been entered onto the database and all data 
queries have been resolved, and the assignment of subject to the analysis sets has 
been completed. 
 
Drug Accountability 
The Investigator is responsible for maintaining accurate study drug accountability 
records throughout the study. 
Each dispensing of study drug will be documented in the eCRF. 
The Investigator is responsible for returning all unused study drug to Ora at the 
completion of the study. Ora will ensure no remaining supplies are in the Investigator’s 
possession and agree with the Sponsor the fate of returned study drug. 
 
Compliance 
Study drug shall be administered by qualified unmasked staff at the clinical site; the 
procedure must be recorded in the eCRF. 


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Concomitant Medications/Therapy 
The concomitant use of the following medications will not be allowed in the study: 
 
Anti–VEGF administered systemically; 
 
Any treatment in the study eye or given intravitreally in the study eye for DME 
other than the study medication. Note, the fellow (non-study) eye may be treated 
for DME at the Investigator’s discretion; 
 
Steroid administered systemically, intravitreally in the study eye, or topically in 
the study eye; 
 
NSAIDs administered topically in the study eye; 
 
Any Jetrea® (ocriplasmin) intravitreal injection in the study eye. 
 
Any ophthalmic medication that in the opinion of the Investigator may influence 
the interpretation of the safety and/or efficacy parameters in this study. 
Details of all medications (other than those intended to treat the study subjects’ DME), 
therapies and supplements administered within 3 months prior to Screening Visit until 
the end of the study will be recorded in the eCRF. See section 6.3.2.1 for details 
regarding requirements for data collection relative to DME history and previous 
treatments and medications.  With the exception of ocular medications intended to treat 
DME, prior medications are defined as those medications taken within 3 months prior to 
Screening Visit; concomitant medications are defined as those medications ongoing at 
or started after Day 1. 
 
See section 5.8 regarding the collection of rescue treatment medications as concomitant 
medication. 
 
Rescue Treatment 
Rescue intervention (e.g., anti-VEGF, focal/grid macular laser photocoagulation, IVT 
steroids) may be administered due to worsening DME (i.e., attributable to worsening 
DME and not another cause) if either of the following occurs and, where possible, after 
consultation with the Medical Monitor:  
 
During Treatment Phase 
o Best corrected visual acuity (BCVA) deteriorates 3 lines (15 letters) or 
more from baseline 
o Central Subfield Thickness (CST) worsening of >100 µm from baseline 
 
During Follow up Phase (i.e., after Week 16) 
o BCVA deteriorates 3 lines (15 letters) or more from highest BCVA during 
treatment phase or baseline 
o CST worsening of >100 µm from lowest CST during treatment phase or 
baseline. 
 
Subjects who receive a rescue intervention in the study eye will be discontinued from 
further study participation. The Week 24/ED evaluations should be collected prior to 
study discontinuation and prior to administration of the rescue medication. Details 
regarding the medications used as rescue treatment must be entered as concomitant 
medications for the respective study subject.  


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6 
VARIABLES AND METHODS OF ASSESSMENT 
 
Efficacy Variables 
Efficacy variables of interest in this study are: 
 
BCVA in letters as measured by ETDRS; 
 
CST in µm as measured by Spectral Domain OCT; 
 
Retinopathy severity as measured by the DRSS and graded from fundus 
photography. 
 
Safety Variables 
Safety variables of interest in this study are: 
 
AEs; 
 
Ophthalmic and physical findings; 
 
Laboratory test results (clinical chemistry, hematology, and urinalysis); 
 
Vital signs (SBP, DBP, PR, and respiratory rate). 
6.2.1 Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of an 
investigational product (IP) in humans, whether or not considered IP-related. An AE can 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
without any judgment about causality. An AE can arise from any use of the 
investigational product (e.g. off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including an 
overdose. 
All AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded in the source document and on the appropriate 
pages of the CRF. Any clinically relevant deterioration in clinical finding is considered an 
AE and must be recorded. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end 
date, severity, relationship to investigational product, action(s) taken, seriousness, and 
outcome of any sign or symptom observed by the physician or reported by the patient 
upon indirect questioning.  
6.2.1.1 
Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an 
AE as determined by the investigator or reported to him/her by the patient/subject.  The 
assessment of severity is made irrespective of relationship to investigational product or 
seriousness of the event and should be evaluated according to the following scale: 
 
Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere 
with the subject’s daily activities. 
 
Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 


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 
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, 
and interferes with the subject’s daily activities. 
6.2.1.2 
Relationship to Investigational Product 
The relationship of each AE to the investigational product should be determined by the 
investigator using these explanations: 
 
Suspected: A reasonable possibility exists that the investigational product caused 
the AE. 
 
Not Suspected: A reasonable possibility does not exist that the investigational 
product caused the AE. 
Suspected adverse reaction means any AE for which there is a reasonable possibility 
that the investigational product caused the AE.  “Reasonable possibility” means there is 
evidence to suggest a causal relationship between the investigational product and the 
AE.  Types of evidence that would suggest a causal relationship between the 
investigational product and the AE include:  a single occurrence of an event that is 
uncommon and known to be strongly associated with investigational product exposure 
(e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome); one or more 
occurrences of an event that is not commonly associated with investigational product 
exposure, but is otherwise uncommon in the population exposed to the investigational 
product (e.g., tendon rupture); an aggregate analysis of specific events observed in a 
clinical trial (such as known consequences of the underlying disease or condition under 
investigation or other events that commonly occur in the study population independent 
of drug therapy) that indicates those events occur more frequently in the investigational 
product-treatment group than in a concurrent or historical control group. 
6.2.1.3 
Expectedness 
The expectedness of an AE should be determined based upon existing safety 
information about the investigational product using these explanations: 
 
Unexpected:  an AE that is not listed in the Investigator’s Brochure (IB)(IB 2017) or 
is not listed at the specificity or severity that has been observed. 
 
Expected:  an AE that is listed in the IB at the specificity and severity that has been 
observed. 
 
Not applicable: an AE unrelated to the investigational product. 
AEs that are mentioned in the IB as occurring with a class of products or as anticipated 
from the pharmacological/ mechanical (or other) properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation are to 
be considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 
6.2.1.4 
Serious Adverse Events 
An AE is considered serious if, in the view of either the Investigator or Sponsor, it results 
in any of the following outcomes: 


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 
Death; 
 
A life-threatening AE; 
o Note:  An AE is considered “life-threatening” if, in the view of either the investigator 
or sponsor, its occurrence places the patient or subject at immediate risk of death.  It 
does not include an AE that, had it occurred in a more severe form, might have 
caused death. 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
o Note:  The term “inpatient hospitalization” refers to any inpatient admission (even if 
less than 24 hours).  For chronic or long-term inpatients, inpatient admission 
includes transfer within the hospital to an acute/intensive care inpatient unit.  
Inpatient hospitalization does not include:  emergency room visits; outpatient/same-
day/ambulatory procedures; observation/short stay units; rehabilitation facilities; 
hospice facilities; nursing homes; or clinical research/phase 1 units. 
o Note:  The term “prolongation of existing hospitalization” refers to any extension of 
an inpatient hospitalization beyond the stay anticipated or required for the reason for 
the initial admission as determined by the investigator or treating physician. 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
o Note:  A serious adverse event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic nerve). 
 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
6.2.1.5 
Procedures for Reporting Adverse Events 
All AEs and their outcomes must be reported to Ora, the study sponsor, and the IRB/IEC 
as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities and recorded on the appropriate CRF. 
6.2.1.6 
Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora within 24 hours. 
Ora and the Sponsor will immediately conduct an evaluation of the reported event. The 
results of the evaluation will be reported to the IRB within 10 days of Ora and/or the 
Sponsor becoming aware of the event. Events must be reported to the study sponsor 
and the IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities. 


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6.2.1.7 
Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the investigational 
product, must be immediately reported.  All information relevant to the SAE must be 
recorded on the appropriate case report forms.  The investigator is obligated to pursue 
and obtain information requested by Ora and/or the sponsor in addition to that 
information reported on the case report form.  All subjects experiencing a SAE must be 
followed up and the outcome reported. 
In the event of a SAE, the investigator must notify Ora and the sponsor within 24 hours; 
obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
subject; provide Ora and the study sponsor with a complete case history, which includes 
a statement as to whether the event was or was not suspected to be related to the use 
of the investigational product; and inform the IRB of the SAE within their guidelines for 
reporting SAEs. 
Contact information (SAEs): 
 
 
 
 
 
 
 
 
 
6.2.1.8 
Type and Duration of the Follow-up of Subjects after Adverse Events 
All AEs irrespective of the suspected causality will be monitored until the AE has 
resolved or until the end of the study (Week 24), unless the subject is lost to follow–up 
or withdraws consent or the subject died prior to the end of the study. All SAEs, 
irrespective of the suspected causality, will be monitored until the SAE has resolved or 
until the subject is lost to follow-up or the subject has died. 
6.2.1.9 
Pregnancy 
The Sponsor has a responsibility to monitor the outcome of pregnancies where there 
has been maternal exposure to the study drug.  
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study 
drug may have interfered with the effectiveness of a contraceptive medication. 
Elective abortions without complications should not be handled as AEs, unless they 
were therapeutic abortions (see below). Hospitalization for normal delivery of a healthy 
newborn should not be considered a SAE. 
All pregnancies must be reported by the Investigator to Ora/Sponsor on the initial 
pregnancy report form within 30 days after becoming aware of the pregnancy. The 
Investigator must follow-up and document the course and the outcome of all 
pregnancies even if the patient was discontinued from the study or if the study has 
finished. 
All outcomes of pregnancy must be reported by the Investigator to Ora on the pregnancy 
outcome report form within 30 days of becoming aware of the normal delivery or elective 
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Any SAE that occurs during pregnancy (including SAEs occurring after last 
administration of study drug) must be recorded on the SAE report form (e.g., maternal 
serious complications, spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, 
neonatal death, congenital anomaly, or birth defect) and reported within 24 hours in 
accordance with the procedure for reporting SAEs. 
If a female partner of a male study patient who has been exposed to the study drug 
becomes pregnant, the pregnancy and outcome of pregnancy should be monitored 
according to the same guidelines as for female subjects who become pregnant during 
the study. 
6.2.2 Laboratory Variables 
Laboratory assessments will be performed by a central laboratory, as identified in the 
List of Study Personnel. Before starting the study, the central lab will supply a list of the 
normal ranges and units of measurement. 
Blood samples should be taken using standard venipuncture techniques. A lab manual 
will be provided by the central laboratory; this will contain very detailed instructions for 
collection, storage, and shipment of samples (e.g., what kind of tubes, what kind of 
sample preparation, mailing addresses, etc.). 
The following laboratory variables will be determined in accordance with the Schedule of 
Procedures (Table 2): 
Table 1: 
Laboratory Assessments 
Hematology: 
Erythrocytes 
MCV 
MCH 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Platelets 
Leukocytes 
Hemoglobin 
Hematocrit 
Urinalysis: 
pH 
Protein 
Glucose 
Ketone 
Bilirubin 
Blood 
Nitrite 
Microalbuminemia 
Proteinuria 
Clinical chemistry: 
HgA1c 
Creatinine 
Glucose 
Triglycerides 
Urea 
Uric acid 
Bilirubin 
Cholesterol 
Liver enzymes: 
Alkaline phosphatase 
AST 
ALT 
GGT 
Electrolytes: 
Sodium 
Potassium 
 
 
Urine pregnancy test: 
In women with childbearing potential  
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyl transferase; 
HgA1c = Glycosylated hemoglobin; HMWK = high molecular weight kininogen; MCH = mean corpuscular hemoglobin; 
MCV = mean corpuscular volume: pH = potential hydrogen; PKal = plasma kallikrein. 
The Investigator must review screening laboratory results for subject eligibility prior to 
enrolling. 


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Laboratory tests can be repeated earlier than the next scheduled consecutive study visit 
at the Investigator’s discretion and any associated safety issue should be followed up as 
per the Investigator’s clinical judgement until resolution/stabilization. 
Laboratory data will be electronically transferred to the clinical database at specified 
time points during the study. 
 
Methods of Assessment 
The following assessments will be conducted and recorded in the eCRF. The Schedule 
of Procedures and Procedures by Visit can be found in Sections 7.1 and 7.2, 
respectively. 
6.3.1 Subject Demography 
Subject demography will be performed at the Screening visit and consists of: 
 
Date of birth; 
 
Height; 
 
Weight; 
 
Race and ethnicity; 
 
Gender 
 
Iris color 
6.3.2 Medical and Ocular History 
For the documentation of the medical history, any relevant previous and concurrent 
diseases will be documented. 
The medical history will be obtained by interviewing the subject or by inspecting relevant 
medical records.  
For coding of medical history, see Section 9.4. 
6.3.2.1 
DME Disease History 
DME disease history will be recorded at the Screening visit. For disease history the 
following will be documented: 
 
Date of first diagnosis of DME in the study eye 
 
Date and details of the first anti-VEGF injection 
 
Dates and details of the last three anti-VEGF injections 
o BCVA score or Snellen equivalent of each VA assessment in the study 
eye beginning with the VA assessment immediately prior to the last three 
anti-VEGF injections 
o CST from each OCT assessment in the study eye beginning with the 
OCT assessment immediately prior to the last three anti-VEGF injections 
 
Estimate or actual total number of anti-VEGF injections 
 
Date of last IVT steroid injection (if any) 
 
Estimate or actual total number of IVT steroid injections (if any) 
The Investigator’s assessment of the subject’s response to anti-VEGF treatment after 
the last 3 IVT injections compared to baseline will be recorded using the following scales 
(baseline is defined as the status of edema and vision immediately prior to the first of the 
3 injections):  


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Edema: 
o Satisfactory response – Absence of intraretinal/subretinal fluid; 
o Partial response 1 – Significant reduction of intraretinal/subretinal fluid; 
o Partial response 2 - Little or some reduction (~20%) of 
intraretinal/subretinal fluid; 
o No response – No reduction or worsening of intraretinal/subretinal fluid. 
Vision: 
o No change in or worsening of BCVA 
o Gain of 1-4 letters 
o Gain of 5 to 9 letters 
o Gain 10 to 14 letters 
o Gain of ≥15 letters 
6.3.3 Previous and Concomitant Medications 
Previous and concomitant medication will be documented as described in Section 5.7. 
6.3.4 Vital Signs 
The following vital signs will be assessed at rest (5 minutes in a supine position) in 
accordance with the Schedule of Procedures (Table 2). The same equipment for each 
vital sign evaluation should be used on given patient for all study visits. Vital signs 
should be conducted prior to study drug administration and approximately 30 minutes 
post-study drug administration on applicable visits. 
 
Blood pressure (SBP and DBP; mmHg); 
 
Pulse rate (beats per minute); 
 
Body temperature (°C);  
 
Respiration rate (breaths per minute). 
6.3.5 Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Procedures 
(Table 2). The physical examination should be symptom directed and include the 
following body systems: general appearance, skin, lymphatic, head and neck, ears, 
nose and throat, chest and lungs, cardiovascular, abdomen, extremities, 
musculoskeletal and neuromuscular.   
6.3.6 Safety Laboratory Assessments 
Laboratory assessments will be conducted in accordance with Section 6.2.2. The central 
laboratory will provide a lab manual with detailed procedures. Safety labs should be 
collected prior to study drug administration on applicable visits.  
6.3.7 Ophthalmic Assessments 
Ophthalmic findings will be performed in accordance with the Schedule of Procedures 
(Table 2). All ophthalmic assessments will be conducted on both eyes except fundus 
photography which will be taken in both eyes at the Screening visit and only in the study 
eye at subsequent visits. 
 
Best Corrected Visual Acuity Early Treatment Diabetic Retinopathy Study (BCVA 
ETDRS): 


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BCVA of both eyes will be assessed using the ETDRS protocol. Detailed instructions for 
performing manifest refraction and BCVA will be provided in the study-specific BCVA 
manual. BCVA should be performed prior to all other ophthalmic assessments at all 
visits. 
 
Slit Lamp Biomicroscopy:  
The eyelids, cornea, conjunctiva, anterior chamber, iris/pupil and lens should be 
evaluated. Findings will be graded as normal, abnormal non-clinically significant, or 
abnormal clinically significant. Slit lamp biomicroscopy will be performed on both eyes 
and should be conducted prior to study drug administration on applicable visits. 
 
Intraocular Pressure (IOP):  
IOP will be assessed in both eyes at all study visits. IOP will be assessed with either 
applanation tonometry or tonopen; the method should be consistent throughout the 
study. IOP will be assessed at both pre- and post- injection at visits with study drug 
administrations. Pre-injection IOP must be performed prior to dilation. Post-injection IOP 
should be assessed within 60 minutes after study drug or sham administration and 
should be assessed by someone who is unmasked.  
 
Dilated Indirect Ophthalmoscopy:  
The vitreous, macula, choroid, optic nerve, and retina of both eyes will be assessed. 
Findings will be graded as normal, abnormal non-clinically significant, or abnormal 
clinically significant. The dilated indirect ophthalmoscopy will be performed on both eyes 
and should be conducted prior to study drug administration on applicable visits. 
 
Fundus Photography:  
Color fundus photographs will be taken in both eyes at Screening and in the study eye 
at subsequent visits to evaluate retinal anatomy and grade DRSS. Photographs will be 
transferred to the CIRC for independent analysis. Detailed instructions for imaging and 
data transfers will be provided in the study-specific Image Acquisition and Submission 
Protocol. Fundus photography should be conducted prior to study drug administration on 
applicable visits. 
 
Spectral Domain Optical Coherence Tomography (SD-OCT):  
SD-OCT will be utilized to assess retinal thickness. All sites will be required to use a 
Heidelberg Spectralis SD-OCT. OCT imaging data will be transmitted to a Central CIRC 
for independent analysis. Detailed instructions for imaging and data transfers will be 
provided in the study-specific Image Acquisition and Submission Protocol. SD-OCT 
should be conducted prior to study drug administration on applicable visits. 
 
 
 
 
 
 
 


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7 
STUDY CONDUCT 
 
Schedule of Procedures 
A list of procedures to be conducted, by visit, is described in Table 2. 
Visits should occur on: 
 
Day 1 and Weeks 4, 8, and 12 during the Treatment Phase; 
 
Weeks 16, 20, and 24 during Follow–up Phase.  
Changes to the dosing schedule outside of the specified windows must be discussed 
with the Medical Monitor. All times should be recorded using the 24-hour clock 
(e.g., 23:20, not 11:20 pm). 


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Table 2: 
Schedule of Procedures 
 
 
Clinic Visit (V) 
Visit 1  
Screen 
Visit 2  
Call 
Visit 3 
Call 
Visit 4 
Call 
Visit 5 
Call 
Visit 6 
Visit 7 
Visit 8/ 
ED Visit 
Day (D) 
Week -4  
to Day -1 
Day 1 
Visit 2 
+1 day 
Week 4 
(-3 to  
+7 days)  
Visit 3 
+1 day 
Week 8 
(-3 to  
+7 days) 
Visit 4 
+1 day 
Week 12 
(-3 to 
+7 days) 
Visit 5 
+1 Day 
Week 16 
(±1 Week) 
Week 20 
(±1 Week) 
Week 24 
(±1 Week) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination (height, 
weight, BMI) 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Ocular History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsa  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Safety Laboratoryb 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
(KVD001 Injection) or Sham 
Procedure 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Urine Pregnancy Test 
(women) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Adverse Eventsc  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 2 
Schedule of Procedures (Cont’d) 
.
Clinic Visit (V) 
Visit 1 
Screen 
Visit 2 
Call 
Visit 3 
Call 
Visit 4 
Call 
Visit 5 
Call 
Visit 6 
Visit 7 
Visit 8/ 
ED Visit 
Day (D)  
Week -4  
to Day -1 
Day 1 
Visit 2 
+1 day 
Week 4 
(-3 to  
+7 days) 
Visit 3 
+1 day 
Week 8 
(-3 to  
+7 days) 
Visit 4 
+1 day 
Week 12 
(-3 to  
+7 days) 
Visit 5 
+1 day 
Week 16 
(±1 Week) 
Week 20 
(±1 Week) 
Week 24 
(±1 Week) 
OCULAR  
SE 
FE 
SE 
FE 
 
SE 
FE 
 
SE 
FE 
 
SE 
FE 
 
SE 
FE 
SE 
FE 
SE 
FE 
BCVAd,e 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Slit Lamp 
Biomicroscopyd 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Dilated Indirect 
Ophthalmoscopyd 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
IOPf 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Fundus Photographyd 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
SD-OCTd 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Abbreviations: AEs = Adverse events; BCVA = Best corrected visual acuity; BMI = Body mass index; ED Visit = Early discontinuation visit; FE = Fellow eye;  
IOP = Intraocular pressure; SD-OCT = Spectral domain optical coherence tomography; SE = Study eye. 
a Vital signs include pulse rate, respiratory rate, systolic and diastolic blood pressure, and temperature. Vital signs will be taken prior to and approximately 
30 minutes after study drug 
b Safety labs are detailed in Section 6.2.2. 
c  AEs to be recorded from time of signing of informed consent form 
d Procedure will be performed prior to study drug administration or sham procedure on applicable visits.  
e BCVA will be performed prior to all other ophthalmic procedures. 
f IOP will be taken prior to and within 60 minutes following study drug administration or sham procedure at applicable visits. Pre-study drug administration IOP must 
be performed prior to dilation. Post study-drug administration IOP must be performed by unmasked personnel.  


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Procedures by Visit 
Prior to any study activities, subjects will be asked to read and sign an ICF that has been 
approved by an Independent IEC/IRB and the Sponsor and which complies with 
regulatory requirements. 
All times should be recorded using the 24-hour clock (e.g., 23:20, not 11:20 pm). 
Ophthalmic procedures are proposed to occur in the following order at Visits 2-5: 
 
BCVA (must be performed prior to all other ophthalmic procedures) 
 
Slit lamp biomicroscopy 
 
Pre-Injection IOP/IOP at visits with no study drug administration (must be done 
prior to dilation) 
 
Dilated indirect ophthalmoscopy  
 
Fundus photography 
 
SD-OCT 
 
Intravitreal injection 
 
Post-Injection IOP 
7.2.1 Screening Phase (Weeks -4 to Day -1 [Visit 1]) 
Subjects will undergo screening during a visit that can occur up to 4 weeks prior to the 
Day 1 Visit. Following full discussion of the study and the signing of ICF, a screening 
subject ID number will be assigned. All subjects will be assessed for eligibility against 
the inclusion and exclusion criteria.  
The following screening and baseline assessments will be performed: 
 
Obtain subject’s full medical history, including ophthalmic ocular history with 
DME disease history, concomitant illnesses/diseases and medications, therapies 
and supplements taken within the past 3 months, previous participation in 
interventional clinical studies in the past three months; 
 
Record demographic information including race, ethnicity and date of birth; 
 
Conduct the following ophthalmic measurements and examinations in both study 
eye and fellow eye in accordance with procedures as described in Section 6.3.7; 
- 
BCVA;  
- 
Slit lamp biomicroscopy; 
- 
IOP (prior to dilation); 
- 
Dilated indirect ophthalmoscopy; 
- 
Fundus photography; 
- 
SD-OCT;  
 
Collect blood and urine samples per Section 6.3;        
 
Perform measurements of height (meters [m], without shoes) and weight 
(kilogram [kg], without shoes or overcoat). Calculation of body mass index (BMI) 
will be automated in the database; 
 
Vital signs (Blood pressure [BP], PR, respiratory rate, and body temperature [ºC]) 
– BP and PR will be recorded after subject has been supine for 5 minutes; 
 
Urine pregnancy test (women of childbearing potential); 


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 
Perform eligibility check, evaluating all results of the screening assessment 
results against the inclusion and exclusion criteria; 
 
All AEs reported after signing of the ICF will be recorded; 
 
Review the study procedures and study visit schedule with the subject. 
7.2.2 Treatment Phase 
7.2.2.1 
Day 1 and Weeks 4, 8, and 12 (Visits 2, 3, 4, and 5) 
Visits are to occur within -3 to +7 days for Weeks 4, 8, and 12. Subjects should attend 
Clinic Visit 2 within 4 weeks of screening.  
The following assessments will be performed: 
 
Reconfirm eligibility (Day 1 only); 
 
Collect blood and urine samples per Section 6.2.2;         
 
 
 
Collect any changes to medical or ocular history; 
 
Record any AEs; 
 
Record any change to the concomitant medication; 
 
Urine pregnancy test (women of childbearing potential); 
 
Vital signs (BP, PR, respiratory rate, and body temperature [ºC]) – BP and PR 
will be recorded after subject has been supine for 5 minutes. Vitals signs will be 
collected prior to and approximately 30 minutes after study drug administration or 
sham procedure; 
 
Conduct the following ophthalmic measurements and examinations in both study 
eye and fellow eye (except fundus photograph) in accordance with procedures as 
described in Section 6.3.7; 
- 
BCVA;  
- 
Slit lamp biomicroscopy; 
- IOP will be collected performed prior to and within 60 minutes (Post study-drug 
administration IOP must be performed by unmasked personnel) after study drug 
administration or sham procedure. Pre-study drug administration IOP must be 
conducted prior to dilation; 
- 
Dilated indirect ophthalmoscopy; 
- 
Fundus photography (SE only); 
- 
SD-OCT;  
 
Administer the study drug administration or sham procedure to the study eye.  
7.2.2.2 
Post–treatment Follow–up Call 
Approximately twenty-four (24) hours after each study drug administration or sham 
procedure on Day 1 and Weeks 4, 8, and 12), subjects will be contacted by telephone to 
evaluate any reported AEs and changes in concomitant medications. In the event of any 
reported AEs, the subjects will return to the clinic for assessment. 


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7.2.3 Follow–up Phase 
Following Week 12 (Visit 5) of study drug administration or sham procedure, subjects will 
be followed up monthly at the clinic for 12 weeks (Weeks 16, 20, and 24 [Visits 6, 7, and 
8, respectively]). 
7.2.3.1 
Weeks 16, 20, and 24 (Visits 6, 7, and 8) 
Visits are to occur within ± 1 week of the target visit date. At the visit the following 
procedures will be conducted: 
 
Collect blood and urine samples per section 6.2.2 (Week 16 only);     
 
Collect any changes to medical or ocular history; 
 
Record any AEs; 
 
Record any change to the concomitant medication; 
 
Urine pregnancy test (women of childbearing potential) (Week 16 only); 
 
Vital signs (BP, PR, respiratory rate, and body temperature [ºC]) – BP and PR 
will be recorded after subject has been supine for 5 minutes (Week 16 only); 
 
Conduct the following ophthalmic measurements and examinations in both study 
eye and fellow eye in accordance with procedures as described in Section 6.3.7; 
- 
BCVA;  
- 
Slit lamp examination biomicroscopy; 
- 
IOP (prior to dilation); 
- 
Dilated indirect ophthalmoscopy; 
- 
Fundus photography (SE only); 
- 
SD-OCT;  
7.2.4 Early Discontinuation Visit 
If any subject discontinues the trial early, every effort should be made to complete the 
Week 24/early discontinuation (ED) evaluations as soon as possible and, whenever 
possible, prior to starting any new medication or treatment (including rescue treatment). 
All attempts will be made to not discontinue the subject unless necessary. 
 
If a study subject completes an early discontinuation evaluation for the purpose of 
receiving rescue treatment, then the medications used as rescue treatment will be 
detailed in the respective concomitant medications section of the study’s EDC system. 
 


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8 
STATISTICAL METHODS 
The statistical considerations summarized in this section outline the plan for data 
analysis of this study.  
Before unmasking, a separate statistical analysis plan (SAP) will be finalized, providing 
detailed methods for the analyses outlined below.  
Any deviations from the planned analyses will be described and justified in the final 
integrated study report. 
Subjects will be randomized by the IRT in a 1:1:1 ratio to 1 of the 3 treatment groups:  
KVD001 Injection (6 µg/eye or 3 µg/eye) or sham.  Allocation to the treatments will be 
stratified by baseline BCVA (≤55 letters vs >55 letters) and CST at Screening (≤450 µm 
vs >450 µm) as determined by the study center. 
 
Study Subjects 
8.1.1 Disposition of Subjects 
The number and percentage of subjects entering and completing each phase of the 
study will be presented, stratified by treatment. Reasons for withdrawal 
post-randomization will also be summarized. 
8.1.2 Protocol Deviations 
Deviations from the protocol including violations of inclusion/exclusion criteria will be 
assessed as “minor” or “major” in cooperation with the Sponsor. Major deviations from 
the protocol that have the potential to impact the efficacy results will lead to the 
exclusion of a subject from the Per Protocol Set (PPS). Deviations will be defined prior to 
unmasking. 
8.1.3 Analysis Sets 
The following analysis sets have been defined for this study: 
Full Analysis Set (FAS): 
All randomized subjects following the principle of 
intention-to-treat (ITT). Subjects will be included in the 
analysis according to the treatment to which they were 
randomized. 
Per-Per Protocol Set (PPS): 
All randomized subjects who are compliant with the 
study protocol, i.e., who do not experience any major 
protocol deviations.  Subjects will be included in the 
analysis according to the treatment received. 
Safety Set (SAF): 
All randomized subjects who received at least one 
dose of study treatment. Subjects will be included in 
the analysis according to the treatment received. 
The primary efficacy analysis will be based on the FAS and a secondary analysis will 
also be performed based upon the PPS, to assess the sensitivity of the analysis to the 
choice of analysis set. All safety analyses will be based upon the SAF. 
Demographic and baseline characteristics will be evaluated for the FAS and for the PPS. 
If one or more subject(s) received incorrect trial drug, these data will also be presented 
for the SAF. 


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General Considerations 
All statistical tests will be two-sided and will be performed at the 5% level of significance, 
unless otherwise stated. 
Continuous data will be summarized by treatment group using descriptive statistics 
(number, arithmetic mean, median, standard deviation [SD], minimum, and maximum). 
Categorical data will be summarized by treatment group using frequency tables 
(frequencies and percentages). 
All analyses will be carried out using SAS Version 9.4 or higher or using other validated 
software. 
Analysis and data conventions: 
Definition of baseline 
The baseline assessment will be the latest, valid pre-dose assessment available. 
Visit windows 
Assessments taken outside of protocol allowable windows will be displayed according to 
the case report form (CRF) assessment recorded by the Investigator. 
Unscheduled assessments 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries. If more than one laboratory value is available for a given 
visit, the first valid observation will be used in summaries and all observations will be 
presented in listings. It is noted that invalid laboratory data may not be used (from 
hemolyzed samples, mishandled samples, quantity not sufficient, or other conditions that 
would render values invalid).  
Unit of Analysis 
Ophthalmic safety endpoints will be analyzed for both eyes.  Non-ophthalmic safety 
endpoints will be analyzed with subject as the unit of analysis.  For efficacy endpoints, 
the unit of analysis will be the study eye.   
Missing data conventions 
In general, data will not be imputed for safety analysis. The primary and secondary 
efficacy data analyses will be performed on the FAS 
 
  An analysis using observed data 
only will also be performed in both the FAS and PPS.  Additionally, 
 
 
the FAS for the analysis of the primary and secondary efficacy variables. No exploratory 
efficacy endpoints or safety endpoints will be imputed. Additional details will be provided 
in the SAP. 
Multiplicity Considerations 
No multiplicity adjustments are planned in this exploratory Phase 2a study. 
Other considerations 
Since central randomization will be used, no testing for treatment by center interaction 
will be conducted. No multiplicity adjustments are planned. 
Any outliers that are detected during the masked review of the data will be investigated. 
If necessary, queries will be issued to the Investigator, to either correct or confirm the 
outlier. 


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Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications 
Demographic data, medical history, concomitant diseases, and concomitant medications 
will be summarized via descriptive statistics, as appropriate, (overall and stratified by 
treatment group). 
Medical history, concomitant medications and AEs will be coded to MedDRA and WHO 
Drug dictionaries, as appropriate, for the purpose of summarization. 
 
Treatment Compliance 
IVT injection compliance for the study eye will be assessed by determining if subjects 
received one, two, three or four IVT injections. 
 
Efficacy Analyses 
All efficacy variables will be displayed in subject listings. 
8.5.1 Primary Efficacy Analysis 
The primary efficacy endpoint is change from baseline in BCVA letter count in the study 
eye at Week 16. Change from baseline in BCVA letter count will be calculated as Week 
16 BCVA letter count minus Day 1 BCVA letter count such that a negative difference 
indicates a worsening in vision. In addition, treatment comparisons between each dose 
of the KVD001 Injection and the sham will be calculated as KVD001 Injection minus 
sham, such that a positive result indicates more letters gained in the KVD001 Injection 
treatment group. 
8.5.1.1 
Hypothesis to be Tested 
The null hypothesis is that the effects changes from baseline in BCVA letter count at 
Week 16 for each dose of the KVD001 Injection and the sham procedure on BCVA are 
identical: 
H0: µk - µs = µk-µs=0, 
where µk is the effect change from baseline in BCVA letter count at Week 16 for each 
dose of the KVD001 Injection and µs is the effect of change from baseline in BCVA letter 
count at Week 16 for the sham procedure. The alternative hypothesis is that the effect 
change from baseline in BCVA letter count at Week 16 for each dose of the KVD001 
Injection is larger than the effect of change from baseline in BCVA letter count at Week 
16 for the sham procedure on BCVA: 
Ha: µk - µs > 0. 
8.5.1.2 
Statistical Methods 
The study eye ETDRS letter scores including changes from baseline will be summarized 
using continuous descriptive statistics.  An analysis of covariance (ANCOVA) model will 
be used to compare the change from baseline in BCVA letter count at Week 16 between 
each dose of the KVD001 Injection and the sham.  The ANCOVA model will include 
treatment as a main effect and baseline BCVA letter count as a covariate.  Least-
squares means (LSMeans) for each treatment group, the LSMeans difference between 
each dose of the KVD001 Injection group and the sham group, the corresponding CIs 
and the p-values will be presented. 


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As a sensitivity analysis, treatment group differences for changes from baseline in BCVA 
letter count will be evaluated using a mixed model repeated measures (MMRM) 
ANCOVA fitted with treatment group, visit and the treatment by visit interaction as 
categorical variable terms with baseline BCVA letter score and baseline CST as 
covariates with contrasts included for each visit. LSMeans and 95% confidence intervals 
for each treatment group, the LSMeans difference between each dose of the KVD001 
Injection and sham, the corresponding confidence intervals, and the p-values will be 
presented for each visit. 
8.5.2 Secondary Efficacy Analyses 
The secondary efficacy endpoints are: 
 
Change from baseline in CST as measured by Spectral Domain OCT (SD-OCT) 
 
Proportion of eyes with a ≥2 step improvement from baseline in DRSS score  
 
Change from baseline in BCVA letter count as measured by ETDRS 
 
Proportion of study eyes with ≥5, ≥10, and ≥15 BCVA letter change from baseline 
(gain and loss). 
Change from baseline in BCVA letter count in the study eye at Week 24 and change 
from baseline in CST in the study eye as measured by SD-OCT at Week 16 and 
Week 24 will be analyzed using the same method described for the primary efficacy 
analysis.  Note that change from baseline in CST will be in favor of KVD001 if the 
treatment difference is <0. 
The proportion of study eyes with improvement of 2 or more steps on the ETDRS DRSS 
score between the sham procedure group and each of the KVD001 injection groups will 
be summarized by visit using discrete summary statistics, including 95% asymptotic 
normal CIs for each treatment group.  The difference in proportions between each of the 
KVD001 groups and the sham procedure group will be analyzed at Week 16 and 
Week 24 using a Pearson’s chi-squared test.  95% asymptotic normal CIs for the 
differences in proportions will also be calculated.  Fisher’s exact tests and exact CIs will 
be employed in cases of expected counts <5. 
The proportion of study eyes with ≥5, ≥10 and ≥15 BCVA letter change (gain and loss) 
between baseline and Weeks 16 and 24 will be analyzed using the same method 
described for the proportion of study eyes with improvement of 2 or more steps on the 
ETDRS DRSS score. 
 
Safety Analyses 
Safety endpoints include AEs, manifest refraction/BCVA, slit lamp biomicroscopy, dilated 
ophthalmoscopy, IOP, SD-OCT, ETDRS DRSS, physical exam findings, laboratory test 
results, and vital signs. 
8.6.1 Adverse Events 
AEs will be coded using the MedDRA dictionary. Frequencies and percentages of 
subjects with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs 
causing premature discontinuation will be provided by treatment group. An AE is 
treatment emergent if it 1) occurs after the first dose of randomized study treatment or 2) 
if it is present prior to receipt of randomized study treatment but worsens in severity or 
increases in frequency after the first dose of randomized study treatment. Furthermore, 
frequencies will be given of subjects with TEAEs by system organ class and preferred 
term; by system organ class, preferred term and maximal severity; by system organ 


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class, preferred term and strongest relationship; by system organ class and preferred 
term for SAEs; and by system organ class, preferred term, and day of onset. Separate 
analyses will be performed for ocular specific and all AEs (including systemic). AEs will 
be classified by System Organ Class (SOC) and preferred term in the MedDRA coding 
dictionary. AEs will be tabulated both as the total events (regardless of relationship to 
treatment) and as drug-related events. The number of subjects with one or more events 
versus no events will be calculated for each treatment. 
Subject listings of all AEs will be provided as well as listings of deaths, SAEs, and AEs 
leading to discontinuation. 
The following summaries will be provided: 
 
Relationship between AE SOC and verbatim text; 
 
On-treatment AEs:  number and percentage of subjects reporting each AE, each 
AE leading to withdrawal, each SAE, each drug-related SAE, each fatal AE, and 
most frequent by treatment; 
 
Post-treatment AEs: number and percentage of subjects reporting each AE; 
 
Listing of all AEs; 
 
Summary of Most Frequent AEs. 
8.6.2 Laboratory Assessments 
Laboratory assay results include hematology, clinical chemistry, liver enzymes, 
electrolytes, and urinalysis.  Each of the continuous parameters will be summarized 
using continuous descriptive statistics for each treatment group and for all subjects at 
each visit.  Changes from baseline will also be summarized for each treatment group 
and for all subjects where appropriate.  Each categorical parameter will be summarized 
using frequency counts and percentages for each treatment group and for all subjects.  
A shift table of the changes from baseline will also be presented.   
The high/low criteria will be determined based on the reference ranges provided by the 
laboratory.  The actual values and change from baseline values for each laboratory 
assessment will be summarized by treatment group. Summaries of assessments outside 
the normal range and the changes from baseline relative to the normal range will also be 
produced. A subject listing of laboratory assessments will also be produced and will 
include changes from baseline at each visit.  Data from subjects who have values 
outside the normal range will be specified in this listing. 
8.6.3 Vital Signs 
Vital sign measurements, including pulse, respiratory rate, blood pressure (SBP, DBP), 
body temperature, height, weight and BMI, will be summarized by visit and time point 
using continuous descriptive statistics for each treatment group and for all subjects.  
Change from baseline to each visit will also be summarized for each treatment group 
and for all subjects.  Systolic and diastolic BP, heart rate, respiration rate, and body 
temperature will be summarized by treatment group at each visit and for the 
maximum/minimum post-baseline. The change from baseline values will also be 
summarized.  A subject listing will also be produced and will include changes from 
baseline at each visit. 
8.6.4 Physical Examination 
A subject listing of the Visit 1 (Screening) physical examination findings will be produced. 


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8.6.5 Slit Lamp Biomicroscopy 
A slit-lamp biomicroscopy examination of the cornea, conjunctiva, anterior chamber, 
iris/pupil, lens, and eyelid will be performed at each visit.  The findings will be graded as 
normal or abnormal [non-clinically significant (NCS) or clinically significant (CS)].  The 
findings will be summarized for each treatment group and for all subjects at each visit for 
each eye (study eye and fellow eye).  The findings will be summarized using counts and 
percentages for each treatment group and for all subjects combined at each visit for 
each eye (study eye and fellow eye).  Shift tables for the slit-lamp biomicroscopy 
parameters will also be provided comparing each follow-up visit to baseline.  A subject 
listing of the slit-lamp biomicroscopy examination parameters will also be produced. 
8.6.6 Indirect Dilated Ophthalmoscopy 
A dilated ophthalmoscopy examination of the vitreous, macula, optic nerve, peripheral 
retina, and choroid will be performed at each visit.  The findings will be graded as normal 
or abnormal (NCS or CS).  The findings will be summarized using frequency counts and 
percentages by treatment group and for all subjects at each visit for each eye (study eye 
and fellow eye).  A shift table of changes from baseline will also be presented.  Cup-to-
disc ratio is also reported for each visit and will be summarized using continuous 
descriptive statistics.  Change from baseline will also be summarized by treatment group 
for each eye (study eye and fellow eye).  A subject listing of the dilated ophthalmoscopy 
examination parameters will also be produced. 
8.6.7 Intraocular Pressure 
IOP of both eyes will be assessed. IOP will be summarized using continuous descriptive 
statistics for each treatment group and for all subjects at each visit for each eye (study 
eye and fellow eye).  Change from baseline will also be summarized for each treatment 
group for each eye (study eye and fellow eye).  Categorical summary statistics will also 
be presented using the following categories: ≤5, 6 to 14, 15 to 21, 22 to 29, and 
≥30 mmHg for each visit and using the following categories: ≤-15, -14 to -10, -9 to -5, -4 
to 0, 1 to 4, 5 to 9, 10 to 14, 15 to 19, and ≥20 mmHg for change from baseline to each 
visit.  A subject listing of IOP will also be produced. 
8.6.8 Best Corrected Visual Acuity and Manifest Refraction 
Best-Corrected visual acuity of both eyes will be measured consistent with the standard 
procedure developed for the ETDRS. The number of letters read correctly will be 
counted and the total BCVA letter score will be reported. The total BCVA letter score will 
be summarized for each treatment group using continuous descriptive statistics at each 
visit for each eye (study eye and fellow eye).  Change from baseline will also be 
summarized by treatment group and visit for each eye (study eye and fellow eye).  
The number of subjects (by eye) with a gain or loss in BCVA letter score ≥15, ≥10, and 
≥5 from baseline will be summarized using counts and percentages for each treatment 
group at each visit.   
A subject listing of BCVA and manifest refraction will also be produced. 
8.6.9 SD-OCT 
The SD-OCT parameter values, including changes from baseline will be summarized for 
each visit using continuous descriptive statistics.  A subject listing of SD-OCT 
parameters will also be produced. 


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8.6.10 ETDRS DRSS 
The ETDRS DRSS scores including changes from baseline will be summarized for each 
visit using continuous descriptive statistics.  A subject listing of ETDRS DRSS will also 
be produced. 
 
Interim Analyses 
No interim analyses are planned. 
 
Determination of Sample Size 
The proposed sample size (41 per treatment group) will provide approximately 80% 
power to detect a difference in change from baseline of 5 letters between either of the 
KVD001 treatment groups and sham based on a two-sided, two-sample t-test with 
significance level 0.05 and assuming a pooled SD of 7.5 letters. 


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9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
 
Data Quality Assurance 
The Sponsor or Sponsor’s designee will conduct a site visit to verify the qualifications of 
each Investigator, inspect the site facilities, and inform the Investigator of responsibilities 
and the procedures for ensuring adequate and correct documentation. Site qualification 
visits may be waived, per the CRO’s SOPs, if the site has participated in a study with the 
CRO within the past 12months. 
The Investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the study for 
each subject. All information recorded on the eCRF system for this study must be 
consistent with the subjects’ source documentation (i.e., medical records). 
9.1.1 Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each study 
center using eCRFs. Data from external sources (such as laboratory data) will be 
imported into the database. Once the eCRF clinical data have been submitted to the 
central server at the independent data center, corrections to the data fields will be 
captured in an audit trail. The reason for change, the name of the person who performed 
the change, together with the time and date will be logged to provide an audit trail.  
If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the EDC application. The appropriate staff at the study site will answer queries 
sent to the Investigator. The name of the staff member responding to the query and time 
and date stamp will be captured to provide an audit trail. Once all source data 
verification is complete and all queries are closed, the monitor will freeze the eCRF 
page. 
The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual. In addition, site 
personnel will receive training on the EDC system/eCRF. 
 
Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the eCRF. All source documents 
from which eCRF entries are derived should be placed in the subject’s medical records. 
Measurements for which source documents are usually available include laboratory 
assessments, and study specific examinations.  
The original eCRF entries for each subject may be checked against source documents 
at the study site by the Ora site monitor.  
Instances of missing or uninterpretable data will be discussed with the Investigator for 
resolution.  
The specific procedures to be used for data entry and query resolution using the eCRF 
will be provided to study sites in a training manual. In addition, site personnel will receive 
training on the EDC system/eCRF. 
9.2.1 Data Collection  
The Investigators (and appropriately authorized staff) will be given access to an on-line 
web-based EDC) system which is 21 CFR Part 11 compliant. This system is specifically 
designed for the collection of the clinical data in electronic format. Access and right to 


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the EDC system will be carefully controlled and configured according to each individual’s 
role throughout the study. In general, only the Investigator and authorized staff will be 
able to enter data and make corrections in the eCRFs. 
The eCRF should be completed for each subject included in the study and should reflect 
the latest observations on the subjects participating in the study. Therefore, the eCRFs 
are to be completed as soon as possible during or immediately after the subject’s visit or 
assessment. The Investigator must verify that all data entries in the eCRF are accurate 
and correct. If some assessments cannot be done, or if certain information is 
unavailable, not applicable or unknown, the Investigator should indicate this in the 
eCRF.  
Computerized data–check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and 
the site will be informed about new issues to be resolved on-line. All discrepancies will 
be solved on–line directly by the Investigator or by authorized staff. Off–line edit checks 
will be done to examine relationships over time and across panels to facilitate quality 
data. 
After completion, the Investigator will be required to electronically sign off the clinical 
data. 
Data about all study product dispensed to the subject and any dosage changes will be 
tracked on the eCRF.  
 
Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare 
eCRF entries and individual subject’s source medical records, assess drug 
accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. The review of medical records will be performed in a manner to 
ensure that subject confidentiality is maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with 
source documents, will be required to monitor the progress of the study. Moreover, 
Regulatory Authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical 
Quality Assurance Group may wish to carry out such source data checks and/or on–site 
audit inspections. Direct access to source data will be required for these inspections and 
audits; they will be carried out giving due consideration to data protection and medical 
confidentiality. The Investigator assures Ora and the Sponsor of the necessary support 
at all times. 
 
Data Processing 
All data will be entered by site personnel into the EDC system/eCRF (as detailed in 
Section 9.2.1). 
The data-review and data-handling document, to be developed during the initiation 
phase of the study, will include specifications for consistency and plausibility checks on 
data and will also include data-handling rules for obvious data errors. Query/correction 
sheets for unresolved queries will be sent to the study monitors for resolution with the 
Investigator. The database will be updated on the basis of signed corrections.  
Previous and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Reference List (DRL), which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Medical history/current medical 


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conditions and AEs will be coded using the medical dictionary for regulatory activities 
(MedDRA) terminology. 
Previous and concomitant diseases as well as AEs will be coded with MedDRA. 
The versions of the coding dictionaries will be provided in the Clinical Study Report. 
 
Archiving Study Records 
According to International Conference on Harmonization (ICH) guidelines, essential 
documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. However, these 
documents should be retained for a longer period if required by the applicable legal 
requirements.   
 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor 
and Investigator abide by the principles of the Good Clinical Practice (GCP) guidelines of 
the ICH, and of the Declaration of Helsinki (1996). The study also will be carried out in 
keeping with local legal requirements.  
 
Informed Consent 
Before each subject is admitted to the study, informed consent will be obtained from the 
subject (or his/her legally authorized representative) according to the regulatory and 
legal requirements of the participating country. This consent form must be dated and 
retained by the Investigator as part of the study records. The Investigator will not 
undertake any investigation specifically required only for the clinical study until valid 
consent has been obtained. The date the consent was obtained must also be 
documented in the eCRF system. 
If a protocol amendment is required, the ICF may need to be revised to reflect the 
changes to the protocol. If the consent form is revised, it must be reviewed and 
approved by the appropriate IEC/IRB, and signed by all subjects subsequently enrolled 
in the study as well as those currently enrolled in the study. 
 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/IRB/Competent Authorities, in accordance with local legal 
requirements. The Sponsor must ensure that all ethical and legal requirements have 
been met before the first subject is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be 
written, receive approval from the appropriate personnel, and receive 
IRB/IEC/Competent Authority approval prior to implementation (if appropriate). Following 
approval, the protocol amendment(s) will be submitted to the Investigational New Drug 
Application (IND) under which the study is being conducted.  
Administrative changes (not affecting the subject benefit/risk ratio) may be made without 
the need for a formal amendment. All amendments will be distributed to all protocol 
recipients, with appropriate instructions. 


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Duration of the Study 
For an individual subject, the maximum duration of the study for each subject will be up 
to 28 weeks (including up to 4 weeks for screening, up to 12 weeks of treatment period, 
and up to 12 weeks for follow–up).  
 Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or 
events that suggest a possible hazard to subjects if the study continues, the study may 
be terminated after appropriate consultation between the relevant parties. The study 
may also be terminated early at the Sponsor’s discretion in the absence of such a 
finding. 
Conditions that may warrant termination include, but are not limited to: 
 
The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study; 
 
Failure to enroll subjects at an acceptable rate; 
 
A decision on the part of the Sponsor to suspend or discontinue development of 
the drug. 
 Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior 
written approval from the Sponsor. 
The anonymity of participating subjects must be maintained. Subjects will be identified 
on eCRF system and other documents submitted to Ora by their subject number, initials 
and/or birth date, not by name. Documents not to be submitted to Ora that identify the 
subject (e.g., the signed informed consent) must be maintained in confidence by the 
Investigator.  
 Other Ethical and Regulatory Issues (optional) 
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the Sponsor will issue prompt notification to all parties – Regulatory 
Authorities, Investigators, and IRB/IECs. 
A significant safety issue is one that has a significant impact on the course of the clinical 
study or program (including the potential for suspension of the development program or 
amendments to protocols) or warrants immediate update of informed consent. 
 Publication Policy 
By signing the study protocol, the Investigator agrees with the use of results of the study 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals. If necessary, Regulatory Authorities will be 
notified of the Investigator's name, address, qualifications, and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with the Sponsor in advance. Details are provided in a separate document. 
















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11 REFERENCE LIST 
Campochiaro, P. A., L. P. Aiello and P. J. Rosenfeld (2016). "Anti-Vascular Endothelial 
Growth Factor Agents in the Treatment of Retinal Disease: From Bench to Bedside." 
Ophthalmology 123(10S): S78-S88. 
Clermont, A., T. J. Chilcote, T. Kita, J. Liu, P. Riva, S. Sinha and E. P. Feener (2011). 
"Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in 
diabetic rats." Diabetes 60(5): 1590-1598. 
Diabetes, C., I. Complications Trial/Epidemiology of Diabetes, G. Complications 
Research, D. M. Nathan, B. Zinman, P. A. Cleary, J. Y. Backlund, S. Genuth, R. Miller 
and T. J. Orchard (2009). "Modern-day clinical course of type 1 diabetes mellitus after 30 
years' duration: the diabetes control and complications trial/epidemiology of diabetes 
interventions and complications and Pittsburgh epidemiology of diabetes complications 
experience (1983-2005)." Arch Intern Med 169(14): 1307-1316. 
Gao, B. B., A. Clermont, S. Rook, S. J. Fonda, V. J. Srinivasan, M. Wojtkowski, J. G. 
Fujimoto, R. L. Avery, P. G. Arrigg, S. E. Bursell, L. P. Aiello and E. P. Feener (2007). 
"Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular 
permeability through prekallikrein activation." Nat Med 13(2): 181-188. 
Gardner, T. W. and D. A. Antonetti (2007). "A prize catch for diabetic retinopathy." Nat 
Med 13(2): 131-132. 
GS, T., C. N, S. R, C. GC and W. TY (2017). "Diabetic Macular Oedema." Lancet 
Diabetes Endocrinol 5(2): 143-155. 
IB (2017). Investigator's Brochure, KalVista Pharmaceuticals, Ltd. 
Kita, T., A. C. Clermont, N. Murugesan, Q. Zhou, K. Fujisawa, T. Ishibashi, L. P. Aiello 
and E. P. Feener (2015). "Plasma Kallikrein-Kinin System as a VEGF-Independent 
Mediator of Diabetic Macular Edema." Diabetes 64(10): 3588-3599. 
Lee, R., T. Y. Wong and C. Sabanayagam (2015). "Epidemiology of diabetic retinopathy, 
diabetic macular edema and related vision loss." Eye Vis (Lond) 2: 17. 
Nguyen, Q. D., D. M. Brown, D. M. Marcus, D. S. Boyer, S. Patel, L. Feiner, A. Gibson, 
J. Sy, A. C. Rundle, J. J. Hopkins, R. G. Rubio, J. S. Ehrlich, Rise and R. R. Group 
(2012). "Ranibizumab for diabetic macular edema: results from 2 phase III randomized 
trials: RISE and RIDE." Ophthalmology 119(4): 789-801. 
Virgili, G., M. Parravano, J. R. Evans, I. Gordon and E. Lucenteforte (2017). "Anti-
vascular endothelial growth factor for diabetic macular oedema: a network meta-
analysis." Cochrane Database Syst Rev 6: CD007419. 
 

SAP_001.pdf: 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A randomized sham-controlled double-masked Phase 2a study of 
the efficacy, safety and tolerability of the intravitreal plasma 
kallikrein inhibitor, KVD001, in subjects with center-involving 
diabetic macular edema (ciDME) who have had prior anti-vascular 
endothelial growth factor (VEGF) treatment 
 
 
 
 
 
 
 
NCT03466099 
 
 
 
 
7 November 2019 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
A randomized sham-controlled double-masked Phase 2a study of 
the efficacy, safety and tolerability of the intravitreal plasma 
kallikrein inhibitor, KVD001, in subjects with center-involving 
diabetic macular edema (ciDME) who have had prior anti-vascular 
endothelial growth factor (VEGF) treatment 
Sponsor:  
KalVista Pharmaceuticals, Ltd. 
Protocol Number: 
KVD001-201 
Author:  
Date: 
07NOV2019 
Version: 
2.0 
SIGN


 
A randomized sham-controlled double-masked Phase 2a study of the efficacy. safety and 
tolerability of the intravitreal plasma kallikreln inhibitor, KVD001, In subjects with center-
Involving diabetic macular edema (clDME) who have had prior anti-vascular endothelial growth 
factor (VEGF) treatment 
Protocol Number: 
KVD001 -201 
SAP Version: 
SAP Date: 
2.0 
07NOV2019 
Statistical Analysis Plan Approval 
Prepared by: 
Reviewed by: 
Approved by: 
Pa<Je 2 of 36 


 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol KVD001-201 SAP, Version 2.0 
Table of Contents 
1. 
Introduction...............................................................................................................................7 
2. 
Study Objectives ......................................................................................................................7 
2.1 Primary Efficacy Endpoint ........................................................................................................7 
2.2 Secondary Efficacy Endpoints .................................................................................................7 
2.3 Safety Endpoints ......................................................................................................................8 
2.4 Statistical Hypotheses..............................................................................................................8 
3. 
Study Design and Procedures .................................................................................................8 
3.1 General Study Design ..............................................................................................................8 
3.2 Schedule of Visits and Assessments .......................................................................................9 
4. 
Study Treatments...................................................................................................................10 
4.1 Method of Assigning Subjects to Treatment Groups .............................................................10 
4.2 Masking and Unmasking........................................................................................................11 
5. 
Sample Size and Power Considerations................................................................................11 
6. 
Data Preparation ....................................................................................................................11 
7. 
Analysis Sets..........................................................................................................................12 
7.1 Full Analysis Set.....................................................................................................................12 
7.2 Per Protocol Set .....................................................................................................................12 
7.3 Safety Set...............................................................................................................................12 
8. 
General Statistical Considerations.........................................................................................12 
8.1 Unit of Analysis.......................................................................................................................12 
8.2 Missing Data Conventions .....................................................................................................13 
8.3 Definition of Baseline .............................................................................................................14 
8.4 Data Analysis Conventions ....................................................................................................14 
8.5 Adjustments for Multiplicity.....................................................................................................15 
9. 
Disposition of Subjects...........................................................................................................15 
10. 
Demographic and Other Baseline Variables..........................................................................15 
10.1 Demographic Variables..........................................................................................................15 
10.2 Baseline Disease Characteristics...........................................................................................16 
11. 
Medical History and Prior and Concomitant Medications ......................................................16 
11.1 Medical History.......................................................................................................................17 
11.2 Prior and Concomitant Medications .......................................................................................17 
12. 
Dosing Compliance and Treatment Exposure .......................................................................18 
12.1 Dosing Compliance ................................................................................................................18 
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Protocol KVD001-201 SAP, Version 2.0 
12.2 Treatment Exposure...............................................................................................................18 
13. 
Efficacy Analyses ...................................................................................................................19 
13.1 Primary Analysis ....................................................................................................................19 
13.2 Additional Analyses of the Primary Endpoint .........................................................................21 
13.3 Secondary Analyses ..............................................................................................................22 
14. 
Safety Analyses .....................................................................................................................23 
14.1 Adverse Events ......................................................................................................................23 
14.2 BCVA ETDRS ........................................................................................................................25 
14.3 SD-OCT..................................................................................................................................25 
14.4 EDTRS DRSS ........................................................................................................................25 
14.5 Slit-Lamp Biomicroscopy Examination...................................................................................26 
14.6 Indirect Dilated Ophthalmoscopy ...........................................................................................26 
14.7 Intraocular Pressure (IOP) .....................................................................................................26 
14.8 Vital Signs ..............................................................................................................................27 
14.9 Urine Pregnancy Test ............................................................................................................27 
14.10 
Laboratory Assessments .................................................................................................27 
15. 
.............................................................................................................28 
16. 
Changes from Protocol-Stated Analyses ...............................................................................28 
17. 
References.............................................................................................................................28 
18. 
Revision History .....................................................................................................................28 
18.1 Revision 01.............................................................................................................................28 
19. 
Tables.....................................................................................................................................29 
20. 
Listings ...................................................................................................................................32 
21. 
Figures ...................................................................................................................................33 
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Protocol KVD001-201 SAP, Version 2.0 
List of Abbreviations 
AE 
adverse event 
ANCOVA 
analysis of covariance 
anti-VEGF 
anti-vascular endothelial growth factor 
ATC 
anatomical therapeutic chemical 
BCVA 
best corrected visual acuity 
BMI 
body mass index 
CI 
confidence interval 
ciDME 
center-involving diabetic macular edema 
CIRC 
central image reading center 
CS 
clinically significant 
CSR 
clinical study report 
CST 
central subfield thickness 
DBP 
diastolic blood pressure 
DME 
diabetic macular edema 
DRSS 
Diabetic Retinopathy Severity Scale 
DVM 
data validation manual 
eCRF 
electronic case report form 
ED 
early discontinuation 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
full analysis set 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IOP 
intraocular pressure 
IP 
investigational product 
IQR 
interquartile range 
IRT 
interactive response technology 
ITT 
intention-to-treat 
IVT 
intravitreal 
LSMeans 
least-squares means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
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Protocol KVD001-201 SAP, Version 2.0 
NCS 
not clinically significant 
OD 
right eye 
OS 
left eye 
OU 
both eyes 
PPS 
per protocol set 
PR 
pulse rate 
PT 
preferred term 
SAE 
serious adverse event 
SAF 
safety set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SD-OCT 
spectral domain optical coherence tomography 
SOC 
system organ class 
SOP 
standard operating procedures 
SRS 
study report specifications 
TEAE 
treatment-emergent adverse event 
WHODrug 
World Health Organization Drug Dictionary 
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Protocol KVD001-201 SAP, Version 2.0 
1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol KVD001-201, dated 09 APR 2018. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports (CSR). 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, safety and 
tolerability assessments that will be evaluated. This SAP provides details of the specific statistical 
methods that will be used. The statistical analysis methods presented in this document will supersede 
the statistical analysis methods described in the clinical protocol. If additional analyses are required to 
supplement the planned analyses described in this SAP, they may be completed and will be identified 
in the CSR. 
2. Study Objectives 
The primary objective of this study is to evaluate the efficacy of monthly dosing of intravitreal (IVT) 
injection of KVD001 in subjects with center-involving diabetic macular edema (ciDME) who have had 
prior anti-vascular endothelial growth factor (anti-VEGF) treatment. The secondary objective is to 
evaluate the local and systemic safety and tolerability of monthly dosing of KVD001 Injection in subjects 
with ciDME who have had prior anti-VEGF treatment. 
2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline in best corrected visual acuity (BCVA) letter 
count as measured by Early Treatment Diabetic Retinopathy Study (ETDRS) at Week 16. 
2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
• 
Change from baseline in central subfield thickness (CST) as measured by Spectral-Domain 
Optical Coherence Tomography (SD-OCT) 
• 
Proportion of eyes with a ≥2 step improvement from baseline in Diabetic Retinopathy Severity 
Scale (DRSS) score 
• 
Change from baseline in BCVA letter count as measured by ETDRS at Weeks 4, 8, 12, 20, and 
24 
• 
Proportion of study eyes with ≥5, ≥10, and ≥15 BCVA letter change from baseline (gain and 
loss). 
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Protocol KVD001-201 SAP, Version 2.0 
2.3 
Safety Endpoints 
The safety variables include the following: 
• 
Adverse events (AEs) 
• 
Ophthalmic and physical exam findings 
• 
Laboratory test results (clinical chemistry, hematology, and urinalysis) 
• 
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate [PR], 
temperature, and respiratory rate). 
2.4 
Statistical Hypotheses 
The null hypotheses are that [1] the effect changes from baseline in BCVA letter count at Week 16 for 
each dose of the KVD001 Injection and the sham procedure on BCVA are identical and [2] the effect 
changes from baseline in BCVA letter count at Week 16 between the KVD001 Injection doses are 
identical: 
H0: μk3 - μs = μk6 - μs = μk6 - μk3 = 0, 
where μk3 and μk6 are the effect changes from baseline in BCVA letter count at Week 16 for KVD001 3 
μg Injection and KVD001 6 μg Injection, respectively, and μs is the effect of change from baseline in 
BCVA letter count at Week 16 for the sham procedure. The alternative hypotheses are that [1] the effect 
changes from baseline in BCVA letter count at Week 16 for each dose of the KVD001 Injection is larger 
than the effect of change from baseline in BCVA letter count at Week 16 for the sham procedure and 
[2] the effect changes from baseline in BCVA letter count at Week 16 for KVD001 6 μg Injection is larger 
than the effect of change from baseline in BCVA letter count at Week 16 for KVD 3 μg Injection: 
Ha: μk3 - μs > 0 or μk6 - μs > 0 or μk6 - μk3 > 0. 
All hypothesis testing will be two-sided with a type I error rate (α) of 0.05. There will be no adjustments 
for multiple endpoints or multiple treatment comparisons for this early-phase, exploratory study. 
Specifics of the statistical tests are provided in Section 13. 
3. Study Design and Procedures 
3.1 
General Study Design 
This is a phase 2a, randomized, double-masked, sham-controlled, 3-arm study to evaluate the efficacy, 
safety, and tolerability of KVD001 Injection as monotherapy in adult subjects with ciDME who have had 
prior anti-VEGF treatment. Approximately 123 eligible subjects will be randomized into the study. 
Subjects will undergo screening for fulfilling the inclusion and exclusion criteria in order to be eligible for 
this study. Eligible subjects will be stratified based on visual acuity and CST, and then randomly 
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Protocol KVD001-201 SAP, Version 2.0 
assigned in a 1:1:1 ratio into the 3 groups described below. Stratified randomization will be performed 
centrally by visual acuity and CST at Day 1. 
• 
KVD001 6 μg by IVT injection; 
• 
KVD001 3 μg by IVT injection; 
• 
Sham procedure. 
Rescue intervention (e.g., anti-VEGF, focal/grid macular laser photocoagulation, IVT steroids) may be 
administered due to worsening DME (i.e., attributable to worsening DME and not another cause) if either 
of the following occurs and, where possible, after consultation with the Medical Monitor: 
• 
During Treatment Phase 
o BCVA deteriorates 3 lines (15 letters) or more from baseline 
o CST worsening of >100 µm from baseline 
• 
During Follow up Phase (i.e., after week 16) 
o BCVA deteriorates 3 lines (15 letters) or more from highest BCVA during treatment 
phase or baseline 
o CST worsening of >100 µm from lowest CST during treatment phase or baseline. 
Subjects who receive a rescue intervention in the study eye will be discontinued from further study 
participation. The Week 24/Early Discontinuation (ED) evaluations should be collected prior to study 
discontinuation and prior to administration of the rescue medication. Details regarding the medications 
used as rescue treatment must be entered as concomitant medications for the respective study 
subject. 
3.2 
Schedule of Visits and Assessments 
The schedule of procedures is provided in Appendix A.The screening period will be up to 4 weeks. On 
the day of first study drug administration (Day 1), eligible subjects will be randomized to a 12-week, 
double-masked treatment period (a total of 4 doses given at approximately monthly intervals). Subjects 
will visit the study clinic on Day 1 and Weeks 4, 8, and 12 during the Treatment Phase. The visit window 
for these visits is -3 days to +7 days. All subjects will visit the clinic at Weeks 16, 20, and 24 after the 
last study drug administration or sham procedure for safety and ophthalmic assessments. The visit 
window for Weeks 16, 20, and 24 is ±7 days. For ED visits, the visits will be windowed according to the 
Protocol windows defined above and in Table 1. 
Summaries and analyses utilizing timepoints will be completed using the nominal visit recorded in the 
electronic case report form (eCRF), except in the case of ED visits where the visit will be windowed to 
a scheduled visit using Table 1. In the case where a subject has a scheduled visit and a windowed ED 
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Protocol KVD001-201 SAP, Version 2.0 
visit mapped to the same visit name, the observation closest to the planned study day will be used for 
analysis. 
Table 1. Study Visit Windows for Early Discontinuation Visits 
Scheduled Visit 
Planned Study Day 
Visit Window 
Day 1 
1 
N/A 
Week 4 
28 
15-42 
Week 8 
56 
43-70 
Week 12 
84 
71-98 
Week 16 
112 
99-126 
Week 20 
140 
127-154 
Week 24 
168 
155-182 
4. Study Treatments 
Subjects will be randomized by the Interactive Response Technology (IRT) in a 1:1:1 ratio to 1 of the 3 
treatment groups: KVD001 Injection (6 µg/eye or 3 µg/eye) or sham. Allocation to the treatments will be 
stratified by baseline BCVA (≤55 letters vs >55 letters) and CST at Screening (≤450 µm vs >450 µm) as 
determined by the study center. 
1:1:1 randomization: 
-
KVD001 6 μg by IVT injection; 
-
KVD001 3 μg by IVT injection; 
-
Sham procedure. 
4.1 
Method of Assigning Subjects to Treatment Groups 
Screened subjects who sign an informed consent form (ICF) will be assigned a Subject ID number that 
will be entered on the eCRF. The Subject ID number will consist of 3 digits. Stratified randomization will 
be used to avoid bias in the assignment of subjects to treatment, to increase the likelihood that known 
and unknown subject attributes (e.g., demographics and baseline characteristics) are evenly balanced 
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Protocol KVD001-201 SAP, Version 2.0 
across treatment groups, to reduce the possible influence of covariates on the drug evaluation, and to 
enhance the validity of statistical comparisons. 
Subjects who satisfy all the entry criteria will be centrally assigned to study medication at the study site 
on Day 1 after stratification according to visual acuity (Baseline BCVA: ≤55 Letters versus >55 Letters) 
and CST (screening CST: ≤450 µm versus >450 µm) through the use of the IRT. 
4.2 
Masking and Unmasking 
staff are masked to the treatment group assignments during the randomization 
process and for the duration of the study. 
This
staff, the sponsor 
 and site 
 study. Subjects, Investigators
masked
double
a
 is
-
Under normal circumstances, the mask should not be broken. When medically necessary, an 
Investigator may need to determine what treatment has been assigned to a subject. The Investigator 
will contact the Sponsor with the details of the emergency unmasking request. The sponsor will make 
the final determination if the unmasking request will be granted. If granted, the unmasking information 
may be accessed through the use of an IRT system or provided by the unmasked designee. The 
Investigator must also indicate in source documents and in the eCRF that the mask was broken and 
provide the date, time, and reason for breaking the mask. 
5. Sample Size and Power Considerations 
The proposed sample size (41 per treatment group) will provide approximately 80% power to detect a 
difference in change from baseline of 5 letters between either of the KVD001 treatment groups and 
sham based on a two-sided, two-sample t-test with significance level 0.05 and assuming a pooled 
standard deviation (SD) of 7.5 letters. 
6. Data Preparation 
Data management procedures, including database design, selection of the data dictionary, and coding 
of all AEs and medications, will be performed 
. All reported study data will be recorded on 
eCRFs supplied 
. Clinical personnel at the study center and 
are 
responsible for ensuring that the protocol is followed and that the eCRFs are properly completed. 
After data are entered into the clinical study database, electronic edit checks will be performed, including 
checks for missing data, out of range values, discrepancies within and across visits, and cross checks 
between different data tables. All data validation specifications and procedures are detailed in the Data 
Validation Manual (DVM), and manual data checks are documented in the Study Report Specifications 
(SRS). When the database has been declared to be complete and accurate, the database will be locked 
and treatment codes unmasked. Any changes to the database after that time can only be made with the 
approval of the Sponsor in consultation with Ora, Inc. 
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All final analyses outlined in this document will be performed after: 
• 
All data management requirements are met according to 
Standard Operating Procedures 
(SOP), including performance of edit and validation checks, documentation and resolution of 
data queries, and database lock with written authorization provided by appropriate 
and 
Ora/Sponsor personnel; 
• 
All protocol deviations have been classified as major or minor and the Per Protocol Set (PPS) 
has been determined; and 
• 
The treatment codes have been unmasked. 
7. Analysis Sets 
7.1 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized subjects who received at least one dose of study 
treatment. Subjects will be included in the analysis according to the treatment to which they were 
randomized. 
7.2 
Per Protocol Set 
The PPS will include all randomized subjects who: 
• 
Received all four injections of study treatment 
• 
Have a non-missing BCVA ETDRS result at Week 16 
• 
Were not discontinued prior to Week 16 for any reason 
• 
Have not experienced any major protocol deviations that have the potential to impact the 
efficacy results. 
Subjects will be included in the analysis according to the treatment received. 
7.3 
Safety Set 
The Safety Set (SAF) will include all randomized subjects who received at least one dose of study 
treatment. Subjects will be included in the analysis according to the treatment received. 
8. General Statistical Considerations 
8.1 
Unit of Analysis 
Ophthalmic safety endpoints will be analyzed for both eyes. Non-ophthalmic safety endpoints will be 
analyzed with subject as the unit of analysis. For efficacy endpoints, the unit of analysis will be the 
study eye. 
The study eye will be defined as the eye that meets all of the inclusion and none of the exclusion criteria. 
If both eyes qualify, the eye with the worse BCVA ETDRS at Day 1 will be used as the study eye. If both 
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eyes have the same BCVA ETDRS at Day 1, the eye with the highest CST on SD-OCT on Day 1, as 
assessed by the Investigator, will be used as the study eye. If both eyes qualify and neither is preferred 
based on the inclusion/exclusion criteria and have the same BCVA ETDRS and CST on Day 1, either 
eye may be chosen as the study eye. In this instance, the Investigator should select the eye that, in their 
opinion, is most likely to respond to treatment as the study eye. 
8.2 
Missing Data Conventions 
Partial/missing start and end dates for AEs and concomitant medications will be imputed to create 
complete dates for the determination of treatment-emergent AEs or medications concomitant with study 
treatment. 
Partial/missing start dates: 
• 
Dates with missing day only will be imputed as the 1st of the month unless the month and year 
are same as the month and year of first dose of study medication, in which case missing day 
will be imputed as the first dose day of study medication. 
• 
Dates with both day and month missing will be imputed as 1 Jan unless the year is same as the 
year of first dose of study medication, in which case missing day and month will be imputed as 
the first dose day and month of study medication. 
• 
Completely missing dates will be imputed as the first dose date of study medication unless the 
end date is on or before the first dose date of study medication, in which case missing date will 
be imputed as 1 Jan of the same year as the end date. 
Partial/missing end date: 
• 
Dates with missing day only will be imputed as the last day of the month unless the month and 
year are the same as the month and year of the last dose of study medication, in which case 
missing day will be imputed as the last dose day of study medication. 
• 
Dates with both day and month missing will be imputed as 31 Dec unless the year is same as 
the year of the last dose of study medication, in which case missing day and month will be 
imputed as the last dose day and month of study medication. 
• 
If the ongoing flag is missing or “Yes” then the date will not be imputed unless death date is 
available, in which case the missing date will be imputed as the death date. 
• 
If the imputed date is after the date of death, then the end date will be set equal to the date of 
death. 
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergence status, etc.). 
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The primary and secondary efficacy data analyses will be performed on the FAS 
. An analysis using observed 
data only will also be performed in both the FAS and PPS. 
will be used to impute missing data in the FAS for the analysis 
of the primary and secondary continuous efficacy variables. No exploratory efficacy endpoints or safety 
endpoints will be imputed. 
8.3 
Definition of Baseline 
The baseline assessment will be the latest, valid pre-dose assessment available. Laboratory data may 
not be used from hemolyzed samples, mishandled samples, quantity not sufficient, or other conditions 
that would render the values invalid. 
8.4 
Data Analysis Conventions 
All data analysis will be performed 
The final analysis will be performed after the study is 
completed and the database has been locked and released for unmasking. Statistical programming and 
analyses will be performed using SAS Version 9.4 or higher. 
Quantitative variables will be summarized using descriptive statistics including the number of 
observations (n), mean, SD, median, interquartile range (IQR), minimum, and maximum values. Means, 
medians, and confidence intervals (CIs) will be reported based on the level of precision for each variable. 
Summaries for discrete variables will include frequency counts and percentages. All percentages will be 
rounded to one decimal place (i.e., XX.X%). Change from baseline will be calculated as post-baseline 
value minus baseline value. 
All efficacy analyses will be two-sided at a significance level of 0.05. The CIs for differences between 
treatment groups will be two-sided at 95% confidence. All p-values will be rounded to four decimal 
places; p-values less than 0.0001 will be presented as “<0.0001”; p-values greater than 0.9999 will be 
presented as “>0.9999.” 
Extra assessments (i.e., unscheduled laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in listings, but not 
summaries. If more than one laboratory value is available for a given visit, the first valid observation will 
be used in summaries and all observations will be presented in listings. If the relative time is 
indeterminable, then the average of values at that visit will be used. It is noted that invalid laboratory 
data may not be used (from hemolyzed samples, mishandled samples, quantity not sufficient, or other 
conditions that would render values invalid). 
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8.5 
Adjustments for Multiplicity 
Adjustments for multiple treatment comparisons, analysis time points, and/or endpoints will not be made 
for this exploratory study. 
9. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
screened, screen failures, randomized, randomized but not treated, completed the Week 16 visit 
(without rescue medication/procedure prior to the visit), completed the study, discontinued from the 
study, and rescued prior to the Week 16 visit. Subjects who are not discontinued from the study will be 
considered study completers. Disposition will be summarized by treatment group and for all enrolled 
subjects. 
The number and percentage of subjects completing the study or who prematurely discontinued from the 
study and the reasons for study discontinuation will be summarized by treatment group for all 
randomized subjects. The reasons for study discontinuation prior to completion include: adverse event, 
use of rescue medication, subject compliance, withdrawal of consent, lost to follow-up, sponsor 
termination of study, positive pregnancy test, and other. A subject listing will be provided that includes 
the date of completion or discontinuation and reason for premature study discontinuation. 
The number and percentage of subjects with protocol deviations will be summarized by treatment group 
for all randomized subjects. A subject listing will be provided that includes the start/end date of the 
deviation, the deviation description, deviation code, 
(informed consent, inclusion/exclusion and 
randomization, test article/study drug administration at site, improper protocol procedures at site, site 
failure to report serious adverse event (SAE)/AE, visit out of window, subject’s use of prohibited 
concomitant medication, subject’s failure to follow instructions, or other reasons) and the classification 
of whether the deviation was judged to be major or minor. 
In addition, listings for all enrolled subjects will be provided that include informed consent date, 
randomization date/time, randomization number, inclusion and exclusion criteria violations, unmasking 
information, and exclusions from the FAS and PPS populations. 
10. Demographic and Other Baseline Variables 
10.1 
Demographic Variables 
Demographic and baseline characteristics will be summarized by treatment in the FAS and PPS 
populations. 
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The demographic variables collected in this study include age, sex, race, ethnicity, iris color, study eye, 
height, weight, and body mass index (BMI). Subjects who record more than one race will be grouped 
into a single category denoted as Multiple Race. 
Age (years) will be summarized, by treatment, using descriptive statistics for continuous variables. Age 
will also be categorized as follows: <65 years and ≥65 years. Age will be reported in years and calculated 
using the following formula: 
Age = (Informed Consent Date – Date of Birth) / 365.25, truncated as an integer 
The number and percentage of subjects will be presented, by treatment and over all subjects, for age 
category, sex, race, ethnicity, iris color, and study eye. 
A subject listing that includes all demographic variables, including Screening physical examination 
findings, will be provided. 
10.2 
Baseline Disease Characteristics 
Baseline disease characteristics will be summarized by treatment in the FAS and PPS populations. 
Continuous summary statistics (n, mean, SD, median, IQR, minimum, maximum) will be presented for 
BCVA letter count at baseline, CST at baseline, time since DME diagnosis in the study eye, the 
estimated or total number of prior anti-VEGF injections administered in the study eye, CST prior to the 
first anti-VEGF injection, CST prior to each of the last three anti-VEGF injections, the estimated or total 
number of IVT steroid injections ever administered, and time since last IVT steroid injection. 
Categorical summary statistics (counts and percentage) will be presented by treatment and over all 
subjects for the randomization stratification factors of visual acuity (Baseline BCVA: ≤55 Letters versus 
>55 Letters), CST (screening CST: ≤450 µm versus >450 µm), duration of DME (<6 months, 6 months­
<1 year, 1 year-<2 years, 2 years-<3 years, ≥3 years), time since first anti-VEGF injection (<6 months, 
6 months-<1 year, 1 year-<2 years, 2 years-<3 years), and time since last anti-VEGF injection (<6 
months, 6 months-<1 year, 1 year-<2 years, 2 years-<3 years). The Snellen visual acuity prior to the 
first anti-VEGF injection, Snellen visual acuity prior to each of the last three anti-VEGF injections, and 
investigator assessment of edema and vision in the study eye compared to baseline after at least three 
anti-VEGF injections will also be summarized. 
A listing of baseline disease characteristics will be produced. 
11. Medical History and Prior and Concomitant Medications 
Ocular and non-ocular medical history and prior and concomitant medications will be summarized 
separately by treatment in the FAS population. 
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11.1 
Medical History 
Medical history will be summarized using discrete summary statistics and presented by treatment group 
and over all subjects at the subject and event level by system organ class (SOC) and preferred term 
(PT), separately for ocular and non-ocular SOCs. If a subject reports the same PT multiple times within 
the same SOC, that PT will only be reported once within that SOC. As with the PT, if a subject reports 
multiple conditions within the same SOC, then that SOC will only be reported once. Separate tables will 
be created for ocular and non-ocular medical history. Medical history will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA), version 20.1. The summaries will be based on the FAS 
population. 
Listings of medical history will be generated separately for ocular and non-ocular SOCs. 
11.2 
Prior and Concomitant Medications 
Prior medications are defined as medications that were stopped within the 3 months prior to Day 1; 
concomitant medications are defined as those medications ongoing at or started after Day 1. At the 
Screening Visit, subjects will be asked what medications they are taking, as well as those the subject 
may have taken but discontinued within the 3 months prior to Visit 1. At each study visit, subjects will 
be asked what concomitant medications they are currently taking or if there have been any changes to 
their medications since their first visit. 
All prior and concomitant ocular and non-ocular medications will be listed including preferred name, 
indication, route of administration, start date, stop date, dosage, and frequency of administration. Prior 
and concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHODrug) Global, B3, September 2017 to the appropriate Anatomical Therapeutic Chemical (ATC) 
classification and WHO generic term. 
Counts and percentages of ocular and non-ocular prior and concomitant medications will be summarized 
separately using ATC classification and preferred name. Summaries will include concomitant ocular 
medications for each eye (study eye and fellow eye), concomitant non-ocular medications, prior anti-
VEGF ocular medications in the study eye, prior non-anti-VEGF ocular medications in the study eye, 
prior ocular medications in the fellow eye, and prior non-ocular medications. Summaries will be 
displayed by treatment group and over all subjects. Subjects with multiple medications in the same ATC 
class or preferred name will be counted only once for that respective ATC class or preferred name. 
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12. Dosing Compliance and Treatment Exposure 
12.1 
Dosing Compliance 
Subjects who complete the study are scheduled to receive 4 injections [Visit 2 (Day 1), Visit 3 (Week 4), 
Visit 4 (Week 8), Visit 5 (Week 12)]. 
The number of masked injections, either KVD001 injection or a sham procedure, administered and the 
number of planned injections prior to study discontinuation will be summarized as counts and 
percentages in the SAF population. The number of planned injections is the number of masked injections 
that the subject would have taken if all scheduled visits occurred and injections were administered at all 
scheduled visits prior to discontinuation. If a rescue medication was administered at a visit, then that 
visit will not contribute to the planned injections. 
Compliance will be calculated as 
Number of Masked Injections Received 
Compliance (%) = 100 × 
Number of Planned Injections 
The number of masked injections administered and the number of planned injections prior to study 
discontinuation will be summarized as counts and percentages in the SAF Population. Dosing 
compliance (%) will be summarized with continuous descriptive statistics for each treatment group, using 
the SAF population. 
Subject listings of study drug assignment, study drug administration, and study treatment compliance 
will also be produced. 
12.2 
Treatment Exposure 
Treatment exposure will be measured by time-on-study, time from first injection to last injection, and 
time to last exposure to study treatment for the analysis of on-treatment AEs (time from first injection) 
plus additional at-risk period following the last injection (the minimum of 28 days and time from last 
injection to last study visit). 
Time on study is defined as 
Time on Study (Days) = [Date of Last Visit – Date of Visit 2 (Day 1)] + 1. 
Time from first injection to last injection is defined as 
Time from First to Last Injection (Days) = (Date of Last Injection – Date of First Injection) + 1. 
Time to last exposure to study treatment for the analysis of on-treatment AEs is defined as 
Time Exposed (Days) = (Date of Last Injection – Date of First Injection) + ADT, 
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where ADT is the additional time exposed after the last injection and is evaluated as 
ADT = Minimum (28, Date of Last Visit – Date of Last Injection) +1. 
Time on study, time from first injection to last injection, and time exposed for on-treatment adverse event 
analysis for each subject exposed to study drug will be summarized with continuous descriptive statistics 
(n, mean, SD, median, IQR, minimum, maximum) for each treatment group, using the SAF population. 
A subject listing of treatment exposure will also be produced. 
13. Efficacy Analyses 
13.1 
Primary Analysis 
The primary efficacy endpoint is change from baseline in BCVA letter count in the study eye at Week 
16. Change from baseline in BCVA letter count will be calculated as Week 16 BCVA letter count minus 
Day 1 BCVA letter count such that a negative difference indicates a worsening in vision. In addition, 
treatment comparisons between each KVD001 Injection dose and the sham will be calculated as 
KVD001 Injection minus sham, such that a positive result indicates more letters gained in the KVD001 
Injection treatment group. Treatment comparison between the KVD001 Injection doses will be calculated 
as KVD001 6 µg Injection minus KVD001 3 µg Injection, such that a positive result indicates more letters 
gained in the KVD001 6 µg Injection treatment group. 
The study eye ETDRS letter scores including changes from baseline will be summarized using 
descriptive statistics for continuous variables. An analysis of covariance (ANCOVA) model will be used 
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to compare the change from baseline in BCVA letter count at Week 16 between each KVD001 Injection 
dose and the sham and between the KVD001 Injection doses. 
Least-squares means 
(LSMeans) for each treatment group and its 95% CI will be presented. The LSMeans difference between 
each KVD001 Injection dose and the sham and between the KVD001 Injection doses, their 
corresponding CIs, and the p-values will be presented. 
Comparisons will use two-tailed, alpha=0.05 t-tests on the LSMeans from the ANCOVA. LSMeans for 
each treatment, the estimated treatment difference and the 95% CI for the difference will be calculated 
based on the ANCOVA model. An example of SAS® code implementation for changes from baseline in 
number of letters read correctly (using BCVA) is as follows: 
where 
As a safeguard, the normality assumptions of the ANCOVA model used will be checked using a normal 
probability plot of the residuals and a plot of the residuals versus the fitted values (i.e., checking the 
normality assumption and the constant variance assumption of the model, respectively) to ensure that 
the model assumptions are reasonable. If there are any departures from the distributional assumptions, 
alternative methods of transformations may be explored. 
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13.2 
Additional Analyses of the Primary Endpoint 
An analysis using observed data only will also be performed in both the FAS and PPS. Additionally, 
multiple imputation methodology will be used to impute missing data in the FAS for the analysis of the 
primary efficacy variables. 
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-
As a sensitivity analysis, treatment group differences for changes from baseline in BCVA letter count 
will be evaluated using a mixed model repeated measures (MMRM) ANCOVA fitted with treatment 
group, visit and the treatment by visit interaction as categorical variable terms with baseline BCVA letter 
score and baseline CST as covariates with contrasts included for each visit. LSMeans and 95% CIs for 
each treatment group, the LSMeans difference between each KVD001 Injection dose and the sham and 
between the KVD001 Injection doses, the corresponding CIs, and the p-values will be presented for 
each visit. The covariance matrix will be attempted first with an unstructured covariance matrix, then 
with autoregressive 1 if the unstructured is not estimable. 
Subgroup analyses of the primary endpoint for the study stratification factors will be presented. 
13.3 
Secondary Analyses 
The secondary endpoints are the following: 
• 
Change from baseline in CST as measured by SD-OCT 
• 
Proportion of eyes with a ≥2 step improvement from baseline in DRSS score 
• 
Change from baseline in BCVA letter count as measured by ETDRS 
• 
Proportion of SEs with ≥5, ≥10, and ≥15 BCVA letter gain from baseline and the proportion of 
SEs with ≥5, ≥10, and ≥15 BCVA letter loss from baseline. 
Change from baseline in BCVA letter count as measured by ETDRS in the study eye and change from 
baseline in CST in the study eye as measured by the central image reading center (CIRC) using SD­
OCT will be analyzed using the same method described for the primary efficacy analysis. Note that 
change from baseline in CST will be in favor of KVD001 if the treatment difference is <0. 
The difference in proportion of SEs with improvement of 2 or more steps on the ETDRS DRSS score 
between each KVD001 injection dose and the sham and between the KVD001 Injection doses will be 
summarized by visit using discrete summary statistics, including 95% Clopper-Pearson CIs for each 
treatment group. The difference in proportions between each KVD001 Injection dose and the sham and 
between the KVD001 Injection doses will be analyzed using a Pearson’s chi-squared test. 95% Clopper­
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Pearson CIs for the differences in proportions will also be calculated. Fisher’s exact tests and exact CIs 
will be employed in cases of expected counts <5. 
The proportion of SEs with ≥5, ≥10 and ≥15 BCVA letter change (gain and loss) between baseline and 
each post-baseline visit will be analyzed using the same method described for the proportion of SEs 
with improvement of 2 or more steps on the ETDRS DRSS score. Additionally, as an exploratory 
endpoint, the proportion of SEs with any BCVA letter loss between baseline and each post-baseline visit 
will be summarized similarly. Note that the categorizations of ≥5, ≥10 and ≥15 BCVA letter change (gain 
and loss) or any BCVA letter loss are not mutually exclusive. 
14. Safety Analyses 
All safety data analyses will be performed on the safety population and displayed in subject data listings 
and summarized in tables. No statistical inferential testing will be performed for safety variables. 
Safety endpoints include AEs, manifest refraction/BCVA, slip lamp biomicroscopy, dilated 
ophthalmoscopy, intraocular pressure (IOP), SD-OCT, EDTRS DRSS, physical exam findings, 
laboratory test results, and vital signs. 
14.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of an investigational 
product (IP) in humans, whether or not considered IP-related. AEs starting on or after the date of first 
exposure to study drug and up to 28 days after last injection will be considered treatment-emergent 
adverse events (TEAEs). AEs with unknown onset dates will be counted as a TEAE. All AEs will be 
assigned a severity grade of mild, moderate, or severe. Their relationship to study drug will be classified 
as suspected or not suspected. TEAEs with a missing relationship to study treatment will assume 
greatest relationship to study treatment (suspected). Only suspected TEAEs are considered as 
treatment-related. TEAEs with missing severity grades will be categorized as severe for tabulation of 
TEAEs by severity. The expectedness of an AE will be classified as unexpected, expected or not 
applicable (not applicable for AEs unrelated to IP). Documentation of AEs will include onset date, 
location (right eye [OD], left eye [OS], both eyes [OU], not ocular), severity, action(s) taken, relationship 
to study drug, expectedness, outcome, resolution date, and seriousness. All AEs will be coded using 
MedDRA classifications with reference to SOCs and PTs (MedDRA version 20.1). 
An AE is considered serious if, in the view of either the investigator or sponsor, it results in any of the 
following outcomes: 
• 
Death 
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
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• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
A congenital anomaly/birth defect 
• 
Medically Significant. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes listed above. 
Overall summaries of AEs will be presented showing: 
• 
Number of AEs and number of subjects with any AEs; 
• 
Number of TEAEs and number of subjects with any TEAEs; 
• 
Number of treatment-related TEAEs and number of subjects with any treatment-related TEAEs; 
• 
Number of SAEs and number of subjects with any SAEs; 
• 
Number of treatment-emergent SAEs and number of subjects with any treatment-emergent 
SAEs; 
• 
Number of subjects with TEAEs leading to premature discontinuation; 
• 
Number of subjects with TEAEs leading to death; and 
• 
Number of subjects with TEAEs by maximum severity. 
Overall summaries of AEs will be presented for the following classes of events: 
• 
All AEs (ocular & non-ocular) 
• 
Ocular events for each eye (study eye and fellow eye) 
• 
Non-Ocular events 
Frequencies and percentages of subjects with TEAEs, serious TEAEs, TEAEs leading to study drug 
discontinuation, and treatment-related TEAEs will be provided by treatment group by SOC and PT. 
Furthermore, summaries will be given of subjects with TEAEs: 
• 
by SOC, PT, and maximum severity; 
• 
by SOC, PT, and strongest relationship; 
• 
by SOC and PT for SAEs; 
• 
by SOC and PT for TEAEs related to study drug; and 
• 
by SOC, PT, and time of onset (i.e., Day 1 to Week 4 [Days 1-28], > Week 4 to Week 8 [Days 
29-56], > Week 8 to Week 12 [Days 57-84], > Week 12 to Week 16 [Days 85-112], > Week 16 
[> Day 112]). 
Separate analyses will be performed for ocular specific AEs, and all AEs (including systemic). 
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Summaries of preferred terms (without regard to SOC) will be presented for TEAEs and the most 
frequent TEAEs (occurring in ≥ 5% of patients treated with KVD001 6 µg or KVD001 3 µg). 
Post-treatment AEs, defined as AEs that started or worsened more than 28 days after last injection, will 
also be summarized. 
Subject listings of all AEs including verbatim text will be provided as well as listings of deaths, SAEs, 
and AEs causing premature discontinuation of study drug. 
14.2 
BCVA ETDRS 
The BCVA of both eyes (study eye and fellow eye) will be assessed using the ETDRS protocol at the 
beginning of every study visit and will be summarized at each visit using quantitative summary statistics 
for each eye by treatment group. 
BCVA of both eyes will be measured consistent with the standard procedure developed for the ETDRS. 
The number of letters read correctly will be counted and the total BCVA letter score will be reported. 
The total BCVA letter score will be summarized for each treatment group and over all subjects using 
continuous descriptive statistics at each visit for each eye (study eye and fellow eye). Change from 
baseline will also be summarized by treatment group and visit for 
eye (study eye and fellow eye). 
The number of subjects (by eye [study eye and fellow eye]) with a gain or loss in BCVA letter score ≥15, 
≥10, and ≥5 or any BCVA letter loss from baseline will be summarized using counts and percentages 
for each treatment group and over all subjects at each visit. 
A subject listing of BCVA and manifest refraction will also be produced. 
14.3 
SD-OCT 
The CIRC SD-OCT parameter values, including changes from baseline will be summarized for each 
visit (by eye [study eye and fellow eye]) using continuous descriptive statistics. Subject listings of CIRC 
and Investigator-assessed SD-OCT parameters will also be produced. 
14.4 
EDTRS DRSS 
Color fundus photographs will be taken in both eyes at Screening and in the study eye at subsequent 
visits to evaluate retinal anatomy and grade DRSS. Photographs will be transferred to the CIRC for 
independent analysis. The EDTRS DRSS scores for the study eye, including changes from baseline 
(i.e., ≥2 step improvement, 1 step improvement, no DRSS change, 1 step worsening, ≥2 step 
worsening), will be summarized for each visit using qualitative summary statistics (frequency counts and 
percentages). Subject listings of EDTRS DRSS parameters will also be produced. 
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Protocol KVD001-201 SAP, Version 2.0 
14.5 
Slit-Lamp Biomicroscopy Examination 
Slit-lamp biomicroscopy examinations will be conducted on both eyes (study eye and fellow eye) at all 
scheduled visits. The slit lamp findings will include examinations of the cornea, conjunctiva, anterior 
chamber, iris/pupil, lens and lid. Each parameter will be graded (normal or abnormal) or marked as not 
done. Abnormal findings will be further classified as not clinically significant (NCS) or clinically significant 
(CS). 
Slit lamp findings will be summarized by treatment group and visit, for the study eye and fellow eye 
separately, using qualitative summary statistics (frequency counts and percentages). Percentages will 
be based on the number of subjects with non-missing responses, including not done, for the treatment 
group at a given visit for a given parameter. 
Shift tables for the slit-lamp biomicroscopy parameters will also be provided comparing each post-
baseline visit to baseline. A subject listing of the slit-lamp biomicroscopy examination parameters 
will also be produced. 
14.6 
Indirect Dilated Ophthalmoscopy  
Indirect dilated ophthalmoscopy examinations will be conducted on both eyes (study eye and fellow eye) 
at all scheduled visits. Indirect dilated ophthalmoscopy findings will include examinations of the vitreous, 
macula, optic nerve, retina, and choroid. The findings will be graded as normal or abnormal (NCS or 
CS). The findings will be summarized using frequency counts and percentages by treatment group at 
each visit for each eye (study eye and fellow eye). A shift table of changes from baseline will also be 
presented. Cup-to-disc ratio is also reported for each visit and will be summarized using continuous 
descriptive statistics. Change from baseline will also be summarized by treatment group for each eye 
(study eye and fellow eye). A subject listing of the dilated ophthalmoscopy examination parameters will 
also be produced. 
14.7 
Intraocular Pressure (IOP) 
IOP will be measured in both eyes at all scheduled visits. At visits where the injection is administered 
[Visit 2 (Day 1), Visit 3 (Week 4), Visit 4 (Week 8) and Visit 5 (Week 12)] IOP will be measured pre­
dilation and within 60 minutes after study drug administration. IOP will be summarized using continuous 
descriptive statistics for each treatment group and over all subjects at each visit, time (pre-dilation, post 
study drug administration) for each eye (study eye and fellow eye). Change from baseline will also be 
summarized for each treatment group and over all subjects for each eye (study eye and fellow eye). 
Categorical summary statistics will also be presented using the following categories: ≤5, 6 to 14, 15 to 
21, 22 to 29, and ≥30 mmHg for each visit and using the following categories: ≤-15, -14 to -10, -9 to -5, 
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Protocol KVD001-201 SAP, Version 2.0 
-4 to 0, 1 to 4, 5 to 9, 10 to 14, 15 to 19, and ≥20 mmHg for change from baseline to each visit. A subject 
listing of IOP will also be produced. 
14.8 
Vital Signs 
Vital signs assessments will be conducted at all scheduled visits except Visit 7 (Week 20) and Visit 8 
(Week 24). At visits where the injection is administered [Visit 2 (Day 1), Visit 3 (Week 4), Visit 4 (Week 
8) and Visit 5 (Week 12)] vital signs will be measured pre-dilation and approximately 30 minutes after 
study drug administration. 
Vital signs assessments, including pulse, respiratory rate, blood pressure (SBP, DBP), and body 
temperature, and changes from baseline in vital signs assessments will be summarized by visit, time 
(pre-dilation, post study drug) and treatment group using quantitative summary statistics (n, mean, 
median, min and max). Change from baseline (Visit 2 [Day 1] pre-dilation to pre-dilation and 30-minutes 
after administration of study drug at Visit 3 [Week 4], Visit 4 [Week 8], Visit 5 [Week 12] and Visit 6 
[Week 16]) will be summarized by treatment group. Systolic and diastolic BP, heart rate, respiration rate, 
and body temperature will be summarized for the maximum/minimum post-baseline, and the change 
from baseline values to maximum/minimum post-baseline will also be summarized. A subject listing will 
also be produced and will include changes from baseline at each visit. 
14.9 
Urine Pregnancy Test 
A listing of urine pregnancy test results at all visits will be presented. 
14.10 
Laboratory Assessments 
Laboratory assay results include hematology, blood chemistry (clinical chemistry, liver enzymes, 
electrolytes), and urinalysis. Laboratory data will be obtained at all scheduled visits except Visit 7 (Week 
20) and Visit 8 (Week 24). Each of the continuous parameters will be summarized using continuous 
descriptive statistics for each treatment group at each visit. Changes from baseline will also be 
summarized for each treatment group. Each categorical parameter will be summarized using frequency 
counts and percentages for each treatment group and for all subjects. 
Laboratory data will be classified as high, low or normal. High and low values will be classified as 
clinically significant or not clinically significant. The high/low criteria will be determined based on the 
reference ranges provided by the laboratory. A shift table of the changes from baseline to each post-
baseline visit will be presented for hematology, blood chemistry (clinical chemistry, liver enzymes, 
electrolytes), and urinalysis. Shift tables will present a crosstabulation of baseline categories versus post 
baseline categories for each post-baseline visit as well as shifts from baseline to post-baseline high and 
post-baseline low. 
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Protocol KVD001-201 SAP, Version 2.0 
Listing of blood chemistry (clinical chemistry, liver enzymes, electrolytes), hematology and urinalysis will 
be presented. 
All laboratory values will be presented using SI units. 
. 
16. Changes from Protocol-Stated Analyses 
The definition of the FAS population has been updated to exclude subjects who did not receive at least 
1 dose of study treatment in Section 7.1. 
The definition of the PPS population has been updated to exclude subjects who did not receive all four 
doses of study treatment, have a missing Week 16 BCVA result, or discontinued prior to Week 16 for 
any reason in Section 7.2. 
The definition of prior medications has been extended to include medications prior to Day 1 in Section 
11.2. 
Between KVD001 Injection dose comparisons were added in Section 2.4, Section 13.1, Section 13.2, 
and Section 13.3. 
Clopper-Pearson CIs instead of asymptotic normal CIs are used for the proportion-based analyses in 
Section 13.3. 
The proportion of SEs with any BCVA letter loss from baseline has been added as an exploratory 
efficacy endpoint in Section 13.3. 
17. References 
Graham, J. W. (2007). How Many Imputations are Really Needed? Some Practical Clarifications of 
Multiple Imputation Theory. Prevention Science, 8, 206-213. 
18. Revision History 
Documentation of revision to the SAP will commence after approval of the final version 1.0. 
18.1 
Revision 01 
Summary of Changes 
Section # 
Description of Change 
Rationale 
7.1 
Update the FAS population 
definition to further restrict the 
population to subjects with at 
Client request. 
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Protocol KVD001-201 SAP, Version 2.0 
Section # 
Description of Change 
Rationale 
least 
1 
dose 
of 
study 
treatment. 
7.2 
Update the PPS population 
definition to further restrict the 
population to subjects who 
received all 4 injections, have 
a Week 16 BCVA result, and 
did not discontinue prior to 
Week 16 for any reason. 
Client request. 
11.2 
Update the definition of a prior 
medication. 
Client request. 
13.2 
Increase 
number 
of 
imputations from fifty to 250. 
Client request. 
13.3 
Change the 95% CIs from 
asymptotic 
normal 
CIs 
to 
Clopper-Pearson CIs. 
Client request. 
16 
Add 
the 
changes 
from 
Protocol-stated 
analysis 
requested in Sections 7.1, 7.2, 
11.2 and 13.3. 
Client request. 
21 
Update the populations of 
figures to match source tables. 
Client request. 
19. Tables 
Table Number 
Title 
Population 
14.1.1.1 
Subject Disposition 
All Subjects 
14.1.2.1 
Demographics and Baseline Characteristics 
FAS Population 
14.1.2.2 
Demographics and Baseline Characteristics 
PPS Population 
14.1.2.3 
Baseline Disease Characteristics 
FAS Population 
14.1.2.4 
Baseline Disease Characteristics 
PPS Population 
14.1.3.1 
Ocular Medical History 
FAS Population 
14.1.3.2 
Non-Ocular Medical History 
FAS Population 
14.1.4.1 
Ocular Concomitant Medications by Eye 
FAS Population 
14.1.4.2 
Non-Ocular Concomitant Medications 
FAS Population 
14.1.4.4 
Prior Anti-VEGF Medications in the Study Eye 
FAS Population 
14.1.4.5.1 
Prior Non-Anti-VEGF Ocular Medications in the 
Study Eye 
FAS Population 
14.1.4.5.2 
Prior Ocular Medications in the Fellow Eye 
FAS Population 
14.1.4.6 
Prior Non-Ocular Medications 
FAS Population 
14.1.5.1 
Study Treatment Compliance 
SAF Population 
14.1.7.2 
Study Treatment Exposure 
SAF Population 
14.2.1.1.1 
Analysis of Covariance of Change from Baseline in 
BCVA Letter Count in the Study Eye by Visit 
FAS Population 
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Protocol KVD001-201 SAP, Version 2.0 
14.2.1.1.2 
Analysis of Covariance of Change from Baseline in 
BCVA Letter Count in the Study Eye by BCVA 
Randomization Stratum and Visit 
FAS Population 
14.2.1.1.3 
Analysis of Covariance of Change from Baseline in 
BCVA Letter Count in the Study Eye by CST 
Randomization Stratum and Visit 
FAS Population 
14.2.1.2 
Analysis of Covariance of Change from Baseline in 
BCVA Letter Count in the Study Eye by Visit 
FAS Population 
14.2.1.3.1 
Analysis of Covariance of Change from Baseline in 
BCVA Letter Count in the Study Eye by Visit 
FAS Population 
14.2.1.3.2 
Analysis of Covariance of Change from Baseline in 
BCVA Letter Count in the Study Eye by Visit 
PPS Population 
14.2.1.4 
Mixed Model Repeated Measures Analysis of 
Covariance of Change from Baseline in BCVA 
Letter Count in the Study Eye by Visit 
FAS Population 
14.2.1.5.1 
Proportion of Study Eyes with a ≥ 5, ≥ 10, and ≥ 15 
BCVA Change from Baseline (Gain or Loss) by Visit 
FAS Population 
14.2.1.5.2 
Proportion of Study Eyes with a ≥ 5, ≥ 10, and ≥ 15 
BCVA Change from Baseline (Gain or Loss) by Visit 
PPS Population 
14.2.2.1 
Analysis of Covariance of Change from Baseline in 
Central Subfield Thickness (µm) in the Study Eye by 
Visit 
FAS Population 
14.2.2.2 
Analysis of Covariance of Change from Baseline in 
Central Subfield Thickness (µm) in the Study Eye by 
Visit 
FAS Population 
14.2.2.3 
Analysis of Covariance of Change from Baseline in 
Central Subfield Thickness (µm) in the Study Eye by 
Visit 
FAS Population 
14.2.2.4 
Analysis of Covariance of Change from Baseline in 
Central Subfield Thickness (µm) in the Study Eye by 
Visit 
PPS Population 
14.2.2.5 
Mixed Model Repeated Measures Analysis of 
Covariance of Change from Baseline in Central 
Subfield Thickness (µm) in the Study Eye by Visit 
FAS Population 
14.2.3.1 
Proportion of Eyes with a ≥2 Step Improvement 
from Baseline in Diabetic Retinopathy Severity 
Scale Score by Visit 
FAS Population 
14.2.3.2 
Proportion of Eyes with a ≥2 Step Improvement 
from Baseline in Diabetic Retinopathy Severity 
Scale Score by Visit 
PPS Population 
14.3.1.1.1 
Overall Summary of Adverse Events (Ocular & 
Non-Ocular) by Treatment Group 
SAF Population 
14.3.1.1.2 
Overall Summary of Adverse Events (Ocular) by 
Eye and Treatment Group 
SAF Population 
14.3.1.2.1 
Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
SAF Population 
14.3.1.2.2 
Ocular Treatment-Emergent Adverse Events by 
Eye, System Organ Class, and Preferred Term 
SAF Population 
14.3.1.2.3 
Serious Adverse Events by System Organ Class 
and Preferred Term 
SAF Population 
14.3.1.2.4 
Ocular Serious Adverse Events by Eye, System 
Organ Class, and Preferred Term 
SAF Population 
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Protocol KVD001-201 SAP, Version 2.0 
14.3.1.2.5 
Treatment-Emergent Adverse Events Leading to 
Study Drug Discontinuation by System Organ Class 
and Preferred Term 
SAF Population 
14.3.1.2.6 
Ocular Treatment-Emergent Adverse Events 
Leading to Study Drug Discontinuation by Eye, 
System Organ Class, and Preferred Term 
SAF Population 
14.3.1.2.7 
Treatment-Related Treatment-Emergent Adverse 
Events by System Organ Class and Preferred Term 
SAF Population 
14.3.1.2.8 
Ocular Treatment-Related Treatment-Emergent 
Adverse Events by Eye, System Organ Class, and 
Preferred Term 
SAF Population 
14.3.1.2.9 
Post-Treatment Adverse Events by System Organ 
Class and Preferred Term 
SAF Population 
14.3.1.3.1 
Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Maximum 
Severity 
SAF Population 
14.3.1.3.2 
Ocular Treatment-Emergent Adverse Events by 
Eye, System Organ Class, Preferred Term, and 
Maximum Severity 
SAF Population 
14.3.1.4.1 
Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Relationship to 
Study Drug 
SAF Population 
14.3.1.4.2 
Ocular Treatment-Emergent Adverse Events by 
Eye, System Organ Class, Preferred Term, and 
Relationship to Study Drug 
SAF Population 
14.3.1.5.1 
Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Time of Onset 
SAF Population 
14.3.1.5.2 
Ocular Treatment-Emergent Adverse Events by 
Eye, System Organ Class, Preferred Term, and 
Time of Onset 
SAF Population 
14.3.1.6.1 
Treatment-Emergent Adverse Events by Preferred 
Term 
SAF Population 
14.3.1.6.2 
Ocular Treatment-Emergent Adverse Events by 
Eye and Preferred Term 
SAF Population 
14.3.1.7.1 
Most Frequent (≥ 5% of KVD001-Treated Subjects) 
Treatment-Emergent Adverse Events by Preferred 
Term 
SAF Population 
14.3.1.7.2 
Most Frequent (≥ 5% of KVD001-Treated Subjects) 
Ocular Treatment-Emergent Adverse Events by Eye 
and Preferred Term 
SAF Population 
14.3.4.1 
Best Corrected Visual Acuity (Letter Count) by Visit 
and Eye 
SAF Population 
14.3.4.2 
Central Subfield Thickness (µm) by Visit and Eye 
SAF Population 
14.3.4.3 
Early Treatment Diabetic Retinopathy Study 
Diabetic Retinopathy Severity Score in the Study 
Eye by Visit 
SAF Population 
14.3.4.4.1 
Slit Lamp Biomicroscopy by Visit and Eye 
SAF Population 
14.3.4.4.2 
Shifts from Baseline in Slit Lamp Biomicroscopy by 
Visit and Eye 
SAF Population 
14.3.4.5.2 
Shifts from Baseline in Indirect Dilated 
Ophthalmoscopy by Visit and Eye 
SAF Population 
14.3.4.5.1 
Indirect Dilated Ophthalmoscopy 
SAF Population 
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Protocol KVD001-201 SAP, Version 2.0 
14.3.4.6 
Intraocular Pressure (mmHg) by Visit and Eye 
SAF Population 
14.3.4.7 
Vital Signs by Visit 
SAF Population 
14.3.4.8.1.1 
Blood Chemistry by Visit 
SAF Population 
14.3.4.8.1.2 
Shifts from Baseline in Blood Chemistry by 
Category, Parameter, and Visit 
SAF Population 
14.3.4.8.2.2 
Shifts from Baseline in Hematology by Parameter 
and Visit 
SAF Population 
14.3.4.8.2.1 
Hematology by Visit 
SAF Population 
14.3.4.8.3.1 
Urinalysis by Visit 
SAF Population 
14.3.4.8.3.2 
Shifts from Baseline in Urinalysis by Parameter and 
Visit 
SAF Population 
20. Listings 
Listing Number 
Title 
Population 
16.1.7 
Randomization Schedule 
All Randomized Subjects 
16.2.1.1 
Subject Disposition 
All Randomized Subjects 
16.2.1.2 
Subject Disposition-Rescue Medication Information 
All Randomized Subjects Who 
Discontinued for Use of 
Rescue Medication 
16.2.1.3 
Subject Unmasking 
All Randomized Subjects 
16.2.2.1 
Protocol Deviations 
All Randomized Subjects 
16.2.2.2 
Inclusion/Exclusion Criteria 
All Enrolled Subjects 
16.2.3.1 
Study Population Inclusion 
All Randomized Subjects 
16.2.3.2 
Screen Failures 
All Enrolled Subjects Who 
Were Screen Failures 
16.2.4.1.1 
Demographics 
All Randomized Subjects 
16.2.4.1.2 
Baseline Disease Characteristics 
All Randomized Subjects 
16.2.4.1.3 
Prior Visual Acuity Measurements in the SE 
All Randomized Subjects 
16.2.4.1.4 
Prior OCT Measurements in the SE 
All Randomized Subjects 
16.2.4.1.5 
Rescue Procedures in the SE 
All Randomized Subjects 
16.2.4.2.1 
Ocular Medical History 
All Randomized Subjects 
16.2.4.2.2 
Non-Ocular Medical History 
All Randomized Subjects 
16.2.4.3.1 
Prior and Concomitant Ocular Medications 
All Randomized Subjects 
16.2.4.3.2 
Prior and Concomitant Non-Ocular Medications 
All Randomized Subjects 
16.2.4.3.3 
Prior Anti-VEGF Medications in the SE 
All Randomized Subjects 
16.2.4.3.4 
Anti-VEGF Medication Log 
All Randomized Subjects 
16.2.4.3.5 
IVT Steroid Use 
All Randomized Subjects 
16.2.4.3.6 
Rescue Therapy Administration in the SE 
All Randomized Subjects 
16.2.5.1 
Study Drug Administration 
All Randomized Subjects 
16.2.5.2 
Exposure and Compliance 
All Randomized Subjects 
16.2.7.1 
All Adverse Events (Ocular and Non-Ocular) 
All Randomized Subjects 
16.2.7.2 
Serious Adverse Events 
All Randomized Subjects 
16.2.7.3 
Adverse Events Causing Premature 
Discontinuation 
All Randomized Subjects 
16.2.7.4 
Adverse Events Resulting in Death 
All Randomized Subjects 
16.2.8.1.1 
BCVA Observed and Change from Baseline 
All Randomized Subjects 
16.2.8.1.2 
BCVA Manifest Refraction 
All Randomized Subjects 
16.2.8.1.3 
BCVA (EDTRS) 
All Randomized Subjects 
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16.2.8.2 
Retinal Central Subfield Thickness (CST) (Using 
SD-OCT by CIRC and Investigator) 
All Randomized Subjects 
16.2.8.3 
Diabetic Retinopathy Severity Scale (DRSS) 
Observed and Change from Baseline 
All Randomized Subjects 
16.2.8.4 
Slit Lamp Biomicroscopy 
All Randomized Subjects 
16.2.8.5 
Dilated Indirect Ophthalmoscopy 
All Randomized Subjects 
16.2.8.6 
Intraocular Pressure (IOP) 
All Randomized Subjects 
16.2.8.7 
Fundus Photography 
All Randomized Subjects 
16.2.9 
Vital Signs 
All Randomized Subjects 
16.2.10.1 
Urine Pregnancy Test Results 
All Randomized Subjects 
16.2.10.2 
Blood Chemistry 
All Randomized Subjects 
16.2.10.3 
Hematology 
All Randomized Subjects 
16.2.10.4 
Urinalysis 
All Randomized Subjects 
16.2.11 
Physical Exam 
All Randomized Subjects 
16.2.12 
Biometrics 
All Randomized Subjects 
21. Figures 
Figure Number 
Title 
Population 
14.2.1.1.1 
Box Plot of BCVA Letter Count in the Study Eye at 
Scheduled Visits 
FAS Population 
14.2.1.1.2 
Line Chart of Change from Baseline in BCVA Letter 
Count in the Study Eye at Scheduled Visits 
FAS Population 
14.2.1.2.1 
Box Plot of BCVA Letter Count in the Study Eye at 
Scheduled Visits 
PPS Population 
14.2.1.2.2 
Line Chart of Change from Baseline in BCVA Letter 
Count in the Study Eye at Scheduled Visits 
PPS Population 
14.2.2 
Line Chart of Change from Baseline in BCVA Letter 
Count in the Study Eye at Scheduled Visits by Visual 
Acuity Group 
FAS Population 
14.2.3 
Line Chart of Change from Baseline in BCVA Letter 
Count in the Study Eye at Scheduled Visits by CST 
Group 
FAS Population 
14.2.4.1.1 
Box Plot of Central Subfield Thickness (CST) as 
Measured by Spectral-Domain OCT (SD-OCT) in the 
Study Eye at Scheduled Visits 
FAS Population 
14.2.4.1.2 
Line Chart of Change from Baseline in Central 
Subfield Thickness (CST) as Measured by Spectral-
Domain OCT (SD-OCT) in the Study Eye at 
Scheduled Visits 
FAS Population 
14.2.5.1 
Bar Chart of Proportion of Subjects with BCVA Gain 
of 15 or More Letters from Baseline in the Study Eye 
at Scheduled Visits 
FAS Population 
14.2.5.2 
Bar Chart of Proportion of Subjects with BCVA Gain 
of 10 or More Letters from Baseline in the Study Eye 
at Scheduled Visits 
FAS Population 
14.2.5.3 
Bar Chart of Proportion of Subjects with BCVA Gain 
of 5 or More Letters from Baseline in the Study Eye 
at Scheduled Visits 
FAS Population 
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Protocol KVD001-201 SAP, Version 2.0 
Figure Number 
Title 
Population 
14.2.5.4 
Bar Chart of Proportion of Subjects with Any Loss in 
BCVA Letters from Baseline in the Study Eye at 
Scheduled Visits 
FAS Population 
14.2.6.1 
Bar Chart of Proportion of Eyes with a ≥ 2 Step 
Improvement from Baseline in DRSS Score 
FAS Population 
14.2.6.2 
Bar Chart of Proportion of Eyes with a ≥ 2 Step 
Improvement from Baseline in DRSS Score 
PPS Population 
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Protocol KVD001-201 SAP, Version 2.0 
Appendix A. Schedule of Procedures 
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Protocol KVD001-201 SAP, Version 2.0 
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